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AML Research Updates: News from ASH 2020

AML expert Dr. Jeffrey Lancet shares news from the 2020 American Society of Hematology (ASH) annual meeting. Dr. Lancet sheds light on headlines from the meeting including FLT3 inhibitor research, combination therapies with venetoclax, a promising inhibitor therapy, and shares his optimism about the future of AML treatment.

About the Guest:
Dr. Jeffrey Lancet is Chair and Program Lead in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, FL. He is nationally and internationally recognized for his clinical research in the field of acute leukemias. Learn more about Dr. Lancet, here.

See More From INSIST! AML


Transcript

Katherine:

Hello and welcome, I’m Katherine Banwell. Today we’ll discuss the latest news from ASH 2020 and how AML patients can advocate for personalized care. Joining me is Dr. Jeffrey Lancet. Welcome, would you please introduce yourself?

Dr. Lancet:

Hi, sure. My name is Dr. Jeff Lancet. I’m at the Moffitt Cancer Center in Tampa, Florida where I am the Chair of the Malignant Hematology Department. We spend a lot of time treating patients and conducting clinical trials of Acute Myeloid Leukemia.

Katherine:

Dr. Lancet, the American Society of Hematology annual meeting just closed. What are the AML headlines from this year’s meeting?

Dr. Lancet:

Yeah, so as usual AML was a very busy area for clinical presentations this year at the ASH meeting focusing largely on novel and targeted therapies. I don’t believe that there were many practice changing delevelopments, per se, but rather discussions about many promising therapeutic strategies that are still under development and moving forward rapidly largely in the areas of targeted therapy, low intensity therapy, measurable residual disease, and things of that nature.

Katherine:

What does this research news mean for patients?

Dr. Lancet:

Well, I think that there is a lot to be encouraged about and maybe I’ll take the time to review some of the highlights in what was presented with respect to some of the novel therapeutic approaches that many of our patients can look forward to receiving in the not-too-distant future.

So we often talk about targeted therapy instead of, of course, one of the major targets over the years has been that of a mutated FLT3, which is one of the most common mutations in AML.

And at this meeting, we saw several presentations on clinical trials results utilizing Inhibitors of FLT3 with some emphasis on the most recently approved 2nd generation drug called gilteritinib.

There were, I thought, three major presentations focusing on gilteritinib. One was an update on a randomized phase 3 trial comparing gilteritinib plus azacitidine versus azacitidine alone in newly diagnosed unfit for induction chemotherapy patients with FLT3 mutations. Preliminary showing good tolerability and high composite complete response rates in the combination arm. 

There was another trial of gilteritinib plus venetoclax in relapsed refractory FLT3 mutated AML and what was interesting was that a very high percentage of patients achieved response with this combination of gilteritinib plus venetoclax. Many of whom were heavily pre-treated previously and many of whom had also got prior FLT3 inhibitor therapy during an earlier stage of the disease, so the combination of gilteritinib plus venetoclax in this more refractory setting was encouraging to see these promising responses.

And then we say some data reporting the effects of gilteritinib in combination with more traditional chemotherapy induction with a couple of studies demonstrating both high complete response rates, as well as high rates of mutation clearance of the FLT3 mutation. So those are very encouraging data that were presented with respect to the FLT3 mutated AML population. 

So another very important drug that reached the marketplace for AML recently is a drug called venetoclax, which is an inhibitor of a protein called BCL2. And this drug was recently FDA approved for use in combination with low-intensity chemotherapy drugs such as azacitidine or decitabine. And it seems as though the combination of venetoclax plus one of these hypomethylating agent drugs, azacitidine or decitabine, has resulted in very strong efficacy signals as recently published in the New England Journal of Medicine paper that reported on the results of the Phase 3 trial of venetoclax plus azacitidine.

So that has now become standard of care for older, less fit adults with newly diagnosed AML. The combination of venetoclax plus hypomethylating agent such as azacitidine. And naturally there’s been interest in really kind of taking it several steps further to advance the role of these combinations and to also look at additional drugs in combination with venetoclax plus hypomethylating agent therapy. So, we saw some of that at the ASH meeting this year.

One approach would be to take venetoclax and then to combine it with more intensive chemotherapy for perhaps more fit patients or younger patients that could undergo a more intensive program. So we saw presentations of venetoclax being combined with a drug called CPX-351 which is a novel liposomal formulation of two common chemotherapy drugs that had been approved a few years ago for secondary AML. And we also saw a combination strategy with venetoclax and a regimen known as FLAG-IDA, which is a commonly used induction regimen in Acute Myeloid Leukemia.

I think it’s important to recognize that although these trials they combine venetoclax with more intensive chemotherapy show signs of good efficacy with good response rates, there are definitely signals of increased toxicity, hematologic toxicity, primarily. Which is not really unexpected with venetoclax knowing that it can cause significant lowering of white blood cells, platelets, and hemoglobin.

Then finally, there is a lot of interest in doing these types of combinations with venetoclax in different subsets of AML. And one subset of AML that has been very important recently is that of the IDH-mutated AML population of patients. IDH is a fairly common mutation that occurs in either in the form of IDH1 or IDH2, and there’s about a 15-20% incidence of IDH mutations in AML. Though we do have an inhibitor for both of these types of mutations, ivosidenib for IDH1 and enasidenib for IDH2, but there also appears to be a strong role for venetoclax plus azacitidine in IDH mutated AML. We saw from a series of patients presented by a physician at MD Anderson looking at outcomes with venetoclax plus azacitidine in IDH mutated AML. The response rates were very high when you give HMA plus venetoclax to these patients with IDH mutated AML. But, I think more importantly, is that there were what we call high intra-patient response rates when switching between venetoclax and HMA therapy with IDH inhibitor continued regimen. In other words, a patient would have a good chance of responding to the initial therapy, then, if or when that therapy stops working, having a good effect from the salvage therapy with the other regiment, So if you received initially azacitidine plus venetoclax, and then had a relapse, the IDH inhibitors worked well and vice-versa if have received an IDH inhibitor, then subsequently received HMA/venetoclax at a later time point, that also worked well.

So it’s encouraging to see that you can potentially sequence these drugs and get continued responses along the way that ultimately we think that will help survival and keep patients in a better state of health for longer.

So I just wanted to take a few minutes also and discuss some of the newer more novel therapies that are really hitting or approaching the landscape right now. One of these is called CC-486, also known as oral azacitidine or onureg, and this drug was shown in a recent literature to prolong overall survival in patients who are in first remission from their AML who had received induction chemotherapy. So this drug was used as maintenance therapy after a variable number of consolidation regimens and people who got this onureg or azacitidine drug as maintenance therapy, it resulted in longer survival compared to those who had received placebo. This was presented at last year’s ASH meeting, but this year’s ASH meeting provided an update, a very important update, showing that the overall survival advantage from this drug, this oral azacitidine drug, when used as maintenance was independent of whether a patient had measurable residual disease at the time that they went on to the maintenance therapy. In other words, whether you had MRD (measurable residual disease) or not at the time of the study entry, your responses were still more favorable, your outcomes were more favorable if you received this oral azacitidine drug. So this was FDA approved earlier this year for patients in the maintenance phase of therapy for AML who had got prior induction chemotherapy. 

And importantly, this drug was also shown to be able to convert about 25% of patients who were positive for measurable residual disease, to convert them from positive to negative. So even though they were in remission, they had measurable residual disease and this drug in about 25% of the cases converted them from positive to negative. So that’s a very important finding as well. 

Another important drug that I think you should keep your eye on is a drug called magrolimab. This is an antibody against a certain type of protein that is present on an immune system cell called the macrophage. And when this magrolimab drug is combined with azacitidine in a recent clinical trial, it was demonstrated very high response rates of over 65%, and in particular in patients with P53 mutation, which is a very bad mutation to have in most cancers including AML. In patients with this high-risk mutation, the combination magrolimab with azacitidine appears to be effective based on the early data that we have with high response rates.

And then finally, I just wanted to make mention of another important area in, not really just AML, but all cancer, and that’s outcomes disparities between different races and ethnic groups. And we saw a very important presentation at the plenary session this year where the authors reported outcomes amongst younger patients with AML who are African American compared with caucasion. And the data clearly indicated a worse overall survival amongst black patients compared to white patients under age 60. And this included patients who are enrolled in clinical trials. So that, it appeared that African American patients had a worse outcome than Causian patients with Acute Myeloid Leukemia. Highlighting the need to better understand various risk factors and other factors that play into these disparate outcomes between our black American population and our white American population, which I think could shed light on additional disease characteristics that many help everybody.

Katherine:

Dr. Lancet, thanks so much for joining us today

Dr. Lancet:

Thank you very much for having me. It was good to be with you.

Katherine:

And thank you to our audience, I’m Katherine Banwell.


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Staying Updated on AML Research News: Advice from an Expert

Staying Updated on AML Research News: Advice from an Expert from Patient Empowerment Network on Vimeo.

Dr. Jeffrey Lancet, an AML expert from Moffitt Cancer Center, shares tips for sifting through research news and encourages communication with your healthcare team about what you’ve learned.

Dr. Jeffrey Lancet is Chair and Program Lead in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, FL. He is nationally and internationally recognized for his clinical research in the field of acute leukemias. Learn more about Dr. Lancet, here.

Download Program Resource Guide

See More From INSIST! AML

Related Resources:

Essential Testing in AML: How Results Impact Care & Treatment Choices

Navigating AML Treatment Decisions

Key AML Testing for Better Care: Understanding Prognosis and Treatment Choices

Transcript:

Katherine:      

Well, patients are often educating themselves about developing research and new treatment options. Do you have advice for patients who, when it comes to talking with their doctors about what they’ve learned?

Dr. Lancet:                   

I think it’s important for patients to speak to their doctors directly and as soon as possible as opposed to going on the internet and doing a Google search for this drug or that because every patient’s situation is unique and how to apply these new drugs is very different amongst patients.

And some patients may qualify for certain approaches and others do not. So, it’s very important to talk to your doctor about how you can individualize your treatment based upon your specific scenario. What type of mutation does a patient have, what is their level of fitness, are they potentially candidates for bone marrow transplant? Those are some of the basic questions that come up all the time to determine what is the best treatment approach.

And as we’re developing new therapies, and more of them, there will be more options for patients and a more personalized approach that can be taken that really can only be decided based upon that individual patient’s unique profile. So, it’s very important to really recognize that one size does not fit all when it comes to treatment of this disease and that certain drugs may be helpful and certain drugs may be unhelpful in that particular site.

Katherine:                   

What would you like to leave patients with today? Are you hopeful about the future of AML treatment and research?

Dr. Lancet:                   

Yes, I’m very hopeful. I think AML is a disease that is really a very diverse and complex one. It doesn’t lend itself well to huge immediate breakthrough therapies that will immediately change the landscape by double digit percentages for example. This is a disease that, again is very complex, and in which advances are made slowly but steadily. And I think we’ve seen that over the past to 5 to 10 years is that we are gradually incorporating new drugs into our treatment regimens with gradually increasing levels of success as we learn more about these drugs starting out as single agents and then beginning to combine them.

I think that we’re learning an awful lot about the molecular landscape about AML and how it impacts treatments and treatment decisions and prognoses. I think our ability now to detect what we recall measurable residual disease is very important. Also, because now we can get a grasp of how well our treatments are working and are we knocking out enough bad cells to expect good outcomes, and if we’re not, then hopefully we can intervene and kind of hit it while it’s down so to speak and use some of these new therapies to knock out what might be left over to give patients better overall long term responses and results.

So, definitely reason to be hopeful, but we have to stay patient as well. It’s difficult because it’s a, it’s a terrible disease but we have to recognize that it’s something that requires very careful research to develop the appropriate clinical trials that will have the highest chance of success.

Katherine:                   

Dr. Lancet, thanks so much for joining us today.

Dr. Lancet:                   

Thank you very much for having me. It was good to be with you and I appreciate the opportunity.

Katherine:

And thank you to our audience. I’m Katherine Banwell.

 

 

 

AML Research Updates: News from ASH 2020

AML Research Updates: News from ASH 2020 from Patient Empowerment Network on Vimeo.

AML expert Dr. Jeffrey Lancet shares the latest news from the 2020 American Society of Hematology (ASH) annual meeting. Dr. Lancet sheds light on headlines from the meeting including FLT3 inhibitor research, combination therapies with venetoclax, a promising inhibitor therapy, and shares his optimism about the future of AML treatment.

Dr. Jeffrey Lancet is Chair and Program Lead in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, FL. He is nationally and internationally recognized for his clinical research in the field of acute leukemias. Learn more about Dr. Lancet, here.

Download Program Resource Guide

See More From INSIST! AML

Related Resources:

Navigating AML Treatment Decisions

New AML Therapies vs. Traditional Chemotherapy: What’s the Difference?

Transcript:

Katherine:      

Hello, and welcome. I’m Katherine Banwell. Today we’ll discuss the latest news from ASH 2020 and how AML patients can advocate for personalized care. Joining me is Dr. Jeffrey Lancet. Welcome. Would you please introduce yourself?

Dr. Lancet:                   

Hi, sure. My name is Dr. Jeff Lancet. I’m at the Moffitt Cancer Center in Tampa, Florida, where I am the Chair of the Malignant Hematology Department. We spend a lot of time treating patients and conducting clinical trials of Acute Myelogenous Leukemia.

Katherine:                   

Okay. Thank you. Dr. Lancet, the American Society of Hematology Annual Meeting just closed. What are the AML headlines from this year’s meeting?

Dr. Lancet:                   

Yeah, so as usual, AML was a very busy area for clinical presentations this year at the ASH meeting focusing largely on novel and targeted therapies.

I don’t believe that there were many practice changing developments per se, but rather discussions about many promising therapeutic strategies that are still under development and moving forward rapidly largely in the areas of targeted therapy, low intensity therapy, measurable residual disease and things of that nature.

Katherine:                   

What does this research news mean for patients?

Dr. Lancet:                   

Well, I think that there’s a lot to be encouraged about and maybe I’ll take the time to review some of the highlights in what was presented with respect to some of the novel therapeutic approaches that many of our patients can look forward to receiving in the not too distant future.

So, we often talk about you know, targeted therapies and, of course, one of the major targets over the years has been that of mutated FLT3 which is one of the most common mutations in AML.

And at this meeting we saw several presentations on clinical trials resolved to utilizing inhibitors of FLT3, with some emphasis on the most recently approved second generation drug called gilteritinib.

There were I thought three major presentations focusing on gilteritinib and one was an update on a randomized Phase III trial comparing gilteritinib plus azacitidine versus azacitidine alone in newly diagnosed unfit for induction chemotherapy patients with FLT3 mutations, preliminarily showing good tolerability and high composite complete response rates in the combination on.

There was another trial of gilteritinib plus venetoclax in relapsed and refractory FLT3 mutated AML.

And what was interesting was that a very high percentage of patients achieved response with this combination of gilteritinib plus venetoclax, many of whom were heavily pretreated previously and many of whom had also gotten prior FLT3 inhibitor therapy during an early stage of the disease. So, the combination of gilteritinib and venetoclax and this more refractive study, it was encouraging to see these promising responses.

And then we saw some data reporting the effects of gilteritinib in combination with more traditional chemotherapy induction with a couple of studies demonstrating both a high complete response rates as well as high rates of mutation clearance of the FLT3 mutation.

So, those were very encouraging data that were presented with respect to the FLT3 mutated AML population.      

So, another very important drug that reached the marketplace for AML recently is a drug called venetoclax, which is an inhibitor of a protein called BCL2.

And this drug was recently FDA approved for use in combination with low intensity chemotherapy drugs such as azacitidine or decitabine.

And it seems as though the combination of venetoclax plus one of these hypomethylating agent drugs, azacitidine or decitabine has resulted in very, very strong efficacy signals as recently published in a New England Journal of Medicine paper that reported on the results of the Phase III trial of venetoclax plus azacitidine.

So, that has now become standard of care for older less fit adults with newly diagnosed AML; the combination of venetoclax plus a hypomethylating agent such as azacitidine.

And naturally, there’s been interest in really kind of taking it several steps further to advance the role of these combinations and to also look at additional drugs in combination with venetoclax plus hypomethylating agent therapy.

So, we saw some of that at the ASH meeting this year. One approach would be to take venetoclax and then to combine it with more intensive chemotherapy for perhaps more fit patients or younger patients that could undergo a more intensive program.

So, we saw presentations of venetoclax being combined with a drug called CPX-351, which is a novel liposome formulation of two common chemotherapy drugs that had been approved a few years ago for secondary AML. And we also saw a combination strategy with venetoclax, and a regimen known as FLAG-IDA, which is a commonly used induction regimen in acute myeloid leukemia.

And I think it’s important to recognize that although these trials that combine the venetoclax with more intensive chemotherapy showed signs of good efficacy with good response rates, there were definitely signals of increased toxicity, hematologic toxicity primarily, which is not completely unexpected with venetoclax knowing that it can cause significant lowering of white blood cells and platelets and hemoglobin.

And then finally, there is a lot of interest in, you know, doing these types of combinations with venetoclax in different subsets of AML and one subset of AML that has been very important recently is that of the IDH mutated AML population of patients.

IDH is a fairly common mutation that occurs either in the Isoform of IDH1 or IDH2 and there’s about a 15 to 20 percent incidence of IDH mutations in AML.

Now we do have an inhibitor for both of these types of mutations: ivosidenib for IDH1 and enasidenib for IDH2, but there also appears to be a strong role for venetoclax plus azacitidine in IDH mutated AML.

We saw from a series of patients presented by a physician at MD Anderson looking at outcomes with venetoclax plus azacitidine in IDH mutated AML. And the response rates were very high when you give HMA plus venetoclax to these patients with IDH mutated AML.

But I think more importantly was that there were what we call high intro patient response rates when switching between venetoclax and HMA therapy with an IDH inhibitor containing regimen.

In other words, a patient would have a good chance of responding to the initial therapy and then if or when that therapy stops working, having a good effect from a salvage therapy with the other regimen. So, when you see initially azacitidine plus venetoclax and then had a relapse, the IDH inhibitors worked well and vice versa if you had received an IDH inhibitor and then subsequently received HMA-venetoclax at a later time point that also worked well.

So, it’s encouraging to see that you can potentially sequence these drugs and get continued responses along the way and ultimately we think will help a survivor and keep patients in a better state of health even longer.               

So, I just wanted to take a few minutes also and discuss some of the newer more novel therapies that are really hitting or approaching the landscape right now. One of these is called CC486, also known as oral azacitidine or ONUREG. And this drug was shown in recent literature to prolong overall survival in patients who are in first remission from their AML who had received induction chemotherapy.

So, this drug was used as maintenance therapy after a variable number of consolidation regimens. And people who got this ONUREG or oral azacitidine drug as maintenance therapy, it resulted in longer survival compared to those who had received placebo.

And this was presented at last year’s ASH meeting, but this year’s ASH meeting provided an update, a very important update, showing that the overall survival advantage from this drug, this oral azacitidine drug, when used as maintenance was independent of whether a patient had measurable residual disease at the time that they went onto the maintenance therapy.

In other words, whether you had MRD, measurable residual disease or not at the time of the study entry, your responses were still more favorable, your outcomes were more favorable, if you received this oral azacitidine drug.

So, this was FDA approved earlier this year for patients in the maintenance phase of therapy for AML who had gotten prior reduction chemotherapy.

And importantly, this drug was also shown to be able to convert about 25% of patients who were positive for measurable residual disease; convert them from positive to negative. So, even though they were in remission, they had measurable residual disease and this drug in about 25 percent of the cases converted that from positive to negative. So, that’s a very important finding as well.

Another important drug that I think you should keep your eye on is a drug called magrolimab. This is an antibody against a certain type of protein that is present on the immune system cell called the macrophage, and when this magrolimab drug was combined with azacitidine in a recent clinical trial, it was demonstrated very high response rates of over 65 percent.

And, in particular, in patients with P53 mutations, which is a very bad mutation to have in most cancers, including AML, in patients with this high-risk mutation, the combination of magrolimab with azacitidine appears to be effective based upon the early data that we have with high response rates.

And then finally, I just wanted to make mention of another important area in, not really just AML, but in all cancer and that’s  outcomes disparities between different races and ethnic groups. And we saw a very important presentation at the plenary session this year where the authors reported outcomes amongst younger patients with AML who were African American compared with Caucasian.

And the data clearly indicated a worse overall survival amongst Black patients compared with white patients under age 60. And this included patients who were enrolled in clinical trials. So, that it appeared that African American patients have a worse outcome than Caucasian patients with acute myeloid leukemia highlighting the need to better understand various risk factors and other factors that play into these disparate outcomes between our Black American population and a white American population, which I think could shed light on additional disease characteristics that may help everybody as well.

 

ASH 2019: Multiple Regimens, Deeper Responses in Multiple Myeloma Treatment

 

Dr. Sikander Ailawadhi of Mayo Clinic provides high-level highlights for multiple myeloma from the 61st American Society of Hematology (ASH) Meeting in Orlando, Florida.

About Diverse Health Hub:

Diverse Health Hub is a health equity education and awareness channel producing educational content for both patients and providers in order to bridge the gaps between healthcare practices and the needs of multicultural communities.  Diverse Health Hub works directly with a diverse patient and respected provider population in multiple therapeutic areas to promote cultural competence in healthcare. The organization believes access to these diverse perspectives cultivates culturally competent communities.

Related Programs:

Good News for Future of Myeloma Treatment, Still Addressing Race-Associated Risks

ASH 2019: Disparities Around Accessing Health Technology Revealed for a Subset of Myeloma Patients

ASH 2019: Disparities Around Accessing Health Technology Revealed for a Subset of Myeloma Patients

In this Diverse Health Hub interview, Dr. Sikander Ailawadhi of Mayo Clinic, discusses disparities around access to care in multiple myeloma from the 61st American Society of Hematology (ASH) Meeting in Orlando, Florida.

About Diverse Health Hub:

Diverse Health Hub is a health equity education and awareness channel producing educational content for both patients and providers in order to bridge the gaps between healthcare practices and the needs of multicultural communities.  Diverse Health Hub works directly with a diverse patient and respected provider population in multiple therapeutic areas to promote cultural competence in healthcare. The organization believes access to these diverse perspectives cultivates culturally competent communities.

Related Programs:

Good News for Future of Myeloma Treatment, Still Addressing Race-Associated Risks

ASH 2019: Multiple Regimens, Deeper Responses in Multiple Myeloma Treatment

Good News for Future of Myeloma Treatment, Still Addressing Race-Associated Risks

Respected myeloma expert, Dr. Ajay Kumar Nooka, provides an update from the 61st American Society of Hematology (ASH) meeting. Dr. Nooka shares why this is a good time in myeloma research and the important work that remains around myeloma treatment disparities for people of color.

About Diverse Health Hub:

Diverse Health Hub is a health equity education and awareness channel producing educational content for both patients and providers in order to bridge the gaps between healthcare practices and the needs of multicultural communities.  Diverse Health Hub works directly with a diverse patient and respected provider population in multiple therapeutic areas to promote cultural competence in healthcare. The organization believes access to these diverse perspectives cultivates culturally competent communities.

Related Programs:

ASH 2019: Disparities Around Accessing Health Technology Revealed for a Subset of Myeloma Patients

ASH 2019: Multiple Regimens, Deeper Responses in Multiple Myeloma Treatment

ASH 2018 – Multiple Myeloma Highlights

A Multitude of Options in Myeloma

Dr. Robert Orlowski, Director of Myeloma and Professor in the Departments of Lymphoma/Myeloma and Experimental Therapeutics at The University of Texas MD Anderson discusses the multiple myeloma highlights and what patients can be excited about from the ASH 2018 meeting.


Transcript:

Esther Schorr: Hi there. This is Esther Schorr from Patient Power coming to you from ASH 2018 in San Diego, and I have with me today Dr. Bob Orlowski who has joined us at Patient Power before. He’s the Director of Myeloma and Professor in the Departments of Lymphoma and Myeloma and Experimental Therapeutics—that’s a very long title—at the University of MD Anderson—University of Texas MD Anderson. Sorry.

Dr. Orlowski: Thanks very much for having me.

Esther Schorr: I’m glad you’re here again.

Dr. Orlowski: It’s a pleasure to be back on Patient Power.

Esther Schorr: Thank you, sir. So what’s going on in myeloma now at ASH? What are the highlights? What are patients going to be excited about, and what are you excited about?

Dr. Orlowski: One of the exciting areas is definitely talking about the different therapies that are targeting what’s called BCMA or B-cell maturation antigen. This is a protein on the surface of myeloma cells, and the excitement about it is it’s a target which is almost only on myeloma or normal plasma cells, not on other kinds of tissues. And that’s important because if you want to target for immunotherapy, you don’t want that target to be on too many normal cells, or the immune therapy will kill those cells and cause side effects.

So there are really three categories of drugs now that are looking very attractive. One is what’s called an antibody-drug conjugate. So this is a plain old antibody that has another chemical attached to it, and it’s given usually IV right now, attaches to the myeloma cell. It then gets inside the cell and the drug is released. So the antibody is essentially like a carrier molecule.

Esther Schorr: Kind of like a cruise missile?

Dr. Orlowski: Sort of like that. I like that analogy, yes. And then it blows up, using that analogy, the cancer cell once it’s inside.

So one of the first of these drugs that already is in the clinic is showing a 60 percent response rate in very heavily pretreated patients. The registration study, meaning the trial that hopefully will get it approved by the FDA, has already finished enrolling, so we’re hopeful that maybe by the end of 2019 this drug as a single agent will be available. And it’s really easy to give. It’s IV once every three weeks, which is pretty darn good.

Esther Schorr: And what’s the drug called? I’m sorry I missed that.

Dr. Orlowski: Well, it’s a good question. Actually, it doesn’t have a name yet, which is why I didn’t tell you what it’s called, but the abbreviation for it is GSK 916.

Esther Schorr: Okay.

Dr. Orlowski: And the reason for that is it’s actually quite expensive to come up with a name, because they have to find a name that, first of all, is not confused with other drugs so that it minimizing errors and also one that us poor feeble-minded doctors will remember so that we prescribe it often.

Esther Schorr: We’re not sure how you can remember all the letters anyway. Okay. So that’s one. Is there something else going on that you got to share?

Dr. Orlowski: So a second category of drugs that target the same protein, BCMA, the first formal presentation of those data were shown here at ASH, and this is what’s called BiTE or Bi-specific T-cell engager. And it’s sort of is a molecule, if you want to use the cruise missile analogy, that has two war heads. One end binds to the cancer cell. The other end binds to the patient’s own T cell, brings them together and the T-cell attacks the cancer cell. So it’s a way to use immune therapy with the patient’s own immune cells, and there are reports here of the first one of these which is called AMG 420. Again, doesn’t have a name yet, but it’s showing in very heavily pretreated patients complete responses with MRD, or minimal residual disease, negativity, which is really exciting.

Esther Schorr: So and that’s different than—and we’ll probably talk about it in a minute—that’s different than CAR-T.

Dr. Orlowski: Exactly.

Esther Schorr: Okay. So we can talk about that in a minute.

Dr. Orlowski: Yeah, that would be great. So the next topic is the CAR-T, also against B-cell maturation antigen, or BCMA. It’s a little more complicated though because what you have to do is you take out the patient’s own T cells and then in a laboratory you infect them with a virus. The virus has a gene in it that expresses a receptor on the T cells so that they can better recognize the cancer cells.

Esther Schorr: An invitation.

Dr. Orlowski: Exactly. Kind of. I like that.

Esther Schorr: Okay.

Dr. Orlowski: And then you infuse the cells back into the patient. They find the cancer cell, they attack it, and they kill it. So it’s great, because it’s personalized. It uses the patient’s own T cells. The problem is that it takes two to four weeks to manufacture the cells after they’ve been taken out of the patients, and so in the meantime the myeloma can sometimes be creeping up. So that’s one problem.

And also there are activities with the disease or with the T cell against myeloma, but there are also some side effects like cytokine release syndrome. But the response rates with some of the more advanced molecules are in the 90 to 100 percent range, and the durability of that is at least a year to 18 months, depending on what patient population you look at. And those are the most mature data of the three categories of immune therapies that we’ve talked about.

Esther Schorr: So of those three are any of them being looked at for first-line therapy, or these are at the moment still for people who have relapsed or are more difficult cases?

Dr. Orlowski: Right now it’s more for very advanced disease, but there are already trials planned with all three of these technologists in earlier patients and some in newly diagnosed patients, especially those with high-risk disease, because they still don’t do as well with standard therapies that we have. So it’s really an exciting time because these are some of the best results we’ve had in very difficult to treat patients, which means they should work even better when we give them earlier.

Esther Schorr: So one other question then. What’s happened to stem cell transplants for multiple myeloma patients? With all of these new combinations of treatment s, where is that in the mix of consideration for treatment?

Dr. Orlowski: Stem cell transplant is still considered part of the standard of care for patients with newly diagnosed myeloma, and in some cases it can be used for relapsed disease, especially if the patient had a really good durable benefit with a first transplant. The advantage of the stem cell transplant right now is that it with works very well, the toxicity profile is very well defined, and compared to a CAR-T cell it’s actually relatively cheap. But as the technology hopefully becomes cheaper and more available there would be great interest in comparing outcomes of people getting chemo plus a transplant, for example, versus chemo plus a CAR-T cell.

Esther Schorr: So it sounds like there’s a lot more options that are coming up for multiple myeloma patients. Is there anything else that patients that are listening would want to know about, that they should feel good about?

Dr. Orlowski: Well, there’s a lot more data with other immune therapies including earlier use of daratumumab (Darzalex), which is an anti-CD38 antibody. One of the presentations, which is still to come on Tuesday, shows the data of that drug with lenalidomide and dexamethasone in previously untreated patients, and the results really look excellent. So that will probably be one of the new standards of care for transplant ineligible patients. And there are studies ongoing with daratumumab in transplant eligible patients as well.

Esther Schorr: That’s a lot.

Dr. Orlowski: And that’s not all of it, but I think that may be all we have time for.

Esther Schorr: Thank you so much, Dr. Orlowski, for being with us again and making this a little more comprehensible for us normal mortals.

Dr. Orlowski: Thank you very much.

Esther Schorr: This is Esther Schorr coming to you from ASH. And remember, knowledge can be the best medicine of all.


Please remember the opinions expressed on Patient Empowerment Network (PEN) are not necessarily the views of our sponsors, contributors, partners or PEN. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

ASH 2018 AML Roundtable

Latest Research in AML


AML experts Dr. Sangmin Lee, Assistant Professor Weill Cornell Medicine, Dr. Ellen K. Ritchie, Associate Professor of Clinical Medicine Weill Cornell Medicine, and Dr. Tapan M. Kadia, Associate Professor Department of Leukemia The University of Texas MD Anderson Cancer Center, join this roundtable to discuss all the new drugs to treat AML.


Transcript:

Andrew:

Hello. I’m Andrew Schorr from Patient Power. Welcome to our program, from San Diego and the American Society of Hematology meeting, where the people from around the world discussing the latest in blood related conditions. And there is a lot of discussion given new drug approvals and lots of research in acute myeloid leukemia. And it gives new hope to patients and their families dealing with this acute condition. So, joining me is Esther Schorr. And Esther, you’ve been talking to people. And we have a wonderful panel we’re going to meet, in a second.

 

Esther:

I have. And, especially with the more acute conditions that these wonderful researchers and clinicians are working with, I think that we need to discuss how family members, care partners, caregivers, what active role they need to play in sort of the rapid fire beginning of getting treatment.

 

Andrew:

How you want the best yourself for a loved one. Let’s meet our panel. So, I’m going to have you introduce yourself, so we get your titles right and your institution, please. 

Go right ahead.

 

Dr. Lee:

So, I’m Sangmin Lee from Weill Cornell Medicine. And I’m part of the leukemia program. And I’m an assistant professor there. And I focus on myelodysplastic syndrome and acute myeloid leukemia.

 

Andrew:

Okay. And next to you is a colleague of yours.

 

Dr. Ritchie:

My name is Ellen Ritchie. I’m an associate professor of clinical medicine and the assistant director of the leukemia program at Weill Cornell Medical College. I treat all myeloid malignancies. And I also treat acute lymphoblastic leukemia.

 

Andrew:

Okay. And both, two New Yorkers. And now, let’s go to Texas.

 

Dr. Kadia:

I’m a Texan but a former New Yorker. My name is Tapan Kadia. I’m currently associate professor in the Department of Leukemia at MD Anderson Cancer Center in Houston Texas. My practice is based on research and clinical work in acute myeloid leukemia, MDS. I also look at bone marrow failure syndromes. And I’m glad to be here, so thank you.

 

Dr. Ritchie:

Thank you for having us.

 

Andrew:

So, Dr. Ritchie, I’m going to start with you for a second. So, are we right? It seems like someone’s head can spin, with all of the new drug approvals, and then, also trying to make sense of what’s right for what patient. So, how much have things changed in AML?

 

Dr. Ritchie:

Well, AML used to be a really simple disease because we had two drugs, and that’s how we treated patients. Now, it’s a more complicated disease, partially, because we’re learning a lot more about this disease molecularly. And there are new targeted agents, which have been recently approved, in the last year, for the treatment of AML. Many of them, just recently, in the past few days. Gilteritinib, which is a second FLT3 inhibitor was in there last week. A lot of these drugs are drugs that fall into two categories. Some which target mutations that may be relatively infrequent like IDH1, IDH2, FLT3.

And these are for those specific populations who have those particular mutations.

There are also drugs that are more blanket that cover patients who have really any abnormality, which are added to standard therapy like Venetoclax. Venetoclax was initially approved for the treatment of CLL and has recently had a new label to add to low dose ARA-C or to hypomethylating agents, for the treatment of AML. And that’s an exciting new development where the response rate with hypomethylating agents goes from about 40% to 70%. So, it’s a real advance, for those particular patients.

Also, in the really older and frail population, I always have problems saying it, Glasdegib, which is really a drug, which is directed at the leukemic stem cell together with low dose ARA-C. These have been approved really for patients who are a little bit more frail and older. And it’s a regimen that is more easily tolerated by that age group.

 

Andrew:

So, just a follow up. So, how much of a difference – the FDA approves effective therapies effective therapies, which, hopefully, make people’s life better and longer. So, is that the hope for our viewers watching that whether it’s themselves or an adult parent or grandparents that they can have a better, longer life?

 

Dr. Ritchie:

Well, there are a lot of aspects to leukemic care. It’s not only having a longer life but having a higher quality of life. So, it’s the quality of life that you have, as well as the length of life that you have. So, just to put it in reference, standard induction chemotherapy, where we use two drugs, Daunorubicin and Cytarabine, which my father used to use when he practiced medicine, and those days are – it’s an old combination. But it really requires the patient be in the hospital for 30 days. And these patients are sick. And they require transfusions.

And most of them require antibiotics. And they don’t feel very well, and it’s a difficult time. So, for older patients, are you really willing to spend a month of your life or maybe two months of your life where you really feel terrible in the hospital? That’s not necessarily something that you want to do. So, part of the breakthrough is not just that we may improve overall survival, which we don’t really know, until it’s out in the community, and we see how it works. But whether we can improve the overall quality of life of older patients who have AML. So, and rather than being in hospital, you can have your therapy, in an outpatient setting.

And rather than it being all intravenous, you might have an oral medical that you could take at home, like you do your hypertension pill, really, for your AML. So, these are really important advances because it enhances the quality of life of patients who have acute leukemia.

 

Esther:

Well, and it also sounds like you referenced that a lot of the patients are older with this. And I just can’t imagine what it must be like, if you have two much older people, and one person is, as you mentioned when we were talking earlier, one is out of commission.

The other is not only going to need support from family, but if their partner doesn’t have to be in the hospital to be able to at least be home, there’s some level of support there.

 

Dr. Ritchie:

Right. Well, you guys can chime in. But a typical situation, really, is two older people who are living together where they’re doing just fine as a symbiotic couple. But they both have their illnesses or both have their problems. But once you take one person out of the picture, and that person is very, very sick, it can be very difficult for the other elderly person to actually handle all of the stress of taking care of themselves and all of the stress of taking care of another person. So, one of the key factors, I think, in overall survival and quality of life in patients who are older who have AML is having a caretaker who is reliable for them.

And that may be your child. It may be your sister. It may be a good friend. But there has to be someone in your life, beyond just your spouse, who can be a caretaker for you for a successful therapeutic result.

 

Dr. Lee:

And one thing that is great about the medicines that are coming out are that they’re very well tolerated, especially the IDH drugs and Venetoclax. They’re very well tolerated. You can do it outpatient. So, for a lot of older patients, as you know, if you stay in the hospital more, you’re exposed to infections. Your performance status may decline. So, patients actually do better with an outpatient therapy. I think that’s beneficial

 

Esther:

And also older people. I have two aging parents, thank goodness doing well. But they’re in their 80s. And just driving to the clinic is a big event. But if you’re having to do that every day for treatment or going to visit.

 

Dr. Ritchie:

Right. And we don’t want sick people driving necessarily to our clinic because, if your hemoglobin is 7, and your platelets are low, you’re not in the best situation to be reactive to the problems of traffic and cars.

So, transportation is also a real issue, I think, when patients are older and coming in for treatment.

 

Andrew:

Dr. Kadia, so we’ve mentioned a couple of these cancer genes. IDH, FLT3, I think. So, these are oncogenes, right?

 

Dr. Kadia:

Right. So, what’s been great, and I think this has been greatly summarized by my colleagues, but we’ve had sort of a revolution in how we treat AML and many cancers, but particularly AML and the liquid tumors. With the advent of what we call next generation sequencing, we’re able to really get the mutations and the data from the leukemia cells. We find that there are recurrent mutations. Mutations are changes in the DNA that happen over and over and over again, in different people with leukemia. So, it made us realize that, if these mutations keep happening in AML, they must drive the AML.

There must be something about them that makes the AML happen. And, in fact, that’s the case. So, in a handful of those mutations, things that people have really studied, we now know that things like FLT3 or “flit 3” is a mutation that really drives proliferative AML. And so, people said, well, if that drives it, can we develop a drug target inhibitor of that mutation to shut the leukemia down? And indeed we can. We used to use a drug call Sorafenib last year, over a year ago. A drug called Midostaurin was approved with chemotherapy in the front line. And just recently, as was describe, just a week ago, Gilteritinib was approved in patients who have the FLT3 mutation, but they’ve had relapsed disease.

So, that’s just one example. The second you said IDH, right, isocitrate dehydrogenase, another mutation. We didn’t know what it meant. But people worked and worked and figured it out. And they found out there’s two mutations, an IDH1 and an IDH2 mutation. Each of those drives that particular subset of leukemia. And it turns out you can make inhibitors to each of those, and they work. An oral medication you take once a day for people with relapsed disease actually works.

And it doesn’t work like regular chemotherapy. We describe intensive chemotherapy. You put them in the hospital, their hair falls out. They have mouth sores and diarrhea and nausea and vomiting. We don’t see that, with these pills. We do see some side effects. And, certainly, the patient and the family member need to recognize those side effects. So, there are side effects. But they’re different. They’re more tolerable. They’re more manageable. And so, that’s what we’ve been able to do, get people home, take these medications, and target these specific mutations.

So, among the many mutations we’ve discovered, we found drugs for probably two to three of those targets. But we also found that some of these mutations will predict for responses to other drugs like Venetoclax.

 

Andrew:

Let’s talk about testing. How do you know?

 

Esther:

I was just going to say it really sounds like you have to be tested.

 

Dr. Lee:

Yes.

 

Esther:

To know where you fall.

 

Dr. Ritchie:

And I think that’s one of the big barriers right now that I feel the insurance industry has not really caught up to what it is that we’re doing in AML. So, every patient who is getting or has a suspicion that patient has AML, that patient, when they have a bone marrow biopsy and they see a doctor should have a next generation sequencing sent.

The problem is this costs thousands of dollars. Now, some insurance companies are not – they don’t really care or aren’t really cognizant of the quality of the different NGS panels. And they make deals to cover with one or not cover at all. So, it can be a hassle for the patient. And it can be thousands of dollars expense. So, that’s something that I think the whole industry is working on to try and enlighten insurance companies and to make them pay for this particular sequencing. MD Anderson has their own in house. And you probably have worked out a deal with insurance companies.

 

Dr. Kadia:

No, we have. So, I think more and more, insurance companies are beginning to realize that this is a part of the disease treatment. If you have pneumonia, you’re going to get a chest x-ray. If you have AML, it’s becoming standard.

It has for years. We do FLT3 mutations. We do something called NPM1 mutations. For years, we’ve been doing this in AML. Now, what they need to realize is that we need to expand that to what we call a sequencing panel, which are 80 different genes, which are commonly mutated. Why? Not just because we’re interested and we’re curious, but because these mutations play an important role in telling the patient this is your prognosis. And this is the drug that we’re going to treat it with.

 

Dr. Ritchie:

Or even, if this patient – and just because you’re older doesn’t mean you’re not a candidate to be a bone marrow transplant candidate, there are some mutations that we find that really propel us to wanting to have that patient –

 

Andrew:

It’s all about getting what’s right for you or your loved one. So, let’s back up for a second, Dr. Lee, just so we understand AML. So, first of all, how old is the typical patient? What are the symptoms that present? For somebody who is watching us, maybe somebody said this could be AML.

 So, what is AML? And how does it typically show up and for who?

 

Dr. Lee:

So, AML stands for acute myeloid leukemia. So, in your bone marrow, bone marrow’s job is to make blood cells, including your white blood cell, which is your immune system, hemoglobin, which are the red cells, and platelets. And they all are manufactured in the bone marrow. So, what we’re talking about here is that, basically, the factory, the stem cells that make the blood cells, have gone wrong, basically. And there are abnormal myeloid stem cells that proliferate. And your bone marrow is full of these abnormal stem cells that are not able to make normal kinds of immune system and hemoglobin and platelets.

So, it’s an acute leukemia meaning that, sometimes, people are doing – a lot of times, people are doing well. And then, all of a sudden, their bone marrow develops a leukemia. And all of a sudden, you become symptomatic.

So, symptomatic means that, if your bone marrow is not making red cells or platelets, you might be more tired. You might see some easy bruising or see these little dots pop up on your skin.

 

Andrew:

Petechiae.

 

Dr. Lee:

Petechiae in your skin. Or you might have an infection that doesn’t go away because your immune system is affected. So, there are various ways that people are diagnosed, based on how they feel. Sometimes, people just get a routine blood work by the primary physician, and they are just discovered to have leukemia, even though they don’t have symptoms. So, it kind of varies.

 

Esther:

But there’s different paths with leukemia, obviously, that there’s AML, which is do not pass go, something needs to happen right now. And some of the more chronic forms where you have a little more time to kind of figure out what’s going on.

 

Dr. Lee:

And a lot of times, you can differentiate because, if you see a primary care physician or Emergency Room, they can actually look at the blood cells and do what’s called a manual differential.

Basically, some person looks at the blood cells under a microscope, and you are able to see abnormal leukemic looking cells that you wouldn’t see in any other condition. So, that’s how you know that you have leukemia.

 

Andrew:

So, a family is saying, okay, did we do something, did the patient do something, did something happen to them that caused this. So, you sort of fall off of this leukemia cliff into this acute I call five alarm fire situation.

 

Dr. Kadia:

No, you’re absolutely right. And I completely agree with that. Leukemia, at least AML, acute leukemia, is a very rapidly progressing disease, in most cases. And it’s, usually, a medical urgency, if not a medical emergency, like you said. Most of the time, no one has done anything to cause leukemia. And many people are doing fine, until they actually have the diagnosis, and they get very, very sick very rapidly. Patients tell me all of the time, I was just traveling. I was on a cruise. I was playing golf. I felt fine. Why do I have AML? It comes on very acutely, hence the name acute, so very quickly.

The risk factors for AML, first, is age. The older you are, the higher the risk of developing AML. The average of developing AML is around 68 years of age. We know that there are younger people who get AML as well. But we know that that AML is a little bit different than people who have older AML. The younger AML’s tend to be more rapidly proliferative. They have high white counts. The older AML is often associated with a disease called myelodysplastic syndrome, which is related. So, they have low counts, feeling kind of icky. Their counts are not great. And then, they develop this surge.

And so, age is certainly a risk factor. Prior exposure to chemotherapy or radiation for another cancer predisposes you to AML. If you are exposed to things like benzine or if you’re a heavy smoker that can sometimes predispose people to AML. But, certainly, it’s not anyone’s fault. And no one knows. And why couldn’t I have detected this earlier? Nine times out of ten, you could not have detected it earlier. It happened two weeks, three weeks prior to what just happened.

 

Esther:

And is the treatment for a younger patient different than for an older patient?

 

Dr. Kadia:

It can be. It can be. And often, what we look at, and age is not the only thing. We don’t look at age as a number but more of a fit and unfit person. So, if an older patient, they tend to have more comorbidities, history of hypertension, diabetes, heart disease just because they’ve lived longer. They have 60, 70-year-old organs. And they may not be as fit as a 25, 30, 40-year-old. And so, then, you base your treatment paradigm on whether you think they can tolerate some intensive chemotherapy versus not.

But a point that I wanted to expand on, when you present in the Emergency Room with acute leukemia, it’s a rare folks, 19,000 cases a year, compared to something like breast cancer or lung cancer, which is very, very common. And so, typically, someone will come to the Emergency Room. They’ll be seen by the Emergency Room. They’ll consult the local hematologist oncologist. They’ll come to see that patient. Or they may know a local hematologist oncologist.

While community physicians can treat the disease, sometimes, in the acute setting, and for reasons we described earlier, it’s nice to go to an academic center or larger center who can do some of the initial work up, the mutation screening, it will be easier.

Maybe not have problems with getting the insurance. Get the diagnosis right. Get the pre-treatment data right, so that you can really formulate a treatment plan. And once that treatment plan is in place, then, you can decide can I get some of this treatment here, can I go back to my local doctor?

 

Andrew:

Well, I think that’s really critical. So, you are both in really big cities. Our largest, New York, Houston. And there are choices of what hospital you go to or what clinic you go to. Some may be in a more suburban or rural area. But it seems like, if this is suspected, if you can get with this changing landscape, at least a consultation or even your community doctor calling one of these folks to have a plan, an architect plan, even if the community doctor is sort of the general contractor, if you will. But there’s a lot –

 

Dr. Ritchie:

But I want to say something about that a little bit.

 

Andrew:

Sure, please.

 

Dr. Ritchie:

These are all very new drugs. And leukemia patients need a lot of care.

And we don’t really know what we need to know about a drug, until a drug is approved, and it’s being used widely. So, it is something that community doctors should confer with people who have used the drugs. And probably the most impressive abstract that I have seen at ASH this week involves really our ability to develop these sorts of drugs where there was an abstract looking at patients who had FLT3 mutations and how many leukemia patients we have every year in the United States who have FLT3 mutations. Looking at the number of trials that we have open for FLT3 inhibitors and now combinations of FLT3 inhibitors with some of these other drugs.

And looking as to whether or not we have enough patients. It’s very sad, in this country, that only five percent of adults are participating in clinical trials.

So, the ability of our leukemic world to develop drugs that are actually going to improve the quality of life and improve the treatment of these diseases has depended on that very generous five percent of the adult population who is enrolled on clinical trials. This contrasts greatly with children. The Children’s Oncology Group manages to enroll about 50% of children in this country on Children’s Oncology Group studies. And the overall survival of children, in every single malignancy where the COG trials are open are superior to adults’ overall survival.

So, now that we have these drugs, we want to hone in and find ways to make these drugs even more effective. The IDH2 inhibitors are about 40% effective CRs. But it would be nice, if we could figure out a way to combine it with something else and make it 80%.

 

Andrew:

CR, complete remission.

 

Dr. Ritchie:

To make it 80% effective. And the way we are going to do that is by enrolling people on clinical trials.

 

Esther:

But it sounds like the onus is really on patient and their care partners to say hey, if I’m in a rural setting, and I’m not near one of these major centers that I want to have a consultation. I want you, doctor, in my city, and consider a trial. It’s a big responsibility.

 

Dr. Kadia:

Absolutely. I think you have to be an advocate for yourself. And I’ve seen patients, when they’re first diagnosed, their head is spinning. It’s a scary, scary thing. You Google AML, and it’s not a fun thing to read.

 

Esther:

No.

 

Dr. Kadia:

So, their heads are spinning. So, this is a really good time for the family, the caregiver, the friend to come and support that patient and say, look, I got you. I’ll go with you to the doctor’s appointment, and I will advocate on your behalf. And you will advocate on your behalf to say, look, you’re my doctor. You’ve been my dad’s doctor.

 You’ve been my cousin’s doctor, and I love you. But I think that I really want to get a specialty opinion from a disease specialist who treats this really, really rare disease that happens to be really aggressive. And where there’s been so much development, just in the last two to three years where things that we used to do before, we don’t do anymore. It’s just not the case. And people get afraid of clinical trials. Well, I don’t want to be a guinea pig. But it’s not necessarily a guinea pig. I think, you can really ask the doctor that you’re seeing what does this clinical trial entail. Am I going to get a placebo?

Am I going to get standard treatment? And what you’ll see, as far as I know, is many of the trials, most of the trials in AML and leukemia these days, are full treatment trials where they’re studying potential combinations and things like that. And really, get to know your risks, before you sign the consent.

 

Andrew:

You referred to people Googling it and whatever. So, Dr. Lee, given what you know and what you’ve been hearing at this meeting like at the convention center next door, would you say that this is changing so much that, probably, what you’d see in a general write up from last year or the year before on AML, is out of date?

 

Dr. Ritchie:

Then, maybe don’t Google.

 

Dr. Lee:

Absolutely. I think Google is very dangerous because a lot of times, your information is based on how updated it is. So, if you have so many drugs that are approved, and whatever you look up is not updated, according to that, then, it’s very outdated. So, I think Google can be very dangerous.

 

Esther:

So, what should a patient do? So, God forbid, something happened with AML, in our family, Andrew or somebody else. What’s the first thing that family should do, in terms of trying to get enough information?

 

Dr. Lee:

I think, for AML, what’s very important to know is that there are two general behaviors of AML. One is something that needs to be treated right away, as in the same day. Typically, those kinds of patients have a very high white blood cell count, and they’re more symptomatic. So, in those cases, I would advocate that you do not have a lot of time to shop around.

So, if you are really far away, you need to do what you can to treat the disease first. Assuming you’re pretty stable, if your blood counts are not proliferative and changing, you do have time to ask for an opinion. And I would, like anything else in medicine, I would go to a person who treats a lot of the condition. AML is not a common disease. And treating an AML patient requires not only giving drugs but a lot of supportive care. So, you need to go to someone who sees more AML patients. So, that’s what the patient needs to advocate.

So, the first question the patient should probably ask a doctor is how many patients of AML have you treated. And is there someone who you know who has expertise in treating AML? And given the acute nature of things, for us, when patients call, we often squeeze them in same day.

Unlike other kinds of cancers that move slowly, we often see patients on a very short notice because it’s an acute leukemia.

 

Andrew:

Decisions have to be made fast. So, we’ve talked a lot about the family role, whether it’s somebody your same age, and you’re an older person, or the adult child, you can play role the terror, as you referred to, that comes with the diagnosis. So, it sounds like it’s important to sort of pick yourself off the floor, identify a team or consulting healthcare team members who have expertise in the field, to make sense of this IDH and FLT3 and all of the different stuff, and, hopefully, have insurance support, so you can get the testing that’s right for you.

Now, with all of these different drugs, if you find that one is not working or no longer working, with this whole array of treatments, is there something else that probably you can switch to, Dr. Kadia?

 In other words, you’re not out of choices.

 

Dr. Kadia:

No, you’re not. And one of the great things about having these trials and having these new drugs approved is now, we have so much more in our toolbox than we used. Before, like we said earlier, we had two drugs. We had a anthracycline and cytarabine, there’s two types of drugs. And we just used those. We combined it with other things. But it was really the same kind of backbone. But now, you have IDH inhibitors. You have FLT3 inhibitors. You have this drug, Venetoclax, which has shown remarkable response rates, with a low intensity chemotherapy that’s tolerable to people who are 60, 70, 80 years of age.

And so, even if you did not respond, or if you responded and relapsed after your first AML treatment, there’s not a significant loss of hope. You say no, there are other things available. There are many drugs in development. There are many clinical trials. And very often, some of the best care you receive is on a clinical trial because you’ll have a research team and research nurse, in addition to your doctor, who is constantly monitoring, following every single side effect that you have, trying to address every question you have because it is regulated very closely.

So, there are many options. And, certainly, many of the academic centers and even certain other organizations now are offering these trials.

 

Dr. Lee:

One thing that is extremely important for patients to realize, actually, for clinical studies, is that each individual patient is not a statistic. So, let’s say a drug only has 20 or 30% response rate. You don’t actually know, a lot of times, if you’re going to respond or not until you take the medicine. But if you happen to fall under that 20 or 30% that works, it doesn’t matter what that success rate is. But you have to make the steps to try. And that’s what’s the most important thing about treating AML patients.

 

Dr. Ritchie:

I want to mention a couple of other drugs, which have been approved that we haven’t talked about. One is Vyxeos, which is a drug, which is the anthracycline or cytarabine, and Daunorubicin that’s enclosed in a fat globule.

 

[00:36:05]

 

And it’s given differently. It can be given twice a week, for example, or three times a week, depending on what the decision is of the clinician. And it can be given on an outpatient basis. You usually do have to come into the hospital, at some point in time. But unlike normal 3+7 chemotherapy, you may even keep your hair with this. But that’s an option for someone who fails some of the upfront drugs, potentially, or has myelodysplastic syndrome, which is a type of pre-leukemia that develops into acute leukemia.

And it looks like, in these pre-leukemia patients who develop acute leukemia who have myelodysplastic syndrome, it may be a very effective drug. We also have, back in the tool box, Gemtuzumab, Ozogamicin, which is also known as Mylotarg, which was a drug originally approved for older patients who fail standard chemotherapy.

 And it’s an antibody, which binds to an antigen on the leukemia cell called CD33. And it’s connected to an antibiotic called Calicheamicin, which can be enclosed into the leukemia cell and kill the cell. This drug was taken off the market for a period of time because of certain liver abnormalities and has been brought back onto the market. The dosing schedule has changed somewhat. But it’s another option. And it’s an immunotherapy option, which we can use for patients who may fail original therapy.

We also are combining it, in younger patients, with standard chemotherapy who may have a better sort of favorable karyotype or their chromosomes have a more favorable response to chemotherapy that we combine that antibody with regular chemotherapy for a better outcome.

 So, the tool box is really expanded. And I think we’ve talked now about all of the agents.

 

Andrew:

We’ve left one area out though, and that is transplant. So, first of all, I’m living with myelofibrosis and know that there’s a percentage of people who progress to secondary AML. And before, you didn’t have much for us, maybe transplant. And also, other primary AML people who would go to transplant. So, where does transplant fit in, whether it’s primary AML or secondary AML or other drugs for secondary AML? Why don’t you take the transplant first? Where does it fit in?

 

Dr. Ritchie:

Well, we look at a lot of things, when we look at an AML patient. We’re looking at their age and their fitness, what their comorbid illnesses are. We look at their disease. We look and see what are the chromosomal abnormalities that we see, in this particular leukemia.

 And we group them according to favorable risk, people that might respond well to chemotherapy alone, people with intermediate risk where they may or may not have a good response to conventional chemotherapies, and poor risk. We are now also doing the molecular testing. So, we do that 50 gene or 80 gene test where we see what mutations there are, in the person’s leukemia. And we put all of that information together to see what we think the prognosis of the patient is.

So, if the patient has already had heart failure and has had bypass surgery, and they have diabetes that’s not on good control, and they have an unfavorable AML that we would transplant, we may not refer that patient to a transplant consultation because we don’t think that they’re strong enough or fit enough to get through a transplant.

 But my 79-year-old tennis player who has been playing tennis every single day, and the only comorbid illness is hypothyroidism, and they have an unfavorable mutational panel or an unfavorable chromosomal karyotype, then, that patient I would refer to a transplant consultation for cure.

 

Andrew:

Okay. And then, secondary AML where my understanding is some of these drugs may help someone like me, if I progressed, from myelofibrosis. I don’t know whether –

 

Dr. Ritchie:

Secondary AML, if you were a fit person, I think most of us would send you for a transplant consultation.

 

Dr. Kadia:

I think the bottom line is we look at two things. We look at the risk of the leukemia and the risk for the patient. So, we look at the disease and the patient. If the disease is high risk or even intermediate to high risk, we consider them candidates for transplant. Then, the next step is fine, we think you should get a transplant.

Would you do well with a transplant? Is the morbidity and mortality rate going to be high, in your case, or is it going to be low? If it’s going to be high or even intermediate to high, then, we can’t do a transplant. We shouldn’t do a transplant, unless we mitigate some of those factors. If the risk is low, then, that patient should try to get a transplant. Then, there’s the whole thing of do we have a donor available. A donor is, typically, a sibling who is a match. We also have national marrow donor program, which you can get an unrelated match. Occasionally, we do something called a haploidentical where you can get a son or daughter or mother or father to be a match.

Those are probably less likely in older patients because they’re a little bit tougher. And we do those more in younger patients. But there are many options for transplant. I don’t think it’s off the table.

 

Dr. Lee:

One thing to be very clear about transplant is that it’s usually an option, once you get rid of the disease. So, it’s not something you go into, when you are first diagnosed.

 

Andrew:

You’re going to knock it back with the drugs we’ve been talking about.

 

Dr. Lee:

Correct. So, transplant is a modality to really keep the disease from recurring.

So, one thing that is very important that is coming out these days, with ASH and other meetings, is importance of how we measure disease, after treatment, before we go to transplant. And increasingly, there’s a way we’re getting more sophisticated into measuring how much disease you have left over, after induction therapy. And it’s called measurable residual disease, MRD. And you can go deeper and deeper and look, and there’s actually data showing that less disease you have, or if you don’t have any disease, you better after transplant. So, one important thing the patients should remember is that it’s very important to try to eradicate your disease, before you go proceed to transplant.

 

Andrew:

Let me see if I’ve got this right then. So, if you can, you’re going to do this testing to see what version of AML do you have, by these panels of genomic testing.

 

 

Dr. Ritchie:

And the karyotype, the chromosomes that are inside of your leukemia cells.

 

Andrew:

Chromosomes, okay. And then, you’re going to see are there drugs that line up with that that can knock it down to minimal measurable disease? Are you a candidate for transplant that can take it further and maybe give you a longer life? Is there a donor? But for people who are not candidates for transplant, Dr. Ritchie, are we just saying there’s not as much hope for them?

 

Dr. Ritchie:

I like to tell my patients that there is always hope. The issue will be, for these patients, that they will, eventually, need to enroll in clinical trials of new drugs and new combinations, to try and keep their leukemia in remission or to treat a relapse of their leukemia. Although we have all of these new combinations, one of the things that we haven’t really established is, when you fail one of these, and you have a relapse of your disease, what is the next best step?

We don’t really know it for any of these drugs. So, clinical trials become very, very important and really the key to a longer life for those people who are not transplant candidates.

 

Andrew:

That’s for ASH –

 

Dr. Lee:

I definitely agree with Dr. Ritchie. I have one example. I have a patient in her mid-80s. She was diagnosed more than three years ago. And she had a very aggressive leukemia that did not respond to the Decitabine. And she was actually very sick and had a lot of heart issues. She happened to have an IDH2 mutation, and we had a trial. So, we gave her the drug. And more than three years later, she’s still taking the drug, has a completely normal blood count, and going about her business. And she remains in remission and ongoing.

So, back then, we didn’t know how good the drug would be, of course. And we had a clinical study, and she enrolled. And you don’t know, when you have clinical study, how well it’s going to work. So, it’s very important to keep an open mind and be proactive about it.

 

Esther:

If one relapses with AML, in that scenario, do they need to be then retested to the –

 

Dr. Ritchie:

Yes.

 

Esther:

Because I know, in some of the other leukemias, that’s the case.

 

Dr. Ritchie:

The NCCN guidelines really recommend that there is a mutational panel done at diagnosis. But if we’re going to send someone to transplant, there’s a lot of sort of disagreement about how you measure minimal residual disease. But one of the things I think most people are beginning to have a consensus about is repeating the molecular panel to see whether or not we still see those molecular abnormalities, in addition to other things.

 

Andrew:

It’s the driver gene.

 

Dr. Kadia:

Exactly.

So, I think, what we realize is that this is a disease that’s constantly evolving. So, we hit it with chemotherapy. It evolves to progress. We hit it again with something else, it evolves. So, the evolution happens either through chromosome abnormalities or to mutations. So, it’s important to recheck some of these mutations to see now, hey, they didn’t have the FLT3 before, but now they do. Now, we can target it with something else.

 

Esther:

It’s kind of wily, isn’t it?

 

Dr. Kadia:

Exactly. It just continues to –

 

Andrew:

So, I just want to ask you, just poll you really quickly. So, for our patients and family members who are watching, you’re their barometer on how things are changing in AML and what it could mean for themselves or loved one. Are you especially hopeful now?

 

Dr. Kadia:

I am hopeful. I am optimistic. I’m excited. I think these are great times at AML. We talk about the new drugs that have been up front for patients who are in upfront setting, people who have relapse disease. There’s hope for them. We talked about what do you do if you’re not a candidate for transplant. We’re looking now at things called maintenance therapy where we give induction, we give consolidation.

We can give you something that’s low intensity for a very long period of time to maintain the remission and not let you relapse because, sometimes, when you relapse, you say now, we’re kind of behind the eight ball. But what if we just don’t let you relapse? We give you a maintenance therapy. So, these are trials that we’re doing. I think they’re exciting times. I’m very hopeful and excited.

 

Andrew:

You’re positive. You two?

 

Dr. Ritchie:

I feel that I’m living in a period of a revolution. And I think it’s not just a revolution in acute leukemia. It’s going to be a revolution in all of medicine that, as we learn about these mutations in the blood, we learn things about not only treating acute leukemia but maybe even about other medical conditions. I’m going to give you an example of that. We have learned that patients who have certain of these mutations, if they don’t have acute leukemia and have myelodysplastic syndrome, some of these mutations make for a higher risk of cardiovascular disease.

 So, that, as a physician, I now am really worried about the cardiovascular risk factors of my patients who fall into that category, in addition to their disease. They’re also finding that some of the mutations that we are finding in blood diseases, they’re finding in the brain. So, some of the drugs that we are using for hematologic cancers may be useful for pretty terrible cancer in the brain called glioblastoma. So, as we start to make these kinds of connections, this is revolutionary. This is unbelievable.

 

Esther:

Well, it’s forcing a more holistic approach, too.

 

Dr. Ritchie:

We’re filling in little pieces of the one million piece jigsaw puzzle that really confers the health of a human.

 

Andrew:

And you grew up with it, right? Your father is a physician?

 

Dr. Ritchie:

My father and my grandfather and my brother are all physicians. My grandfather was the first pediatrician in the state of Iowa.

 

Esther:

Wow. That’s quite a legacy.

 

Andrew:

How about you, Dr. Lee?

 

Dr. Lee:

I’m very excited, and I’m very optimistic. We have spent a lot of time talking about mutations. But one area that is emerging and, hopefully, in the next [Crosstalk] few years, that will be powerful in AML is, of course, immunotherapy. The immunotherapy has transformed solid tumors. Every solid tumor, there is some sort of immunotherapy. And we’re not there yet, but there’s a lot of clinical studies looking at how to harness your immune system into treating leukemia. So, we haven’t even hit that yet. But a few years from now, I’m sure there will be new immunity therapies that will be very relevant in leukemia. So, it’s very exciting.

 

Andrew:

So, for the family members –

 

Esther:

We just have to be hopeful and stay on top of it.

 

Andrew:

But I think connect with the specialist. You have your community doctor, if you haven’t gone to the big, academic medical center, with their specialists in this field. Make that connection because you hear the change.

 You hear the need for testing to know what is your specific situation that you’re dealing with. Or if you are coming out of a remission, do you need to be tested again? Yes, to know what’s going on then. What are your options? But thank you so much to our panel. It’s been a great discussion. And thank you for helping, in the research you do, because you’re helping lead the way. And if that helps with brain cancer and some of these other areas, put the pieces of the puzzle together, Dr. Ritchie, as you said, for you’ll be very pleased. And your father and your grandfather and all of your medical people in your family will be so pleased.

Esther, I’m really delighted that we can tell this story. Serious illness, acute illness, but there’s stuff to talk about with your healthcare team. Thank you for watching. We wish you and your family the best. And remember, from Esther Schorr and Andrew Schorr –

 

Esther:

Knowledge can be the best medicine of all.

Please remember the opinions expressed on Patient Empowerment Network (PEN) are not necessarily the views of our sponsors, contributors, partners or PEN. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.


We thank Daiichi Sankyo and Jazz Pharmaceuticals  for their support.

Myeloma Highlights – #ASH16

MYELOMA HIGHLIGHTS FROM ASH CONFERENCE SAN DIEGO 12/2-6/2016

According to Jack Aiello (definitely not medically trained)

PREFACE

ASH 2016 Conference

ASH 2016 Conference

This is my 11th year attending ASH (American Society of Hematology) Conference, where 25,000 attendees from all over the world (hematologists/oncologists, lab researchers, oncology nurses, scientists & 300 pharma companies) present the latest research results via both oral presentations (1000) as well as posters (3000) on all blood cancers. This year there were nearly 700 abstracts (>100 clinical) on Myeloma alone, many of which were selected for oral presentation. I’m grateful to the IMF (www.myeloma.org) and their pharma donors for sending me to ASH so that I can learn and share my patient perspective with you.

Rather than attending talks on Biology, I typically focus on the Clinical Trials, which I’m able to understand and are more relevant near-term to patients. Even at that, there are overlapping MM oral sessions as well as 4’x6’ posters without reprints, so it’s always possible that I have not included something of interest to you or made a typo because I can’t read my own writing as detailed powerpoint slides are presented quickly. You might want to view the published abstracts at www.hematology.org and various press releases. [Wherever possible, I’ve listed Day-Abstract#-Lead Investigator after the trial results, e.g. {Mon-675-T. Zimmerman} and clicking on the abstract number will take you to the actual abstract.]

There are other ways to learn more about results from this conference. There are scheduled webinars (MMRF 1/11/17, IMF 1/12/17) which you can listen to live or by replay. You’ll also find some patient blogs (including mine) as well as MM expert video interviews posted on the IMF website (http://ash2016blogs.myeloma.org), Patient Power (www.patientpower.info), and Myeloma Crowd (www.myelomacrowd.org) among others. And all of us in the SF Bay Area should attend the LLS Blood Cancer Conference (which includes updates from ASH) Feb 4, 2017 (Register Now). Dr. Jeff Wolf of UCSF will do a great job presenting the latest information.

Presentations and posters of clinical trial results follow the same format: Background (including hypothesis), Study Objective, Design & Treatment schema, Patient Characteristics & Cohorts, Responses (include high-risk cytogenetics), Toxicity (hematological and non-hematological), Conclusion, and Next Step. Remember, the goal of Phase I (typically handful of patients) is to determine “Maximum Tolerated Dose”; Phase I/II and II (typically 25-75 pts) continues to measure dosage escalation and safety while looking at responses; and finally Phase III (several hundred patients) compares response rates between new and current treatments.

Treatment schedules are defined for stages of Induction, and optionally Transplant, Consolidation, and Maintenance with specified Randomization along the way; dosage amounts and scheduling are provided for each drug along with optimum number of treatment cycles (typically 28 days). Risk stratification correlates various techniques such cytogentics-FISH analysis (e.g. chromosome deletions and translocations) and gene-expression profiling (GEP).

HIGHLIGHTS (e.g. My Takeaways)

1. In Nov 2015, 3 new drugs were approved for Myeloma…Daratumumab, Elotumumab (both mAb’s) and Ixazomib (oral PI). At this ASH, trials were presented that provided results for using these drugs beyond their current FDA-approved indications such as Dara in combinations and Ixa before and after transplant.

2. Speaking of transplants (SCT), there were lots of abstracts on specific SCT usage…some contradictory. For example, one trial showed SCT plus consolidation benefitting MM pts while another trial showed no difference whether being treated with a single SCT, SCT + consolidation, or a tandem SCT.

3. There were 3 new drugs of interest: Nelfinivar, Selinexar and Venetoclax. Most impressive is that they were particularly effective in certain scenarios: Nelfinivar (with Velcade) for Vel-refractory pts; Selinexar alone for t(11;14) pts; and Ventoclax + dex for quad- and penta-refractory pts. Quad means refractory to Rev, Vel, Pom and Cfz, while Penta include Dara.

4. Minimum Residual Disease (MRD) testing is still not ready for prime time, but one doctor googled “Myeloma + MRD” and found 45 abstracts. MRD tests are certainly being added and reported in trials and while there’s good correlation between PFS/OS and MRD, it’s still not being used to determine subsequent treatment. Since MRD has the potential to guide therapy, stop therapy and change therapy, it’s something we patients need to keep on our radar.

5. There were several presentations on Immunotherapies (mAb’s, CAR-T’s and checkpoint inhibitors). However other than mAb’s like Dara, Elo, and Isatuximab (not yet approved), CAR-T and checkpoint inhibitors are still in a very early stage of evaluation.

6. More on checkpoint inhibitors. Dr Don Benson (OSU) explained that MM suppresses the immune system from doing its job. Inhibitors of the KIR ligand and PD1/PDL1 pathways enable NK cells and T-cells respectively to do a better job of finding and destroying MM cells. The concern, however, is that normal cells also have these built in checkpoints and you wouldn’t want the immune system destroying these cells as well. One doctor even mentioned that these are still “scary”.

COMMENTS AND DISCUSSIONS I FOUND PROVOCATIVE

7. “For patients in a CR, half will be MRD- and half will be MRD+.” B. Durie (IMF)

8. “I always see SMM patients again 1 month after diagnosis. It’s more important to know the tempo of their disease than risk factors.” S. Lonial (Emory)

9. “I’m afraid that some might interpret MRD- as a cure, which is not true.” J. Mikhael (Mayo)

10. “Half of SMM patients have MGUS-like disease and half are more like MM. If we only knew which patients were which, we would know who to treat.” S. V. Rajkumar (Mayo)

11. “It’s becoming more difficult to select the best treatment option for R/R MM patients.” P. Moreau (France)

12. When discussing the management of ND HRMM pts, Dr A. Dispenzieri (Mayo) reminded attendees that “high risk” not only includes chromosome abnormalities but also fitness/frailty assessment and access/cost of treatment. Whether TE or nTE, these patients should consider Velcade-based induction and maintenance. TE pts should consider Tandem SCT. And for renal-impaired, Velcade triplet is more effective than a Velcade-doublet.

13. “Although CR and MRD- should be the goal, not all patients get there and this needs to be considered.” N. Raje (UMass)

14. “For relapsed patients, doctors must consider previous treatments and responses. R/R MM pts should consider including POM.” N. Raje (UMass)

15. “Every 5 years, folks ask if SCT is dead. But it isn’t…not yet”. P. McCarthy (Roswell-NY)

16. “Today we are curing a subset of patients. We just don’t know who they are.” S. Lonial (Emory)

SMOLDERING MM

17. n=270 in 2 trials demonstrated that multiparameter flow cytometry may represent a better way (actually a “biomarker”) to classify HR SMM. Specifically this test classified these patients as MGUS-like (17%), Intermediate between MGUS & MM (66%) and MM-like (18%). Then 2-yr median Time-to-Progression (TTP) to MM/risk % was shown to be “not reached”/4%, 57 mos/25%, and 16 mos/58% respectively. {Sun-373-B. Paiva}

18. n=34 Elo (weekly)-Rev-dex in High Risk SMM, where HR is based on cytogenetics t(4:14), t(14:16, 17p- or +1q amplification. ORR was 82% (including CR 9%) and thus far no pts have progressed to active MM during or after protocol therapy. {Mon-976-I. Ghobrial}

FRONTLINE THERAPY FOR TRANSPLANT INELIGIBLE (NTE) PATIENTS

19. Ph 3, n=1600 NDMM pts, final PFS & OS results of the FIRST trial were presented comparing Rd continuous vs Rd 18 mos vs MPT. 4-yr PFS % (33 vs 14 vs 14) and median OS mos (59 vs 62 vs 49) and other factors showed overall benefit for continuous Rd. {Sat-241-T. Facon }

TRANSPLANTS

20. Ph 3, n=1400 NDMM pts, EMN02/HO95 MM trial VCD (R1) VMP or SCT (R2) VRD consolidation or none followed by Rev maintenance till progression, examined the impact of consolidation, which benefitted std but not HR pts. Best news was that 3yr OS from R2 was 86% and 87% respectively.{Sat-242-P. Sonneveld}

21. Additional analysis was provided from the EMN02/HO95 MM trial shown above. Specifically, the SCT arm did show benefit over the VMP arm for all pts, e.g. ORR 86% vs 75% and 3yr PFS 65% vs 57%; for HR pts 3yr PFS was 52% vs 30%. So ultimately HR MM pts benefitted by SCT but not from consolidation (above). {Mon-673-M. Cavo}

22. Ph 3, n=581 Myeloma XI study investigated a response-adapted approach to induction. Specifically if pts achieved less than VGPR to induction (IMID regimen), they would be randomized to be given an additional regimen (PI based) before SCT. The consolidation side improved median PFS from 20 to 30 mos. For those having a transplant, the PFS was even better (31 mos versus 55 mos). However even Transplant Ineligible pts showed PFS benefit with consolidation of 14 vs 20 mos. {Sat-244-G. Jackson}

23. n=42, Ph 2. IxaRd –> SCT -> IxaRd -> Ixa maintenance for NDMM pts. Note this all-oral therapy (except for SCT). VGPR (CR) or better at the end of Induction, SCT and Consolidation were 36% (12%), 78% (38%), and 77% (44%) respectively. Adverse events were well-tolerated with no grade 3/4 neuropathy. If the future Dara may be added to this regimen. {Mon-674-P. Moreau}

24. n=76, Ph 2. KRdx4 -> SCT -> KRdx4 -> KRd maintenance (x10) -> Rev maintenance. Analysis were done after cycles 4, 8, and 18. At C18, ORR was 94% with a very high 86% in CR. [BTW, with no SCT for another group of 53 pts, C18 ORR/CR was 90%/40%.] MRD was done by both Flow and NGS. At C8 and C18 MRD- was 86%/64% and 97%/71% respectively by each method. For HRMM pts, ORR was 96% (81% CR) and C18 MRD- was 90%/63%. And 3yr PFS/OS was 86%/95%. When asked to compare this KRd regimen with the IxaRd regimen results above, the speaker said KRd speeds up response but has higher toxicity. {Mon-675-T. Zimmerman}

25. n = 46, KRdx4 -> SCT -> KRdx4 -> Rev maintenance (nearly the same as above) resulted in similar outcomes sCR = 57%, >= VGPR = 91%, MRD- = 70% with no neuropathy. {Mon-1142-G. Jackson}

26. n=111, Ph 2. KTdx4 -> SCT –> KTd x4 (T lowered from 200mg to 50mg). ORR after consolidation was 95% (CR=64%). Overall 3yr PFS and OS were 68% and 90% respectively. For HR pts, responses and OS were about the same while PFS was less. {Mon-1141-R. Wester}

27. n=750 pts were randomized into 3 arms. Arm 1, denote ACM, received one auto SCT, 4 cycles of RVD consolidation, then Rev maintenance until progression. Arm 2, denoted TAM, received a tandem (two) SCT’s and Rev maintenance until progression. Finally Arm 3, denoted AM, received a single auto SCT, then Rev maintenance until progression. After 38 months, the PFS (57%/56%/52%) and OS (86%/82%/63%) were comparable in all three groups. Furthermore, when looking at subgroups such as High Risk, there was no differences (all about 24% PFS and 75% OS). Even overall secondary primary cancers (SPMs) were all about 5%. {Tue-LBA-1-E. Stadtmauer}

TREATMENTS FOR RELAPSED/REFRACTORY (R/R) PATIENTS

28. MRD results were presented for the recent POLLUX (DaraRd vs Rd) and CASTOR (DaraVd vs Vd) trials, which resulted in FDA approval of using Dara with Rev or Vel. MRD- outcomes were typically about 3x in the Dara arms versus the non-Dara arms. Further, MRD- for Dara-Rd was about 2x compared with the Dara-Vd arm (25% vs 10% evaluated by NGS with 10-5 sensitivity). {Sat-246-H. Avet-loiseau}

29. Another update of the Pollux study (DRd vs Rd) for RRMM pts showed benefits in ORR (94% vs 77%), 18 mos PFS (77% vs 50%), and MRD- (25% vs 6%). ORR for HRMM was 89% vs 67%. {Sun-489-P. Moreau}

30. n=41 RRMM pts on Dara-Pom-dex trial also examined “retreatment” with Dara. ORR 89% for Dara & Pom naïve but nearly 35% ORR for pts refractory to both Dara and Pom {Sun-492-A. Nooka}

TARGETED THERAPY

31. Ph 3, n-432. Tourmaline-MM1 study Ixa-Rd vx Rd for RR MM pts that resulted in Ixazomib approval Nov 2015. This sub-analysis examined patient expression level of c-MYC (proto-oncogene regulation cell proliferation & cell death. High c-MYC expression pts showed a 6 month PFS benefit on the Ixa-Rd over Rd. {Sat- 243-A. Di Bacco}

NEW DRUGS

32. n=34 Nelfinavir is an approved, generic oral drug, and HIV protease inhibitor used to treat AIDS. When combined with Vel-dex (NVd) for Vel-refractory ASH16pts (and 76% were also Rev-refractory), ORR = 65% include 5 pts achieving VGPR. {Sun-487-C. Driessen}

33. n=66 (inc 30 pts had t(11;14) MM. Ph 1. Venetoclax, BCL-2 inhibitor, single agent for RRMM showed 21% ORR but 40% ORR for t(11;14) pts (88% if also high BCL-2 expression). {Sun-488-S. Kumar}

34. n=65 Venetoclax + Vel-d for RRMM pts. Overall ORR 67% with best responses ORR=97% for Vel non-refractor and 1-3 prior tx lines. Worst ORR for >6 tx lines (20%) or Velcade-refractory (31%). Likely Ph 3 to be Ven-Vd vs Vd. Higher BCL-2 expression means better ORR. {Mon-975-P. Moreau}

35. n=45, Ph 2 Pembrolizumab (checkpoint inhibitor Keytruda) + Pom-dex for RRMM, all refractory to Rev, 73% double refractory. ORR 65% (inc 27% >= VGPR and median PFS 17 mos. However ASE’s included 40% grade 3 neutropenic and . pts required dose reduction. {Sun-490-A. Badros}

36. n=79 including 48 quad (Rev-Vel-Pom-Cfz) and 31 penta (quad + Dara) refractory. Selinexor (80 mg 2x/wk) (oral XPO1 inhibitor) and dex (20 mg 2x/wk) regimen (Sd) goes by the name STORM study. ORR was about 20% for both quad and penta but also had grade 3/4 hematological events. Median OS was 9.3 mos. {Sun-491-D. Vogl}

37. n=12, Phase 1 study of Selinexor-Cfz-d in RRMM pts. These 12 pts were also refractory to Cfz. ORR for this group was 67% (15% >= VGPR) with 3.7 mos PFS. {Mon-973-A. Jakubowiak}

38. n=22, Ph 1b/2 study of Selinexor (100 mg/wk)-Vel-d (SdB) for RR MM pts, including those refractory to Vel (STOMP trial). Overall ORR=77% (inc 9% CR, 18% VGPR). For Vel-refractory, ORR=67%, while Vel-exposed/naïve had 100% ORR. {Mon-977-N. Bahlis}

39. n=12, Pilot Study of CAR-T CD19 in conjunction with salvage (2nd) SCT for advanced MM. Method: 2 weeks after the SCT, 5 x 107 CAR-T cells are infused. Of these 12 pts, 3 pts had a VGPR and longer PFS than from their first SCT. One patient (featured on the cover of Parade Magazine several months ago) had a 16 mos PFS but then relapsed and is now in a 12-mos CR with Dara. Only one episode of cytokine release for these 12 pts. {Mon-974-A. Garfall}

OTHER RESULTS

40. n=113 For Light Chain MM patients who follow their disease with 24-hr urine analysis (UPEP), the Serum Free Light Chain test offered better correlation with clinical outcomes (e.g. PFS) than urine assessments….and is certainly easier on these patients. {Sun-376-T. Dejoie}

41. There were several presentations on racial disparities. These included {Mon-844-M. Fiala}and {Mon-846-A. Rosenberg}that examined the usage of SCT’s by African American MM pts. The first concluded that when elimininating health disparities and postential access barriers, black pts are will 37% less likely to utilize an SCT. The second focus was on California patients but came up with a similar number 30%. This poster {Sun-3544-S. Ailawadhi}examinedMM complications (CRAB symptoms) among different racial groups with blacks having the highest rate of complications, perhaps being due to reduced access to drugs/supplemental insurance coverage.

42. An interesting study for Myeloma Cast Nephropathy (kidney impairment) comparing Haemodialysis with High Cut-off vs Standard High Flux Dialyzer in pts receiving Velcade-based therapies. With Haemodialysis, 1/2 the pts became dialysis-free versus only 1/3 in the Standard control group. {Mon-978-JP Fermand}

43. n=41 This trial study the efficacy and side effects from administration of Daratumumab via sub-Q injection in R/R MM pts. For pts on the recommended dose of 1800mg given over 30 minutes, the ORR was 41% and Infusion Reaction Rates were lower than with Dara IV infusion. And when asked about pain or bruising at the infusion site, Dr Usmani said that neither were problems. This has the potential to reduce infusion times from six or eight hours to 30 minutes. {Mon-1149-S. Usmani}

SUMMARY

For someone diagnosed with stage III MM 22 years ago with only 2 treatment options available (MP or VAD-SCT) and given 2-3 years expected survival, I’ve seen incredible progress since 2003 when Velcade was first approved. While there continues to be unanswered questions, we now have many more effective treatments for MM, providing patients with better opportunities to manage their disease.

GLOSSARY (according to Jack) Drug (brand names) by Drug Class/Category

IMID – Immunomodulary Drug

T – Thalidomide

R – (Lenalidomide) Revlimid

Pom – Pomalidomide (Pomalyst)

PI – Proteasome Inhibitor

V- Velcade (Bortezomib)

Cfz – Carfilzomib (Kyprolis)

I, Ixa – Ixazomib (Ninlaro)

mAb – Monocloncal Antibody

D, Dara – Daratumumab (Darzalex)

E, Elo – Elotuzumab (Empliciti)

Isa – Isatuximab (SAR650984)

HDAC – histone deacetylase inhibitors

Pano – Panobinostat (Farydak)

Steroids

P – Prednisone

D or d – Dexamethasone

Chemotherapy Drugs

C – Cyclophosphamide (Cytoxan)

M – Melphalan

Treatment Measurements

EFS – Event-free Survival

ORR – Overall response (>=PR)

OS – Overall Survival

PD – Progressive Disease

PFS – Progression-free Survival

PFS2 – PFS + next-line treatment PFS

TTP – Time to Progression

TTR – Time to Respond

Treatment Response

CR – Complete Response: No sign of MM (0 M-spike)

nCR – Near CR (positive M-spike, may be same as VGPR)

MR – Marginal Response: 0-50% reduction in MM

PR- Partial Response: 50% reduction in MM

SD – Stable Disease i.e. no response but also not worse

sCR-Stringent CR: CR+ normal FLC & no clonal cells

VGPR – 90% reduction in MM

MRD – Minimum Residual Disease typically by Flow Cytometry (NGF) or DNA sequencing (NGS) to provide more accurate measure of MM.

Side Effects

AE (ASE) – Adverse Event (Adverse Side Effects)

DVT – Deep Vein Thrombosis (blood clots)

MTD – Maximum Tolerated Dose

ONJ – Osteonecrosis of the Jaw

PE – Pulmonary Embolism

PN – Peripheral Neuropathy

QOL – Quality Of Life

VTE – Venous Thromboembolism (PE + DVT)

Tests/When to treat?

CRAB – High Calcium, Renal, Anemia, and Bone…

CRABi – CRAB + “i” increased infections

FLC – Free Light Chain

SCT – Auto stem cell transplant.

TE, NTE – Transplant Eligible of Not TE

“d” and “D” – Typically both mean Low-dose Dex (40 mg/week) these days

MGUS – Monoclonal Gammopathy of Undetermined Significance

SMM – Smoldering MM

Pt(s) – Patient(s)

n – Number of pts

R/R- Relapsed/Refractory, Ref defined progressing while on Tx or within 60 days.

HR – High Risk

Myeloma Highlights from #ASH15

According to Jack Aiello (definitely not medically trained)

PREFACE

This is my 10th year attending ASH (American Society of Hematology), where 25,000 attendees from all over the world (hematologists/oncologists, lab researchers, oncology nurses, scientists & 300 pharma companies) present the latest research results via both oral presentations (1,000) as well as posters (3,000) on all blood cancers. This year there were nearly 800 abstracts (>100 clinical) on Myeloma alone, many of which were selected for oral presentation. I’m grateful to the IMF (www.myeloma.org) and their pharma donors for sending me to ASH so that I can learn and share my patient perspective with you.

Rather than attending talks on Biology, I typically focus on the Clinical Trials, which I’m able to understand and are more relevant near-term to patients. Even at that, there are overlapping MM oral sessions as well as 4’x6’ posters without reprints, so it’s always possible that I have not included something of interest to you or made a typo because I can’t read my own writing as detailed powerpoint slides are presented quickly. You might want to view the published abstracts at www.hematology.org and various press releases. [Wherever possible, I’ve listed Day-Abstract#-Lead Investigator after the trial results, e.g. {Sat-25-B. Durie} and clicking on the abstract number will take you to the actual abstract.]

There are other ways to learn more about results from this conference. There are scheduled webinars (IMF 1/7/15, MMRF 1/13/15) which you can listen to live or by replay. You’ll also find some patient blogs (including mine) as well as MM expert video interviews posted on the IMF website (www.myelomal.org) and Patient Power (www.patientpower.info) among others. And all of us in the SF Bay Area should attend the LLS Blood Cancer Conference (which includes updates from ASH) Jan 23, 2016 (Register Now). Dr. Jeff Wolf of UCSF will do a great job presenting the latest information.

Presentations and posters of clinical trial results follow the same format: Background (including hypothesis), Study Objective, Design & Treatment schema, Patient Characteristics & Cohorts, Responses (include high-risk cytogenetics), Toxicity (hematological and non-hematological), Conclusion, and Next Step. Remember, the goal of Phase I (typically handful of patients) is to determine “Maximum Tolerated Dose”; Phase I/II and II (typically 25-75 pts) continues to measure dosage escalation and safety while looking at responses; and finally Phase III (several hundred patients) compares response rates between new and current treatments.

Treatment schedules are defined for stages of Induction, and optionally Transplant, Consolidation, and Maintenance with specified Randomization along the way; dosage amounts and scheduling are provided for each drug along with optimum number of treatment cycles (typically 28 days). Risk stratification correlates various techniques such cytogentics-FISH analysis (e.g. chromosome deletions and translocations) and gene-expression profiling (GEP).

 

HIGHLIGHTS (e.g. My Takeaways)

  • In the large French/US study comparing early versus late SCT, the French showed a PFS benefit but not three-yr OS benefit (both arms about 83%), maybe because trial results are not mature. However, the French part of the study only uses one year of maintenance, whereas the US uses maintenance until progression.  The US has yet to report data so will maintenance make a difference to the outcome?  We’ll see.
  • For relapsed patients, treatment isn’t as clear cut but with the recent approvals of Darzalex (Daratumumab), Ninlaro (Ixazomib), and Empliciti (Elotuzumab), patients have more options as they combine each of these with the baseline Rev-dex. How clinicians will use or “sequence” Dara-Rd, Ixa-Rd, and Elo-Rd will likely be better understood over the next one to two years, making it even more beneficial for patients to have a Myeloma expert as part of their treatment team.
  • The Ultra High Risk (plasma% > 60%, FLC ratio > 100, >1 focal lesions) Smoldering multiple myeloma patients (SMM) have already been re-classified as MM pts, even without CRAB criteria. Other SMM pts that have some indication of high-risk features (e.g. perhaps plasma% > 10% and one of FLC ratio > 8 or cytogenetics such as del17p) should investigate participation in a clinical trial such as E3A06 to determine the efficacy of early treatment.
  • Three-drug VRd therapy for newly diagnosed patients has been shown to have longer progression free survival (PFS) and overall survival (OS) than two drugs and should be considered the standard of care. Mayo’s M-SMART (msmart.org) treatment protocol recommendation for newly diagnosed standard and intermediate risk patients has been updated from Rd to VRd (still KRd for high-risk).
  • Minimum Residual Disease (MRD) testing is not ready for prime time, but it has good prognostic value for MM patients, similar to CR being a good prognostic indicator. MRD still needs to be consistently defined using NGS or Flow (8-color/2 tubes). Trade-offs include NGS needs diagnostic sample and has higher cost while Flow needs “fresh” samples. And more trials need to integrate MRD so that clinicians can eventually use MRD results to help guide future treatment plans.  And probably, MRD needs to be combined with PET-CT to get the complete picture.
  • You’ll see reports below that look at survival outcomes such as Progression Free Survival (PFS) and Overall Survival (OS). However, with new treatments available, OS (i.e. death) become less meaningful for a particular drug. Perhaps the assessment of targeted biomarkers will become better measurements of drug efficacy.

 

COMMENTS AND DISCUSSIONS I FOUND PROVOCATIVE

  • We are still trying to determine the role of maintenance. There have been or are currently 242 clinical trials involving maintenance (including “consolidation and “continuous therapy”). Even vaccines (e.g. dendritic cells) are being tested as maintenance. T. Facon (France)
  • Re Using Emerging Therapies up front: “Adding later does not add up.” S. Kumar (Mayo)
  • Re Early Treatment: “In most cancers (lung, breast), early diagnosis and treatment is a prerequisite to OS improvement. When we wait, clones have a chance to develop more aggressive subclones. But we must work to develop predictive biomarkers.” J. San-Miguel (Spain). However, “Should you over-treat 30% of HRSMM pts at the risk of under-treating 70%? What about toxicity? You need more evidence-based medicine.” P. Moreau (France)
  • Flow (NGF) & NGS measure myeloma inside the bone marrow while PET-CT measures myeloma outside the bone marrow. A. Orfao (Spain)
  • I attended an FDA presentation where each FDA MD reviewed their criteria for approving Ixazomib, Daratumumab, and Elotuzumab respectively, citing the specific trial as well as primary and secondary endpoint results. Then Drs. S. V. Rajkumar (Mayo) and P. Richardson (Dana Farber) discussed using these new drugs as front-line and relapsed therapies respectively. Dr. Rajkumar began “Myeloma treatment is moving so fast, the Education Session I gave 2 days ago is already out of date.” To use these drugs front-line, they would be need to be “off-label” and it’s better to use them within a clinical trial for newly diagnosed pts. Dr. Richardson explained the Rd is the “backbone” and we can add V, K, I, D, and E (and SAR in the future?). We’ll understand more about sequencing these combinations in the next 1-2 yrs.

    Convention Hall

    Convention Hall

 

SMOLDERING MM

  • “If it’s smoldering, is there a fire?” S. Lonial (Emory) and “Some pts with SMM really have MGUS and others MM…we just don’t know which ones.” S. V. Rajkumar (Mayo)

 

FRONTLINE THERAPY FOR TRANSPLANT ELIGIBLE PATIENTS

  • Ph 1/2, n=48 NDMM pts, including 30% HR, Panobinostat (10mg) + RVd. ORR after 4 cycles was 94% (CR/nCR 46%…compared with past trials RVd-only CR is 10-20%) and 14 of 26 pts were MRD- before their SCT. ASE Grade 3 nausea 6% and PN 4%. {Sun-187-J. Shah}
  • Ph 3, n=525 NDMM pts, VRd vs Rd. Overall Response Rate ORR (82% versus 72%), CR (16% versus 8%) Progression Free Survival PFS (43 versus 30 mos) and Median Overall Survival OS (75 versus 64 mos) all showed the benefits of triplet therapy over doublet. {Sat-25-B. Durie}
  • Ph 3, n>2000 NDMM pts comparing KCRd with CRd (and CTd). It showed the 4-drug regimen that added Carfilzomib resulted in higher >= VGPR (82% vs 62% vs 55%) and that KCRd had lower (!) hematological suppression than CRd (9% vs 16%). {Sun-189-C Pawlyn, UK}

 

FRONTLINE THERAPY FOR TRANSPLANT INELIGIBLE PATIENTS

  • {FIRST subgroup analysis} n=142 High Risk [del 17p, t(4;14) or t14;16)] NDMM pts randomized to 3 arms: Rd till progression vs Rd 18 cycles vs MPT 12 cycles. In non HR pts, median PFS was 31 mos vs 21 mos vs 25 mos while HR pts were 8/18/15 mos. In non HR, 3yr OS % was 77% vs 71% vs 65% while HR pts were 41/40/47%. So while Rd till progression was the winner overall in the FIRST trial, it did not do so well comparably in High-Risk pts. {Mon-730-H. Avet-Loiseau}
  • Ph 2, n=70 NDMM pts, Ixazomib-Cytoxin-Dex (ICd) randomized to C = 300 or 400 mg all oral therapy. Plus Ixa maintenance. Early ORR results better in C=300 arm (78% vs 75%) and >=VGPR (28% vs 21%). PFS @ 9 mos was 90% but data not yet mature. {Sat-26-M. Dimopoulus}
  • Ph 2, n=40 NDMM pts, “RVd-lite” study Rev = 15mg, days 1-21; Vel = 1.3 mg/m2 once/week; dex = 40 mg/wk for pts <75yo and 20 mg /wk otherwise. After 4 cycles, ORR was 90% (including CR 25%), 2 yr PFS is 68%. {Mon poster-4217-E. O’Donnell}

 

TRANSPLANTS

  • Ph 3, n=389 NDMM pts, SCT vs Cytoxin-Rd followed by RP vs P maintenance. SCT showed improvement in median PFS (43 vs 29 mos) and 4-yr OS (86% vs 73%) Median PFS from the start of maintenance was 38 mos for RP vs 29 mos for R-only but 3-yr OS was similar (83% vs 88%). Of note, at the start of maintenance, MRD- was 48% for the SCT arm vs 28% for CRd, even though CR and VGPR numbers were very close. {Sun-392-F. Gay, Italy}
  • Ph 3, n=700 70 NDMM pts, “Determination” RVd +/- SCT + RVd consolidation + R maintenance. The French side of this study showed benefits in the SCT arm for ORR (88% vs 78%), CR (59% vs 49%), 4-yr PFS (47% vs 35%), and MRD- (80% vs 65%) but no OS difference (83%), which could be due to the short timeframe as well as early crossover to the SCT arm. {Sun-391-M. Attal}
  • Ph 3, n=174 (of 297 enrolled) prior SCT pts. Salvage SCT was defined as a 2nd SCT after relapse > 18 mos from prior SCT. All pts were re-induced with Velcade-Doxorubicin-Dex (PAD) and randomized to either 2nd SCT vs 12 wks Cytoxin with crossover. ORR to re-induction was 79%. 4yr OS was 69% (2nd SCT) vs 61% (crossed over to 2nd SCT) vs 50% (no 2nd SCT), so beneficial to have salvage SCT sooner. {Sun-394-G. Cook, UK}

 

TREATMENTS FOR RELAPSED/REFRACTORY (R/R) PATIENTS

  • {ASPIRE subgroup Analysis} Ph 3, n=100 HR RRMM pts. KRd vs Rd, where High Risk is one of del 17p (>60% of plasma cells), t(4;14) or t(14;16). Median PFS for HR was 23 mos vs 14 mos (compared with std risk 30 mos vs 20 mos). ORR from HR was 79% vs 60% (compared with std risk 91% vs 74%). {Mon-731-H. Avet-Loiseau}
  • {Endeavor subgroup analysis}Ph 3, n=465 RRMM , Kd vs Vd outcomes for 1 and 2+ prior lines of therapy. Median PFS: 1 line 22 vs 10 mos; 2+ lines 15 vs 8 mos. ORR: 1 line 82% vs 66%; 2+ lines 72% vs 60%. This presentation concluded that Kd should be considered in pts who have progressed on Rev maintenance. {Mon-729-P. Moreau}
  • {Eloquent-2} Ph 3, n=646 RRMM pts, Elotuzumab +/- Rd. Elo-Rd showed PFS benefit 4.5 mos (19.4 vs 14.9) with very similar Adverse Events except infusion reaction in 10% pts (of which 63% were in the first infusion). {Sat-28-P. Richardson}
  • Ph 1b, n=98 RRMM pts with at least 2 lines of prior therapy. Dara + Pom-d. 67% of pts refractory for both IMI and PI but Pom-naïve. ORR 71% (nearly same for double-refractory) including 9% CR. PFS @ 6 mos is 66%. ASE’s similar to Pom-d alone other than half of pts had IRR (Infusion Rate Reaction) during the first infusion but only 3% at 2nd {Mon-508-A. Chari}
  • Combination of two Ph 2 trials, n=148 pts, double-refractory to a PI & IMID. Daratumumab alone (!). Dosage 16mg/kg. ORR= 31%; median PFS was 7.4 mos; 1 yr OS 69%. For pts who responded, the OS results were even better: OS for MR/SD pts = 17.5 mos, and not reached for >=PR. 10-18% of pts experienced some hematological ASE’s. {Sat-29-S. Usmani}
  • Ph 2, n=32 RRMM pts. Daratumumab (16mg/kg) + Rd. ORR 81% (compared with Rd ORR 61-66% for similar pts); 63% >= VGPR. PFS @ 12 mos 91% (compared with Rd median PFS 11-15 mos for similar pts) and PFS@18 mos 72%. OS@18 mos 90%. ASE’s similar to Rd-alone other than some infusion reaction, usually only with the first infusion. {Mon-507-T. Plesner, Denmark} Note: Dr. Torben Plesner was the first doctor to treat an MM pt with Dara in 2007.
  • Ph 2, n=152 RRMM pts, 50% prior Velcade treatment, 1-3 prior therapies. Elotuzumab (10 mg/kg) +/- Vd. Benefits in >= VGPR (36% vs 27%), median PFS (10 mos vs 7 mos) while ORR about the same (65% vs 63%). Grade 3/4 AE higher in EVd (71%) than Vd (60%), most of this difference being infections (23% vs 15%). {Mon-510-A. Palumbo}
  • {Endeavor subgroup analysis}Ph 3, n=210 RRMM high-risk pts, Kd vs Vd. PFS benefit ~3 mos (8.8 vs 6 mos); ORR 72% vs 58% (CR 16% vs 4%). 1-2% (3% vs 1%) experience more cardiac issues in the Kd arm. {Sat-30-S. Usmani}
  • {Tourmaline-MM1} Ph 3, n=722 RRMM pts, Ixazomib (4mg days 1, 6, 15) +/- Rd (IRd vs Rd). Note that 70% pts previously had Velcade but were not refractory to Rev or PI. Benefits seen in ORR (78% vs 72%, including CR 12% vs 7% and VGPR 36% vs 32%) and Median PFS (20.6 vs 14.7 mos, including del17 21 mos vs 10 mos). OS data not presented due to lack of maturity. {Mon-727-P. Moreau}
  • A pooled analysis of 3 trials example the usage of Pom-dex in 355 pts with moderate kidney involvement (versus 713 pts with no renal impairment. Similar ORR (30% vs 34%), median PFS (4 mos vs 5 mos) and median OS (11 mos vs 14 mos) as well as Grade 3/4 AEs. {Sun poster-3031-D. Siegel}

 

MAINTENANCE (including CONSOLIDATION)

  • Ph 3, n=1964 pooled analysis examined CR patients who received maintenance or not, and determined a significant 5-yr OS benefit (80% vs 54%) and 5-yr PFS benefit (52% vs 19%) for pts on maintenance. {Sat poster-1974-C. Cerrato}

 

NEW DRUGS

  • Ph 2, n=68 RRMM pts. Carfilzomib +/- Filanesib (ARRY-520), a kinesin spindle protein (KSP) inhibitor. Adding FIL show some benefit: ORR 28% vs 24% and median PFS 9 mos vs 4 mos. {Mon-728-J. Zonder}
  • {Keynote-023} Ph 1, n=17 R/R pts, including 50% refractory to Rev. Pembrolizumab (anti PD-l Antibody) + Rd. Pembro dose confirmed at 200mg. ORR 76% (including 56% for pts Rev-refractory), with 4 of 17 pts VGPR (24%). {Mon-505-J.San Miguel}
  • Ph 2, n=27 RRMM pts, 36% HR, 90% Rev-refractory, 70% refractory to both IMID and PI. Pembrolizumab (anti PD-l Antibody) + Pom-d. ORR 60% (including 55% for double-refractory and 50% HR). Gr3 AEs 10-20% pneumonia/infection. {Mon-506-A. Badros}
  • Selinexor (KPT-330), which enhances the natural cell defenses against cancer, was combined with PI’s Velcade or Carfilzomib and shown to potentially overcome drug resistance {Sunday poster-3048-D. Sullivan}. And when combined with Cfz-dex in a Ph 1 trial for RRMM pts including those refractory to Cfz, >= PR was 75%, although results are still early. {Mon poster-4223-A. Jakubowiak}

ASH 2015

OTHER RESULTS

  • A presentation on Social Media for Hematologists was titled “So You Know How to Treat, But Do You Know How to Tweet?” and discussed the increased usage of Twitter during ASH15 from more than 5K participants, including a number of support group leaders (SGL) in attendance. For a summary of all the SGL tweets, use the hashtag #IMFASH15.
  • I attended a meeting conducted by Takeda on the usage of their new oral PI Ixazomib (Ninlaro). It’s indicated for pts who have had 1 prior treatment and used with Rev-d. It needs to be taken on an empty stomach (1 hr before or 2 hrs after a meal) in order to ensure efficacy. And while the standard dosage is a 4mg capsule, it also comes in 3 mg and 2.3 mg capsules. The name Ninlaro? While in development, the drug was called MLN9708. So Ninlaro comes from Nine (minus the “e”) plus “oral” spelled backwards.
  • I attended a session on Patient-Reported Outcomes (PRO’s) which examine Physical, Mental and Social Health in clinical trials and patient care. PRO data is used by Prescribers, Regulators, and Healthcare Payers. You can learn more about this at healthmeasures.net and www.nihpromis.org.
  • This study examined n=693 SCT pts who had various induction therapies RVd, Rd, Vd, and CVd, specifically at pre-SCT and post-SCT >= VGPR results. Pre-SCT responses were 57%/42%/51%/45% and post-SCT were 65%/63%/65%/58%, all quite close. However, maintenance treatment improved 3-yr PFS to 55% vs 39% for no maintenance. In conclusion, when having an SCT, the choice of induction treatment is less important than maintenance {Sun-396-R. Cornell}
  • MRD was evaluated in the French side of the IFM/DCFI 2009 “Determination” trial. Of n=700 pts, 178 pts were evaluated by NGS after maintenance. For CR pts, 83% were MRD- but 17% were MRD+. {Sat-191-H. Avet-Loiseau}
  • CAR-T therapy for myeloma treatment resulted in several oral presentations. In pre-clinical models, SLAMF7-CAR-T cell therapy was shown to be safe and effective in MM treatment. {Sat-115-S. Danhof}. And a company called Cellectis in France showed that they can use healthy donor T-cells and engineer them for a double KO (both TRAC and SLAMF7) to enhance antitumor activity. {Sat-116-R. Galetto}. And a “Late-Breaking Abstract” highlighted a Ph 1 study of 12 RRMM pts using CAR-T cells engineered as anti-BCMA CARs (CAR-BCMA). The B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells in 60-70% of MM pts. To participate in this NCI trial, pts must have had 3 lines of prior therapy and BCMA expression. Pts were given 3 days of Cytoxin and fludarabine beforehand, but no transplant. All 12 pts achieved at least stable disease (SD) with 1 sCR, 1 VGPR, and 2PR’s, typically better results as dosages increased. Pts incurred substantial toxicity (fever, kidney, cytokine release, and more but these AE’s were all reversible. Still, a follow-up trial eligibility criteria will include pts have less that 50% plasma cells. {Tue-LBA-1-J. Kochenderfer}
  • MRI & PET-CT were evaluated in the French side of the IFM/DCFI 2009 “Determination” trial. At diagnosis for n=134 pts, MRI and PET-CT were positive for 95% and 91% of pts. After 3 cycles of RVd, MRI was still positive in 93% but PET-CT in only 55% and was a better prognostic indicator for PFS but not OS. Before maintenance, MRI was not a good prognostic indicator for PFS or OS but PET-CT results were associated with significant improvement in both PFS and OS. As such, an MRI may not be needed for follow-up, while PET-CT should be part of follow-up. {Sun-395-H. P. Moreau}
  • Ph 2, n=100 pts, 25 per arm. Isatuximimab (SAR650984) single agent at different dose/frequencies: Arm 1: 3mg/kg every other week (q2w); Arm 2: 10mg/kg q2w for 4 doses, then q4w; Arm 3: 10mg/kg q2w; Arm 4: 20mg/kg qw x 4 dose then q2w. ORR: 9%, 20%, 29%, 24%. Gr 3 anemia in 20% of pts. {Mon-509-T. Martin}
  • A Medicare cost study was done for 3000 MM pts that assessed the economic burden for both MM treatment costs and pharmacy antiMM cost PPPM (cost per-patient per-month) for treatment lines First ($14K, $3K). Second ($16K, $3K), and Third ($16K, $3K) in 2015 dollars. Average treatment duration was 8, 6, and 5 mos respectively. {Sat poster-2100-C. Chen}
  • A study examined Cytogenetic (CG) Progression for 130 pts over the course of their disease, taking bone marrow samples and looking for risk factors such as del 17p, t(14;16), t(14;20), t(4;14), del 13 and gain 1q21. 90 (69%) of 130 pts had normal CG at diagnosis but 27% of these pts developed abnormal CG during disease course, resulting in shorter median OS (4 yrs) versus pts with normal CG (11.3 yrs) or even pts with any CG abnormality at diagnosis (7.4 yrs). Bone marrow biopsies/aspirates are important during the course of treatment. {Mon poster-4209-C. Pascal}
  • Palliative Care is a multidisciplinary approach to symptom management, psychosocial support, and assistance in treatment decision-making for both patients with serious illness and their families. Unlike Hospice, PC does not require either a terminal diagnosis or proximity to death.

In the US there are >6500 board-certified palliative medicine physicians and >18,000 certified non-physician palliative care professionals who work together with a patient’s other doctors to provide an extra layer of support. PC in the setting of SCT should be considered from the day of diagnosis and tied to need, not to prognosis. How do we balance the trade off in which life may be prolonged and cancer cured, but quality of life is poor? PC has particular relevance in oncology given recent studies which link PC to improved patient QOL, improved survival, and decreased cost of care.

 

SUMMARY

For someone diagnosed with stage III MM 21 years ago with only 2 treatment options available (MP or VAD-SCT) and given 2-3 years expected survival, I’ve seen incredible progress since 2000, and especially this past year 2015. While there continue to be unanswered questions, we now have many more effective treatments for MM, providing patients with better opportunities to manage their disease.

GLOSSARY (according to Jack)

Drug Class/Category

IMID – Immunomodulary Drug

PI – Proteasome Inhibitor

mAb – Monocloncal Antibody

Drugs (Brand Name)

C – Cyclophosphamide (Cytoxan)

Cfz – Carfilzomib (Kyprolis)

D – Daratumumab (Darzalex)

E – Elotuzumab (Empliciti)

I – Ixazomib (Ninlaro)

M – Melphalan

P – Prednisone

Pano – Panobinostat (Farydak)

Pom – Pomalidomide (Pomalyst)

R – (Lenalidomide) Revlimid

S – Isatuximab (SAR650984)

T – Thalidomide

V- Velcade (Bortezomib)

Treatment Success Measurements

EFS – Event-free Survival

ORR – Overall response (>=PR)

OS – Overall Survival

PD – Progressive Disease

PFS – Progression-free Survival

PFS2 – PFS + next-line treatment PFS

TTP – Time to Progression

TTR – Time to Respond

Treatment Response

CR – Complete Response: No sign of MM (0 M-spike)

nCR – Near CR (positive M-spike, may be same as VGPR)

MR – Marginal Response: 0-50% reduction in MM

PR- Partial Response: 50% reduction in MM

SD – Stable Disease i.e. no response but also not worse

sCR-Stringent CR: CR+ normal FLC & no clonal cells

VGPR – 90% reduction in MM

MRD – Minimum Residual Disease typically by Flow Cytometry (NGF) or DNA sequencing (NGS) to provide more accurate measure of MM.

Side Effects

AE (ASE) – Adverse Event (Adverse Side Effects)

DVT – Deep Vein Thrombosis (blood clots)

MTD – Maximum Tolerated Dose

ONJ – Osteonecrosis of the Jaw

PE – Pulmonary Embolism

PN – Peripheral Neuropathy

QOL – Quality Of Life

VTE – Venous Thromboembolism (PE + DVT)

Tests/When to treat?

CRAB – High Calcium, Renal, Anemia, and Bone…

CRABi – CRAB + “i” increased infections

FLC – Free Light Chain

SCT – Auto stem cell transplant.

“d” and “D” – Typically both mean Low-dose Dex (40 mg/week) these days

MGUS – Monoclonal Gammopathy of Undetermined Significance

SMM – Smoldering MM

Pt(s) – Patient(s)

R/R- Relapsed/Refractory Ref defined progressing while on Tx or within 60 days.

 

 

Events

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Please check back soon as we work to build more resources.