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Unmet Needs and Final Thoughts on Myeloma

Insights From: Ajai Chari, MD, Icahn School of Medicine at Mount Sinai; Andrzej Jakubowiak, MD, PhD, University of Chicago; Sagar Lonial, MD, Winship Cancer Institute of Emory University
Published: Wednesday, Jan 30, 2019



Transcript: 

Ajai Chari, MD: The remaining unmet medical needs in relapsed/refractory myeloma, and I would broaden it to all of myeloma, are really 3. First, being elderly/frail. We know that these patients still do worse. When you look at their overall survival OS curves, the number, the curve is not flat from the very beginning. Secondly, renal dysfunction. Patients with renal dysfunction still have, in many studies, inferior overall survival. And the third are high-risk patients.

Those are the 3 groups of patients that are bringing down the median overall survival for myeloma. So if we can improve their outcomes, the median OS of this cancer will get even better
Sagar Lonial, MD: As we see all these new drugs emerging on the horizon, I think a big question comes up about what are the continuing unmet needs for many of these patients. And I think that a lot of that is beginning to be segmented. We know, for instance, that patients with standard-risk disease can do quite well. And, again, in our series, 70% of them are alive at 10 years.

And so the question becomes, where do we need additional input? I think that patients with plasma cell leukemia, or extramedullary disease, continue to remain a challenge at the time of diagnosis. Patients with early relapse, meaning relapse within a year of transplantation, those continue to remain a challenge for us to manage. And patients with other high-risk genetics continue to remain a challenge for us for where they don’t have that 70% 10-year survival, and so optimizing ways to manage them, utilizing our agents in the most rational way to try and get them to MRD [minimal residual disease]–negativity, all of those remain unmet medical needs in myeloma.

Andrzej Jakubowiak, MD, PhD: There are still very significant unmet needs for treatment of myeloma, especially in relapsed/refractory disease. So we are in a continuous race and search to not be put in a position and we come to the patient’s room and we have to tell the patient that we have exhausted all the possible regimens and drugs, and we, at the moment, have nothing to offer. This is a terrible moment for not only the patient, but also for those who treat. These are most difficult moments for me as a treating physician, and I would rather not have them. That’s why I’m so heavily involved in trying to develop new drugs and regimens.

Now that is the unmet need, which we have in our hand. We have more and more patients who are quadrefractory for both most active drugs in a given class: proteasome inhibitor, and IMiD [immunomodulatory imide drugs], and pentra, which will be with antibody, also refractory. And this is a population, which I mentioned earlier is eventually allowing selinexor to be potentially considered as the next approved drug, because this drug works in this group of patients. This is clearly an unmet need.

In my opinion, another very important unmet need is to try to selectively treat patients with certain abnormalities or risk factors—genetic risk factors. We have tools, and we can potentially implement them and use them more effectively if we are using our knowledge about the biology of the disease and about the drug and potentially matching those two.

So this is an unmet need. We need more research. And that the research is in progress or is about to start. For example, my drug initiative from the Multiple Myeloma Research Consortium [MMRC], which be testing some new class of drugs in combination with existing triplet, which will be testing possibility of reversing difficult consideration for patients with certain mutations or abnormalities. I think a very important unmet need is to achieve more durable response in patients who are relapsing multiple times. Some of the regimens we discussed earlier achieved responses, but were too short to eventually help a patient to the level of his or her expectations, as well as meeting physician expectations—forgetting that the breadth of good response of extended months or years. These are definitely areas where we are potentially needing to move very quickly. And I think new are moving quickly, particularly with new modalities in the broad group of immunotherapy, especially CAR Ts.

My discussion about how to treat the patients is, has been emerging, but for some time, optimism that not only that we are doing better, but that we are potentially having opportunity, and, potentially in the near very foreseeable future—in next 2 or 3, maybe even less years—that we can have strategies, which can cure the proportion of patients with ability to say that we cured. At the moment, we presumed that we cured some patients who are 10 or more years in remission and have not required treatment for many years to come.

We worry that some of them may be relapsing later on. But at that fraction of patients who are achieving that durability of responses is where my optimism is based. I think that some of the best strategies bring proportion of these in longstanding remission to such a high proportion that I can really be sharing that enthusiasm with you.

Sixty percent to 70% of patients achieving with some strategies complete response and MRD negativity, which is predicting—in fact, showing longer remission and survival—is truly a fantastic achievement.

Ajai Chari, MD: What I’m excited about seeing in myeloma are more personalization. I think we treat this disease as 1 entity, and that’s because under the microscope, it looks like 1 entity. But we know that they’re not; these patients are not all the same. And we need to go towards a lymphoma-type of paradigm where we treat low-grade lymphomas with different approach than intermediate grade and high grade. I think we have those similar categories in myeloma. We just haven’t been able to segment patients yet well enough to do randomized clinical trials that personalizes this approach.

We also need to be, I think, thinking about who needs therapy, for how long, and can anybody be discontinued. Because we already know that about 10% of patients don’t relapse in 10 years and that’s functionally cured. And yet right now we couldn’t tell, and so everybody is getting treated to progression. If we could identify these functional cures and discontinue therapy, that would be great for patients to have a long treatment-free interval.

And I would say the third category is really the heavily treated patients. So we are still losing patients every day to this disease, and I think we really need these novel agents, the compounds and strategies that we’ve discussed today, like the GSK [GlaxoSmithKline] compound selinexor, and CAR [chimeric antigen receptor] T, which are the most promising and have gotten some kind of breakthrough designation from the FDA [US Food and Drug Administration]. Hopefully these, some of these agents, will help with that segment of population.

Transcript Edited for Clarity 
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Transcript: 

Ajai Chari, MD: The remaining unmet medical needs in relapsed/refractory myeloma, and I would broaden it to all of myeloma, are really 3. First, being elderly/frail. We know that these patients still do worse. When you look at their overall survival OS curves, the number, the curve is not flat from the very beginning. Secondly, renal dysfunction. Patients with renal dysfunction still have, in many studies, inferior overall survival. And the third are high-risk patients.

Those are the 3 groups of patients that are bringing down the median overall survival for myeloma. So if we can improve their outcomes, the median OS of this cancer will get even better
Sagar Lonial, MD: As we see all these new drugs emerging on the horizon, I think a big question comes up about what are the continuing unmet needs for many of these patients. And I think that a lot of that is beginning to be segmented. We know, for instance, that patients with standard-risk disease can do quite well. And, again, in our series, 70% of them are alive at 10 years.

And so the question becomes, where do we need additional input? I think that patients with plasma cell leukemia, or extramedullary disease, continue to remain a challenge at the time of diagnosis. Patients with early relapse, meaning relapse within a year of transplantation, those continue to remain a challenge for us to manage. And patients with other high-risk genetics continue to remain a challenge for us for where they don’t have that 70% 10-year survival, and so optimizing ways to manage them, utilizing our agents in the most rational way to try and get them to MRD [minimal residual disease]–negativity, all of those remain unmet medical needs in myeloma.

Andrzej Jakubowiak, MD, PhD: There are still very significant unmet needs for treatment of myeloma, especially in relapsed/refractory disease. So we are in a continuous race and search to not be put in a position and we come to the patient’s room and we have to tell the patient that we have exhausted all the possible regimens and drugs, and we, at the moment, have nothing to offer. This is a terrible moment for not only the patient, but also for those who treat. These are most difficult moments for me as a treating physician, and I would rather not have them. That’s why I’m so heavily involved in trying to develop new drugs and regimens.

Now that is the unmet need, which we have in our hand. We have more and more patients who are quadrefractory for both most active drugs in a given class: proteasome inhibitor, and IMiD [immunomodulatory imide drugs], and pentra, which will be with antibody, also refractory. And this is a population, which I mentioned earlier is eventually allowing selinexor to be potentially considered as the next approved drug, because this drug works in this group of patients. This is clearly an unmet need.

In my opinion, another very important unmet need is to try to selectively treat patients with certain abnormalities or risk factors—genetic risk factors. We have tools, and we can potentially implement them and use them more effectively if we are using our knowledge about the biology of the disease and about the drug and potentially matching those two.

So this is an unmet need. We need more research. And that the research is in progress or is about to start. For example, my drug initiative from the Multiple Myeloma Research Consortium [MMRC], which be testing some new class of drugs in combination with existing triplet, which will be testing possibility of reversing difficult consideration for patients with certain mutations or abnormalities. I think a very important unmet need is to achieve more durable response in patients who are relapsing multiple times. Some of the regimens we discussed earlier achieved responses, but were too short to eventually help a patient to the level of his or her expectations, as well as meeting physician expectations—forgetting that the breadth of good response of extended months or years. These are definitely areas where we are potentially needing to move very quickly. And I think new are moving quickly, particularly with new modalities in the broad group of immunotherapy, especially CAR Ts.

My discussion about how to treat the patients is, has been emerging, but for some time, optimism that not only that we are doing better, but that we are potentially having opportunity, and, potentially in the near very foreseeable future—in next 2 or 3, maybe even less years—that we can have strategies, which can cure the proportion of patients with ability to say that we cured. At the moment, we presumed that we cured some patients who are 10 or more years in remission and have not required treatment for many years to come.

We worry that some of them may be relapsing later on. But at that fraction of patients who are achieving that durability of responses is where my optimism is based. I think that some of the best strategies bring proportion of these in longstanding remission to such a high proportion that I can really be sharing that enthusiasm with you.

Sixty percent to 70% of patients achieving with some strategies complete response and MRD negativity, which is predicting—in fact, showing longer remission and survival—is truly a fantastic achievement.

Ajai Chari, MD: What I’m excited about seeing in myeloma are more personalization. I think we treat this disease as 1 entity, and that’s because under the microscope, it looks like 1 entity. But we know that they’re not; these patients are not all the same. And we need to go towards a lymphoma-type of paradigm where we treat low-grade lymphomas with different approach than intermediate grade and high grade. I think we have those similar categories in myeloma. We just haven’t been able to segment patients yet well enough to do randomized clinical trials that personalizes this approach.

We also need to be, I think, thinking about who needs therapy, for how long, and can anybody be discontinued. Because we already know that about 10% of patients don’t relapse in 10 years and that’s functionally cured. And yet right now we couldn’t tell, and so everybody is getting treated to progression. If we could identify these functional cures and discontinue therapy, that would be great for patients to have a long treatment-free interval.

And I would say the third category is really the heavily treated patients. So we are still losing patients every day to this disease, and I think we really need these novel agents, the compounds and strategies that we’ve discussed today, like the GSK [GlaxoSmithKline] compound selinexor, and CAR [chimeric antigen receptor] T, which are the most promising and have gotten some kind of breakthrough designation from the FDA [US Food and Drug Administration]. Hopefully these, some of these agents, will help with that segment of population.

Transcript Edited for Clarity 
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