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Improving the Future Management of Multiple Myeloma

Panelists: Sagar Lonial, MD, FACP, Winship Cancer Institute of Emory University; Amrita Y. Krishnan, MD, City of Hope Comprehensive Cancer Center; Thomas G. Martin, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Krina K. Patel, MD, MSc, University of Texas MD Anderson Cancer Center; Saad Z. Usmani, MD, FACP, Levine Cancer Institute
Published: Wednesday, Aug 07, 2019



Transcript: 

Sagar Lonial, MD, FACP: We did see data on CC-220, and many of you participated in that trial. That’s the newest of the IMiDs [immunomodulatory drugs], or the CELMoDs [cereblon E3 ligase modulator], which is the new hip name for them. It’s basically a more potent cereblon binder than thalidomide, lenalidomide, or pomalidomide. What we showed at this meeting was there was a response rate of about 30% with what I will say was a pretty modest adverse event profile.

It’s an oral approach, weekly dexamethasone. Not a lot of GI [gastrointestinal] toxicity, not a lot of confusion or fatigue as you can sometimes see with the IMiDs, particularly in refractory patients. And heme toxicity was really the biggest issue that we saw, and well above the dose that we expected to be the maximum dose that we would get to. We are now combining with daratumumab, combining with bortezomib, combining with carfilzomib really to see how to best think about bringing this agent forward. I don’t know if you guys have had any experience.

Saad Z. Usmani, MD, FACP: We are latching on to the study with some immune correlatives as a substudy. I think what was interesting is the response with each dose. There were different dose levels and you were seeing responses even with the lower doses, I think as low as 0.45 mg. It would be interesting to see what’s really happening, which mechanism of action is iberdomide relying on at each given dose, whether it’s more immune mediated versus direct cell kill. I think it would be important to understand that so that we can partner it with the right therapies moving forward with so many interesting targets that we’re looking at. I was very impressed with the data that you presented, Sagar.

Thomas G. Martin, MD: I was very impressed by the lack of toxicity. That was amazing actually. In fact, most of the people who are on long-term lenalidomide all get some degree of GI toxicity. And I’ve always assumed that that’s from some immune-related effect. And I thought the CELMoDs actually were going to have more of an immune suppressive or immune stimulatory effects and would potentially have more diarrhea. But this showed just the opposite, which is great.

Sagar Lonial, MD, FACP: We’ve covered a lot of ground. A lot of different areas and a lot of different exciting data from ASCO [the American Society of Clinical Oncology annual meeting]. Do you each want to give me your take-home message, what you may do differently, what you may not do differently, what you learned, short version. Why don’t we start with Saad?

Saad Z. Usmani, MD, FACP: The key message from the large randomized phase III trial, I will have a conversation with my high-risk smoldering myeloma patients now about treating them based on the data that were presented. I left augmented with the feeling the transplant is still the standard of care for frontline patients, as is the use of a PI [proteasome inhibitor]-IMiD-based triplet regimen. And I’m hoping that the subcutaneous data actually lead to an approval, and then we’ll have to figure out how each of the healthcare systems deals with IV [intravenous] versus subq formulation and administration. But I think it’s good for the patients. Those are my key take-aways from a clinical practice standpoint.

Sagar Lonial, MD, FACP: Great, Krina?

Krina K. Patel, MD, MSc: I think we covered so much, even with the orals and all the posters, but I guess I’ll stick more to the relapsed/refractory since you did the smoldering in newly diagnosed. We have so many options, and I think we have more questions now than answers, but I think that’s great for myeloma, the fact that we have more and more and that we are on this cutting-edge immune therapy versus targeted therapies. And myeloma is so different than everything else, and that’s my biggest message.

I think with venetoclax and all these other drugs that work so great, we have to be different with our myeloma patients. They do have different adverse effect profiles. I think the CAR [chimeric antigen receptor] T-cell therapies are not a cure for myeloma patients, but our myeloma patients haven’t had a cure. So when we look at these data, as myeloma doctors, we understand that. But I think the community doctors who are sometimes are saying, “Oh, this isn’t really working on these patients.” In my opinion everything that was presented was actually really amazing. These response rates of single agent for BiTE [bispecific T-cell engager], for CAR Ts, for even venetoclax even though it’s an FDA hold, are actually really promising.

Sagar Lonial, MD, FACP: Yes, I would agree that oral session was a bit like taking the MCATs [medical college admission tests], but there was a lot of interesting stuff there. Amrita?

Amrita Y. Krishnan, MD: I think Saad and Krina covered it mostly in terms of promise. I think for me as a transplanter, I’m still very happy with the FORTE result that, OK, we can go home, we still have a job, that transplants have deep remissions, long remissions, and higher MRD [minimal residual disease]. I think I share their excitement with the multiple immunotherapy approaches, but I’m waiting to see more BiTEs than AMG 420. I don’t think that’s going to be the answer.

Sagar Lonial, MD, FACP: I agree. All right, Tom.

Thomas G. Martin, MD: I think the meeting has been amazing actually with all the data that we’ve seen. However, I’m going to take the future approach. And sorry, Amrita, you might not like what I’m going to say. And that is I do think that the antibody therapy is going to be combined with an IMiD and a proteasome inhibitor. So we’re going to do quads [4-drug combination] as induction therapy for myeloma. I think we’re going to get deeper remissions from quad-based therapy, and I don’t think we’re going to do 4 cycles. We’re going to do 6 to 8 cycles. And at that point in time we are going to evaluate MRD. And MRD in my mind has to be 10-6, and then we’re going to make decisions based on MRD and whether we’re going to do transplant. And there’s going to be some people who don’t need a transplant.

Sagar Lonial, MD, FACP: So, Tom, you’re describing one of our investigator initiative protocols right now.

Thomas G. Martin, MD: Which is perfect. I think that’s where we’re going to be. But then we have so much excitement with these new drugs. Like the bispecific T-cell engagers and CAR T cells. They are in fact in people who are really refractory inducing deep remissions in MRD negativity. That is unbelievable. Anything that has such a potent effect in the relapsed and refractory setting has to be brought on sooner in the therapeutic realm either as part of induction, consolidation, or maintenance, or in early relapse. And I think as we bring these drugs further front line, that transplant’s going to start going away because we’re going to be able to do it without doing the transplant. We’re going to be able to induce these really deep remissions.

Sagar Lonial, MD, FACP: We just have to remind Tom that in CAR T cells, people achieve MRD negativity and they still relapse.

Saad Z. Usmani, MD, FACP: It’s not about 1 timepoint, it’s about sustained MRD negativity.

Thomas G. Martin, MD: Right, we agree, it’s sustained MRD negativity.

Sagar Lonial, MD, FACP: Well thank you all very much. I think this has been a great discussion. On behalf of our panel, we thank you for joining us and hope you found this OncLive Peer Exchange® discussion to be useful and informative. Thank you for your attention.

Transcript Edited for Clarity

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Transcript: 

Sagar Lonial, MD, FACP: We did see data on CC-220, and many of you participated in that trial. That’s the newest of the IMiDs [immunomodulatory drugs], or the CELMoDs [cereblon E3 ligase modulator], which is the new hip name for them. It’s basically a more potent cereblon binder than thalidomide, lenalidomide, or pomalidomide. What we showed at this meeting was there was a response rate of about 30% with what I will say was a pretty modest adverse event profile.

It’s an oral approach, weekly dexamethasone. Not a lot of GI [gastrointestinal] toxicity, not a lot of confusion or fatigue as you can sometimes see with the IMiDs, particularly in refractory patients. And heme toxicity was really the biggest issue that we saw, and well above the dose that we expected to be the maximum dose that we would get to. We are now combining with daratumumab, combining with bortezomib, combining with carfilzomib really to see how to best think about bringing this agent forward. I don’t know if you guys have had any experience.

Saad Z. Usmani, MD, FACP: We are latching on to the study with some immune correlatives as a substudy. I think what was interesting is the response with each dose. There were different dose levels and you were seeing responses even with the lower doses, I think as low as 0.45 mg. It would be interesting to see what’s really happening, which mechanism of action is iberdomide relying on at each given dose, whether it’s more immune mediated versus direct cell kill. I think it would be important to understand that so that we can partner it with the right therapies moving forward with so many interesting targets that we’re looking at. I was very impressed with the data that you presented, Sagar.

Thomas G. Martin, MD: I was very impressed by the lack of toxicity. That was amazing actually. In fact, most of the people who are on long-term lenalidomide all get some degree of GI toxicity. And I’ve always assumed that that’s from some immune-related effect. And I thought the CELMoDs actually were going to have more of an immune suppressive or immune stimulatory effects and would potentially have more diarrhea. But this showed just the opposite, which is great.

Sagar Lonial, MD, FACP: We’ve covered a lot of ground. A lot of different areas and a lot of different exciting data from ASCO [the American Society of Clinical Oncology annual meeting]. Do you each want to give me your take-home message, what you may do differently, what you may not do differently, what you learned, short version. Why don’t we start with Saad?

Saad Z. Usmani, MD, FACP: The key message from the large randomized phase III trial, I will have a conversation with my high-risk smoldering myeloma patients now about treating them based on the data that were presented. I left augmented with the feeling the transplant is still the standard of care for frontline patients, as is the use of a PI [proteasome inhibitor]-IMiD-based triplet regimen. And I’m hoping that the subcutaneous data actually lead to an approval, and then we’ll have to figure out how each of the healthcare systems deals with IV [intravenous] versus subq formulation and administration. But I think it’s good for the patients. Those are my key take-aways from a clinical practice standpoint.

Sagar Lonial, MD, FACP: Great, Krina?

Krina K. Patel, MD, MSc: I think we covered so much, even with the orals and all the posters, but I guess I’ll stick more to the relapsed/refractory since you did the smoldering in newly diagnosed. We have so many options, and I think we have more questions now than answers, but I think that’s great for myeloma, the fact that we have more and more and that we are on this cutting-edge immune therapy versus targeted therapies. And myeloma is so different than everything else, and that’s my biggest message.

I think with venetoclax and all these other drugs that work so great, we have to be different with our myeloma patients. They do have different adverse effect profiles. I think the CAR [chimeric antigen receptor] T-cell therapies are not a cure for myeloma patients, but our myeloma patients haven’t had a cure. So when we look at these data, as myeloma doctors, we understand that. But I think the community doctors who are sometimes are saying, “Oh, this isn’t really working on these patients.” In my opinion everything that was presented was actually really amazing. These response rates of single agent for BiTE [bispecific T-cell engager], for CAR Ts, for even venetoclax even though it’s an FDA hold, are actually really promising.

Sagar Lonial, MD, FACP: Yes, I would agree that oral session was a bit like taking the MCATs [medical college admission tests], but there was a lot of interesting stuff there. Amrita?

Amrita Y. Krishnan, MD: I think Saad and Krina covered it mostly in terms of promise. I think for me as a transplanter, I’m still very happy with the FORTE result that, OK, we can go home, we still have a job, that transplants have deep remissions, long remissions, and higher MRD [minimal residual disease]. I think I share their excitement with the multiple immunotherapy approaches, but I’m waiting to see more BiTEs than AMG 420. I don’t think that’s going to be the answer.

Sagar Lonial, MD, FACP: I agree. All right, Tom.

Thomas G. Martin, MD: I think the meeting has been amazing actually with all the data that we’ve seen. However, I’m going to take the future approach. And sorry, Amrita, you might not like what I’m going to say. And that is I do think that the antibody therapy is going to be combined with an IMiD and a proteasome inhibitor. So we’re going to do quads [4-drug combination] as induction therapy for myeloma. I think we’re going to get deeper remissions from quad-based therapy, and I don’t think we’re going to do 4 cycles. We’re going to do 6 to 8 cycles. And at that point in time we are going to evaluate MRD. And MRD in my mind has to be 10-6, and then we’re going to make decisions based on MRD and whether we’re going to do transplant. And there’s going to be some people who don’t need a transplant.

Sagar Lonial, MD, FACP: So, Tom, you’re describing one of our investigator initiative protocols right now.

Thomas G. Martin, MD: Which is perfect. I think that’s where we’re going to be. But then we have so much excitement with these new drugs. Like the bispecific T-cell engagers and CAR T cells. They are in fact in people who are really refractory inducing deep remissions in MRD negativity. That is unbelievable. Anything that has such a potent effect in the relapsed and refractory setting has to be brought on sooner in the therapeutic realm either as part of induction, consolidation, or maintenance, or in early relapse. And I think as we bring these drugs further front line, that transplant’s going to start going away because we’re going to be able to do it without doing the transplant. We’re going to be able to induce these really deep remissions.

Sagar Lonial, MD, FACP: We just have to remind Tom that in CAR T cells, people achieve MRD negativity and they still relapse.

Saad Z. Usmani, MD, FACP: It’s not about 1 timepoint, it’s about sustained MRD negativity.

Thomas G. Martin, MD: Right, we agree, it’s sustained MRD negativity.

Sagar Lonial, MD, FACP: Well thank you all very much. I think this has been a great discussion. On behalf of our panel, we thank you for joining us and hope you found this OncLive Peer Exchange® discussion to be useful and informative. Thank you for your attention.

Transcript Edited for Clarity
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