Video
Unmet Needs in the Management of Multiple Myeloma
Author(s):
Sagar Lonial, MD, provides insight on mechanisms of resistance to CAR T-cell therapies, and the panel shares unmet needs and future directions for the treatment of multiple myeloma.
Nina Shah, MD: Sagar, for the last couple of minutes, I’ll have you take 2 parts of a question. We know the mechanism of resistance to CAR [chimeric antigen receptor] T-cell therapy. Could you re-treat either with one or a different CAR T? If not, are there other non–BCMA-targeting CAR T cells that are developed?
Sagar Lonial, MD, FACP: Everybody has been appropriately excited and positive about the data on cilta-cel [ciltacabtagene autoleucel] in a small phase 2 study showing a long PFS [progression-free survival] in refractory myeloma. But we have to understand that there are a couple of challenges. Myeloma is smart. Part of why it evaded immune surveillance in the first place is it has an ability to shape the new microenvironment such that T cells often can’t even get in to the collections of plasma cells in the bone marrow, and to modulate T cells that may be targeted for disease and shift them or change their phenotype so that they’re no longer effective. Whether that’s part of what happens to infused CAR T cells over time, they develop an exhausted phenotype, they lose their activation phenotype, or they simply don’t persist, that’s a major problem.
The diseases with CARs that have plateaus are diseases that are intrinsically curable with aggressive chemotherapy. In diffuse large B cell and ALL [acute lymphocytic leukemia], achieving MRD [minimal residual disease] negativity at an early time point translates into long-term plateaus in care. That’s not necessarily the case in myeloma, except in a continuous therapy model. Finding a way to either enhance persistence or put some form of maintenance to build on the degree of cytoreduction that you get with a CAR is ultimately how we’re going to make this useful, and whether maintenance is PD-1. We’ve all seen cases where a patient progresses but has CAR T cells in the blood and you give pembrolizumab or nivolumab and they go back into remission. We’ve got people who were in remission for 2 and 3 years doing that. Or there are other immune manipulations with drugs like iberdomide, using bispecifics on the back end. Those are all potential ways to do it.
Your second question was about other targets. The same other targets we have in myeloma—whether they’re CD38, GPRC5D, or FcRH5—are all great targets for CAR T cells potentially as well. I might favor CD38 less because I worry CD38 is a little ubiquitous, and you may do things to stem cells with CD38-targeted CAR T cells that you don’t do with isatuximab or daratumumab. I’d be a little less enthusiastic about CD38, but that’s certainly a testable hypothesis and those trials are currently in the works.
Nina Shah, MD: Yes, there’s a lot going on, and it was even too much to cover at 1 conference, if that’s possible. Thank you all for this rich and informative discussion. Before we conclude, I’d like to get final thoughts on the unmet needs and future perspectives in multiple myeloma from each of you. We’ll start with Katja to briefly provide closing thoughts.
Katja Weisel, MD: My clear unmet need is to turn the incurable into curable disease. We have the tools, the drugs, and the constructs, and we just have to finally do it all together. This is a big responsibility we all have as a community and we have to work on that. So far, we haven’t reached that goal and we’re sure that some patients eventually will always relapse. We have the unmet need to develop novel drugs to novel targets to give our patients a continuous better perspective to live with myeloma these days.
Nina Shah, MD: Ola?
Ola Landgren, MD, PhD: A big clinical unmet need is that we need to give all the patients access to effective therapy. If we look a few years back, the most effective therapies were too toxic, so they could only be given to the younger, fitter patients. That is changing with all the antibodies coming into the field with subcutaneous delivery. It makes it much more equal, independent of age. The age discrimination goes away. Still, we haven’t come up with a strategy to deal with patients who have a poor biological kind of disease. We call it high risk based on very outdated markers with FISH [fluorescence in situ hybridization] and cytogenetics. We have to use more sophisticated assays.
Many presentations at ASH [American Society of Hematology Annual Meeting] talked about more complex events. There’s chromothripsis, genomic catastrophic events. Myeloma is shaped by 8 different genomic signatures. APOBEC is present in 80% or 90%. If you do multivariate analysis, you see that you can corral biology that completely erases all the old FISH and cytogenetics. If you could use that with standard biology and try to build rational therapies to go after the high-risk disease, that would be huge. We need to focus on these patients with a bad clinical outcome, those who are high-risk, or however we like to define it.
Nina Shah, MD: Sagar?
Sagar Lonial, MD, FACP: We’ve got a wealth of targets, and the question is how we put it together in a different paradigm to eliminate the disease. The idea of induction, consolidation, maintenance—all those things are throwbacks to an era where we had drugs that couldn’t eliminate the clone. We have combinations that probably can, and it’s up to us to create those new total therapy models that are more effective and don’t use old-fashioned chemotherapy that we know only gets us in trouble down the road.
Nina Shah, MD: And Josh.
Joshua Richter, MD: We sit here and talk about all these amazing responses. I’d like to see a world of myeloma almost like urinary tract infections, where you pee in a cup and it comes back and says you take 5 days of ciprofloxacin and you’re fine. We give daratumumab and CAR T because they’re good for everyone, but I’m looking forward to the day where you can go into a clinic, get 1 blood draw, it spits out some combination that is absolutely unique to you—high-risk, standard, old, young—and we give a combination of therapies that aren’t good for everyone but are good for you. Then the next person who gets tested is completely different. Maybe that’s a way to cure.
Nina Shah, MD: That’s a really good goal to have. I want to thank all the members of our panel once again. And to our viewing audience, thank you so much for joining us. We hope you found this OncLive® Peer Exchange discussion to be useful and valuable to the treatment of your patients with multiple myeloma. Thank you again.
Transcript Edited for Clarity
