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New Directions in Drug Development: Multiple Myeloma
Blood Cancers, Multiple Myeloma
Hospital and Institutional Affiliations
Chief Medical Officer, Winship Cancer Institute
Professor and Chair, Department of Hematology and Medical Oncology
Are B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell (CAR-T) therapies the most promising investigational medications for the treatment of multiple myeloma in the future?
In general, BCMA-directed therapy is an exciting target in myeloma. CAR-T-cell therapy represents one way to target BCMA. The real question about CAR-T therapy is the long-term durability of those responses. That is an area where we do not have a lot of data. If we see that a fraction of patients are ultimately cured of the disease, similar to all acute lymphoblastic leukemia and large cell lymphoma, then there is no question that it will be as impactful in myeloma as it is in those diseases. There are other BCMA-directed therapies, such as BiTEs [bispecific T-cell engagers] or antibody-drug conjugates, that may also have an impact, and [there] may be ways to bridge to a CAR-T cell transplant perhaps, presuming that they [the CAR-T therapies] ultimately cure a subset of patients. It is a little early to answer that question in totality.
Do you predict that the introduction of CAR-T earlier in the myeloma treatment paradigm will boost its efficacy?
Almost every drug that we have – and I am thinking about CARs as a therapeutic agent – when you move it earlier in the disease course you get better responses. What we don’t necessarily know is whether the mechanisms of resistance for CAR-T is the same in an earlier-relapse population as it is in a late-relapse population. Presumably, it is not. But again, we need data to speak to that. Trials answering this question are currently under way.
What are some of the most encouraging new targets in multiple myeloma?
Anything that targets BCMA certainly looks really interesting and promising. The next generation
immunomodulatory agents such as CC-220, on which I presented at ASCO and EHA,1,2 certainly look
very promising, particularly in the context of pomalidomide-resistant myeloma. Targeting the death
pathway with either BCL2-directed therapy or MCL1-directed therapy, from a laboratory perspective,
looks very exciting and interesting.
For a BCL2-directed therapy like venetoclax, we do have some encouraging data in a subset of patients, and with good trial design, I think we can confirm this benefit. MCL1-targeted agents are currently in phase 1 and, hopefully, we will see some interesting clinical data on that in the near future as well.
What do you predict will be the true role of checkpoint inhibition in myeloma, if any?
That is an interesting question. All of us were pretty encouraged by some of the PD-1 plus
immunomodulatory drug data that we saw in phase 2 studies and were sobered by the phase 3 studies.
It wasn’t just the question about early death. It was the lack of significant clinical benefit as measured by
overall response rate in the randomized trial arms that really was a major set back.
One of the areas where checkpoint inhibitors are going to be of interest is in the context of CAR-T– cell directed therapy. We know that in lymphoma and other diseases, people are already beginning to combine checkpoint inhibitors with CAR-T cells as way to increase the longevity of cells or get longer persistence of those cells. That is one area where it certainly would be interesting to look at as a series of trials to try to enhance the efficacy or durability of CAR-T cells.
There are second- and third-generation checkpoint inhibitors that may be more relevant for myeloma than PD-1 or PD-L1, which has really been a mainstay in both the solid and liquid tumor world. Things like LAG-3 and TIM-3 may much be more important, particularly in the context of daratumumab resistance, than PD-1 or PD-L1. We need to look at some of those newer checkpoints to really understand where there may be benefit.
Do adjunct therapies that alter the tumor microenvironment seem feasible?
Things that enhance either immune function or suppress the microenvironment in support of a plasma
cell certainly are really nice laboratory concepts. So far, in the clinical world, they have not yet panned
out because they rarely have single-agent activity. That is the benchmark we use to take a drug forward.
Second- and third-generation checkpoint inhibitors may be a different way to look at that. Other drugs that may have secondary effects on the microenvironment may also be very interesting and intriguing as well. As an example, we know that one of the predictors of progression from soldering myeloma to symptomatic myeloma is immune control of the clone. In the data I presented at ASCO, we showed that lenalidomide was able to prevent progression compared withto placebo, despite the fact that lenalidomide alone had a very low overall response rate.3 This to me speaks to that microenvironment question. I do think that things that target the microenvironment, particularly the immune portion, might have the ability to prevent progression or minimize progression in the short-term or the long-term.
Although earlier this year FDA’s Oncologic Drugs Advisory Committee (ODAC) recommended the agency wait to make a regulatory decision on selinexor in myeloma until after the BOSTON trial readout next year, the FDA ultimately gave the drug an accelerated approval designation a few months later. What is your opinion on this decision?
The FDA was in a tough position there because they had a lot of people that were clinical trial purists
saying that the drug shouldn’t be approved. At the same time, there were a lot of patients and patient
advocates saying that this would provide one more option for patients that are limited in terms of what
they can get, or in those who do not qualify for clinical trials.
Selinexor clearly is a drug that has activity. How to optimally use it and what the partner combinations are, I think, are still being developed in phase 1 and phase 2 trials. In centers who that have experience with it, and understand how to provide supportive care, it might represent something that patients who don’t have other options can get access to. It [The drug] might ultimately improve their [patient] outcomes. I would be very hesitant for people who have not used it to broadly adopt it because it is a drug that has a bit of a learning curve. Experienced centers are the ones who that know how to manage it and maximize the benefit.