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New Directions in Drug Development: Multiple Myeloma
San Francisco, California
Blood Cancers, Multiple Myeloma
Hospital and Institutional Affiliations
Associate Professor, Medicine
University of California, San Francisco
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?
BCMA-directed CAR-T therapies are [some] of the most promising agents available, but there are other agents that are targeting BCMA and other targets that are also promising. BCMA CAR-T is the most developed so far. These other promising agents include BiTE [bispecific T-cell engager] therapies and BCMA antibody-drug conjugate therapy.
Do you predict that the introduction of CAR-T earlier in the myeloma treatment paradigm will boost its efficacy?
Moving anything earlier in the paradigm makes it work better for myeloma. That is what we have seen over the years. I think that will probably be true for CAR-T. I don’t know yet whether that will lead to using the word “cure”, because it may not get rid of all the myeloma. It may get rid of all the myeloma we can see, but may not get rid of everything we can’t see.
What are some of the most encouraging new targets in multiple myeloma?
Obviously, BCMA is a good target because it is exclusively expressed on B cells and plasma cells so it narrows the toxicity window for targeting that type of cell. There are ways to combine things, like using a gamma secretase inhibitor to encourage the BCMA to be maintained on the cell surface so that the BCMA-targeting agent can work more efficiently. There is also the possibility of targeting GPRC5D, which has been looked at in a CAR-T preclinical model. Finally, there are some early plasma cell markers — cells before they have differentiated themselves as plasma cells — in the SLAM group that are promising, and may be good targets as well.
What do you predict will be the true role of checkpoint inhibition in myeloma, if any?
Checkpoint inhibition should still be explored in myeloma, but in the context of augmenting immunotherapy. For example, one place checkpoint inhibition could be used is after CAR-T cell therapy is given. If there is not a good enough in vivo signal of expansion — if we could measure that in real time — then we could potentially give a dose of checkpoint inhibitor to see if we can boost T-cell activation. Similarly, for vaccine therapy, if we do not see enough T-cell expansion, we could give a checkpoint inhibitor.
I do not know what the role is going to be with combining checkpoint inhibitors with other traditional therapies because of the difficulty in getting those studies done, but I don’t think we should stop doing them. We still do not know exactly how checkpoint inhibitions works in myeloma, so it is worth exploring.
Do adjunct therapies that alter the tumor microenvironment seem feasible?
In general, addressing the microenvironment in myeloma is important, and we haven’t done a good enough job of doing it. It is hard to assess and hard to get answers without having a true preclinical model. It does have the potential for us to be more effective with myeloma treatments that we know work and maybe allow treatments to work better, but a lot of research still needs to be done.
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?
By the time patients are penta-refractory, which is the group of patients studied in the STORM trial, they have very few other options. If there is something that can help patients live a few more months, it is appropriate to try. The ultimate implementation will depend on how comfortable physicians feel using the drug.
One of the notable adverse events that occurred with [selinexor] was gastrointestinal side effects. [These side effects are] not insurmountable, but we have to be good at managing them and be proactive about asking patients about them, and understanding that even when [patients] start therapy, it is good to give extra medication to mediate this.