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New Directions in Drug Development: Multiple Myeloma
Blood Cancers, Multiple Myeloma
Hospital and Institutional Affiliations
Assistant Professor, Medicine
Perelman School of Medicine, University of Pennsylvania
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 among the most promising therapies. However, all of the data we have are from small, heterogeneous phase 1 studies. It is hard to say how these therapies will compare to the other promising investigational therapies, like bispecific antibodies, and anti-BCMA antibody-drug conjugates that also have phase 1 data published showing impressive responses. It is really exciting that there are so many promising new agents for myeloma. CAR-T cells are just one of a number of them.
Do you predict that the introduction of CAR-T earlier in the myeloma treatment paradigm will boost its efficacy?
It is likely. The general trend in myeloma therapy has been to take treatments that show effectiveness in relapsed or refractory patients and move them up to earlier lines of therapy. There are a couple of reasons why I think that is going to happen with CAR-T cells as well. First, the potency and effectiveness of CAR-T cells depends on the health of the T cells the patient starts with. In patients who have not had a lot of prior myeloma therapy, and whose burden of myeloma is low, you would expect them to make more potent CAR-T cells. Also, as a one-time therapy with a fixed cost, it makes sense to use it at a time when it will have the most durable effect. That is early on.
The toxicity profile could affect the decision to move CAR-T cells to earlier lines, however. There are some reasons to believe that the toxicity profile would also be better if given earlier because a lot of toxicities depend on disease burden. Patients with a lot of myeloma may experience more toxicity than patients with a lower burden of myeloma. We have seen that in phase 1 study results.1 If it proves true that CAR-T cells are also less toxic in earlier lines of therapy, that would further support its use in earlier lines.
What are some of the most encouraging new targets in multiple myeloma?
BCMA is a promising target and is being investigated in many different modalities, but it is not the only promising target. There are also some studies in the US and a couple of other locations looking at anti-CS1 CAR-T cell therapy (ClinicalTrials.gov Identifier: NCT03710421). In addition, the University of Pennsylvania is participating in a study looking at CD38 with CAR-T cells (ClinicalTrials.gov Identifier: NCT03464916). Another new target for CAR-T is GPRC5D, which is in a trial with a bispecific antibody.2 Another target called integrin β7 is being investigated by a group in Japan,3 and I think trials of CAR-T cells against this target will begin sometime soon.
What do you predict will be the true role of checkpoint inhibition in myeloma, if any?
The data with PD-L1 inhibitors are a little disappointing, but in the phase 2 study looking at pembrolizumab with pomalidomide, there were perhaps some long-term responders who may have benefitted.4,5 It may be a matter of trying to identify patients who will benefit from anti-PD1 therapy using more sophisticated testing, but that has not been established yet. There are some new checkpoint inhibitors against other targets that are entering clinical trials.
Do adjunct therapies that alter the tumor microenvironment seem feasible?
Altering the tumor microenvironment may be a promising approach based on what we understand about the biology of multiple myeloma. For example, in some ways, the various bone therapies that we use – bisphosphonates, denosumab – arguably work by modifying the microenvironment. A lot of myeloma therapies that were not necessarily designed to target the microenvironment, with time, we have learned that perhaps they modulate some of their effect through the microenvironment. Everybody recognizes that the microenvironment is important to the pathogenesis of multiple myeloma. I think a therapy developed with a good target in the microenvironment would be an appealing new strategy.
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?
I am not an expert on all the regulatory requirements that guide the FDA’s decision. We participated in trials of selinexor, so our group has treated many patients with the drug. We think that it is a drug that has activity in multiple myeloma, so I am glad to have it available for my patients while we await results of the randomized trial. However, it is also a fairly toxic drug and it is the type of drug that might show activity in a small study, but in a larger phase 3 study we might find that the effectiveness is mitigated by toxicity or other new problems that emerge.
It is important to see the results of the larger studies that are ongoing, but in the meanwhile, for patients who have no other options, I am glad to have this drug available. I think for experienced centers that are comfortable with the drug and can manage it, it is worthwhile to have it available.
1. Brudno JN, Maric I, Hartman SD, et al. T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J Clin Oncol. 2018;36:2267-2280.
2. Smith EL, Harrington K, Staehr M, et al. GPCR5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Science Translational Medicine. 2019;doi:10.1126/scitranslmed.aau7746.
3. Hosen N, Matsunaga Y, Hasegawa K, et al. The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy. Nat Med. 2017;23(12):1436-1443.
4. Badros AZ, Hyjek E, Ma N, et al. Pembrolizumab in combination with pomalidomide and dexamethasone for relapsed/refractory multiple myeloma (RRMM). Blood. 2016;128(22):490.
5. Badros AZ, Ma N, Rapoport A, et al. Long-term remissions after stopping pembrolizumab for relapsed or refractory multiple myeloma. Blood Adv. 2019;3(11):1658-1660.