During a Targeted Oncology™ Case-Based Roundtable™ event, Rafael Fonseca, MD, discusses how targeting patients with relapsed/refractory multiple myeloma with B-cell maturation antigens like teclistamab is changing the treatment landscape.
• A 63-year-old man who was diagnosed 8 years ago with multiple myeloma (IgG-kappa)
• He lives in a rural community.
• He now presents with penta-refractory disease progression and had 4 prior lines of therapy that included ASCT (autologous stem cell transplant), 2 PIs (protease inhibitors), 2 IMiDs (immunomodulatory drugs), and 1 anti-CD38 antibody.
• Personal medical history includes hypertension controlled with lisinopril.
• ECOG performance score: 1
• He asked about CAR (chimeric antigen receptor) T-cell therapy, but after counseling, opted to pursue an alternative therapeutic due to the length of waiting lists at accessible institutions.
Targeted OncologyTM: What are the latest discussion topics around the treatment of patients with relapsed/refractory multiple myeloma?
FONSECA: [A patient like] this is typical for what we anticipate in a patient with multiple myeloma—more and more, we're seeing patients in our practice who come in with multiple lines of therapy, and probably more important now, multiple exposures to the various agents. In fact, there was a [recent] meeting with the FDA where the whole meeting was about the design of clinical trials.
A big push at that meeting was that we should not talk about lines of therapy, but we should talk more about exposure to the various agents. This is relevant because that dictates essentially not just what happens because of several lines of therapy, but what we anticipate for the possibility of resistance to a specific drug. [There are strong] peaks and intensity [with this] disease, but ultimately, [we need to] somewhat shorten the intervals between the various phases of disease control.1
This still holds true to this day, but…one [thing to note] is that the first remission [for a patient] can be significantly longer than anything that was published back in 2013.1 Our ability to induce very long remissions is greater than it has ever been. The second one is—although this is certainly not universal—with some of the immunotherapies, the duration of second or third or fourth or fifth remission might end up being as long, if not longer, than some of the previous ones. And some of them are quite durable. I would anticipate not quite what we have seen with CAR T-cell therapies in the areas of lymphoma, but still the possibilities are there for quite durable responses.
How is utilizing the B-cell maturation antigen (BCMA) important to treating these patients?
This is a B-cell-specific antigen associated with signaling that normally occurs in B cells.2 But it turns out that BCMA is highly conserved in very late B cells and primarily in plasma cells, and perhaps a little bit more in malignant [disease], although the normal plasma cells do have this as part of normal signaling. This has proven to be an excellent target for a number of approaches.
I used to say we shouldn’t talk about BCMA-targeting agents, because that just tells you about the target. We should be talking more about the mechanism of action we're targeting with BCMA. I think that holds true, in that it's not the same to talk about an ADC [antibody-drug conjugate] vs a bispecific [agent] or CAR T-cell therapy. But having said that, there are some important considerations. The first one is, given that BCMA has been at the forefront for targets that we developed agents against, immediately and practically, we're facing questions about sequencing. “Can you use a BCMA agent, such as an ADC, before you use a CAR T-cell therapy?” And so forth, with the permutations of that. That would be the second aspect that makes it very important.
However, we now have more targets for the bispecific agents and the CAR T-cell therapies. Those targets include GPRC5D, against which we have bispecific agents and CAR T-cell therapies, and FcRH5. However, that is a target that has been used to develop another bispecific, which is cevostamab [BFCR4350A].
Lastly, even though I said BCMA is highly conserved, as with every target of every cancer, there is a possibility of resistance [to] bilateral expression. This has been already documented in the medical literature. Perhaps one of the most interesting studies was…where they did single-cell sequencing analysis, and they found that there were some clones of cells that don't express BCMA.3 As we continue to make progress in the fight against myeloma, one of the things we're perhaps going to end up doing is combination-based strategies.
BCMA has now made it all the way to the NCCN [National Comprehensive Cancer Network] guidelines.4 These are guidelines for patients who have had previous treatment, and therapies for patients with late relapses are mentioned. We have the 2 commercial CAR T-cell therapies, idecabtagene vicleucel [ide-cel; Abecma] and ciltacabtagene autoleucel [cilta-cel; Carvykti], but more recently, we also have teclistamab [Tecvayli].
We’re [discussing] within our institutions [now] because we’re chomping at the bit to be able to use [BCMA therapies] commercially. Beyond the FDA approval, there are a lot of steps that need to happen, but the reality is…it’s happening and it's available for patients.
Can you discuss the recent approval for teclistamab, in the context of other therapies?
The most recent example is teclistamab, approved on October 25, 2022 by the FDA, which is the first bispecific BCMA-targeting CD3 T-cell engager.5 The caveat is [it’s indicated for patients with] relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, which needs to include a PI, an IMiD, and an anti-CD38 monoclonal antibody.
[With an] ADC…it binds to BCMA and then it has a payload [it delivers].2 In this case, the one is belantamab mafodotin [Blenrep], which has a microtubule disrupter. That was one of the ways by which we could approach multiple myeloma therapeutics. The CAR T-cell therapies were the first to demonstrate not only the activity, but led ultimately to the approval of this, and both commercial CAR T-cells therapies for multiple myeloma target BCMA.6 Then with the races on now, it's with a bispecific antibody.
We have bispecific antibodies with multiple targets, but the first one that has crossed the finish line is teclistamab, which targets BCMA. We also have other antibodies that are coming behind it, and other targets that are coming with other antibodies.
1. Kurtin SE, Bilotti E. Novel agents for the treatment of multiple myeloma: proteasome inhibitors and immunomodulatory agents. J Adv Pract Oncol. 2013;4(5):307-321.
2. Yu B, Jiang T, Liu D. BCMA-targeted immunotherapy for multiple myeloma. J Hematol Oncol. 2020;13(1):125. Published 2020 Sep 17. doi:10.1186/s13045-020-00962-7
3. Samur MK, Fulciniti M, Aktas Samur A, et al. Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma. Nat Commun. 2021 Feb 8;12(1):868. doi: 10.1038/s41467-021-21177-5
4. NCCN Clinical Practice Guidelines in Oncology. Multiple myeloma, version 3.2023. Accessed March 16, 2023. https://bit.ly/2T0mDYS
5. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. October 25, 2022. Accessed March 16, 2023. https://bit.ly/3ZRsGhf
6. Lancman G, Sastow DL, Cho HJ, et al. Bispecific antibodies in multiple myeloma: present and future. Blood Cancer Discov. 2021;2(5):423-433. doi:10.1158/2643-3230.BCD-21-0028