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Each of the BCMA-targeting modalities reviewed here have advantages and disadvantages. The ADC, belantamab mafodotin, is an “off-the-shelf” therapy that is FDA approved and can be given at any infusion center without requiring lymphodepletion or use of steroids. ORR is perhaps not as impressive as we have seen for other approaches but can be an effective option for patients with heavily pretreated R/R MM. As discussed, belantamab mafodotin must be prescribed under REMS program and requires ophthalmic assessment due to risk of ocular toxicity, including keratopathy.
The CAR T‑cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel are a personalized treatment approach and require only a single infusion. However, the logistics of providing these therapies are challenging. They are costly and require some wait time, so patients must be healthy enough to endure that treatment delay. The major safety issues are CRS and neurotoxicity, which require access to intensive care and neurology services.
Finally, bispecific antibodies are not yet approved but appear to present several advantages. They are also “off-the-shelf” therapies, do not require lymphodepletion and only minimal steroids, and appear to be very effective based on early data. However, they require initial hospitalization and present risk of CRS and neurotoxicity, although these appear to be manageable. After the first 1 or 2 doses of these agents, they may be able to be given in an outpatient setting (but will require ongoing administration).
Myeloma patients are a large population, and it is likely there is a role for each of these options, given that each class of agents offers different advantages and disadvantages. Understanding when to use which type of BCMA-targeted agent will be based on the availability, AE profiles, and patient preferences. .
The possibility of sequencing of BCMA‑targeting agents is another interesting debate in myeloma management currently. It is important to remember that patients who progress on one BCMA-targeted therapy may remain eligible for another. In the KarMMa study, a small percentage of patients progressing on CAR T-cell therapy showed BCMA loss,13 but many patients retain BCMA expression on their plasma cells despite relapse and may still be eligible for a different CAR T‑cell therapy or bispecific therapy, or changing therapy altogether. Ongoing studies of BCMA-targeted therapy are also including cohorts with prior BCMA-targeted therapy exposure and, hopefully, these data will help answer the question of how we can sequence these agents effectively. For example, the MagnetisMM-1 trial with elranatamab included people with prior BCMA exposure and showed response in this population.36 I commend the investigators for permitting enrollment of these patients, because it allows us to see if there is potential for sequential anti‑BCMA therapy. Of course, there are also ongoing trials with agents for other MM targets, but hopefully we are going to get some mileage from targeting BCMA alone.
There also has been interest in measuring soluble BCMA as a biomarker for patients with MM. We know that soluble BCMA is a reflection of disease burden. We know that administration of a γ-secretase inhibitor to a patient with MM decreases soluble BCMA because surface binding increases. Whether the amount of soluble BCMA can predict outcomes for patients is less clear. It can be used as a reflection of B‑cells returning, but whether those are malignant B‑cells in a relapse or normal healthy B‑cells has yet to be determined and may even be patient specific.
Right now, some think that increasing levels of soluble BCMA may be most useful as an early biomarker of progression, so if assays can be improved, I think this will be another way for us to detect if patients are progressing.
The studies we discussed today show that targeting BCMA is an effective way to eliminate malignant plasma cells. We have unprecedented phase I and II data of single agent therapy for patients with heavily pretreated R/R MM, yielding response rates as high as 98% (in the case of ciltacabtagene autoleucel). The long-term duration of response with these agents is unclear so far and we are excited to see longer‑term data in the future.
One of the next steps for BCMA-targeted agents is to bring these therapies forward in the treatment course. Combining these BCMA-targeted immunotherapies with other anti-myeloma treatments to reach the goal of steroid independence is attractive to patients and using these approaches in earlier lines of therapy can eliminate the worry of having exhausted T‑cells in heavily pretreated disease. We are also exploring novel targets beyond BCMA, including GPRC5D, FcRH5, and other therapies, targets, and sequences with a view to optimizing therapy for myeloma patients and sustain disease control.