Quadruplet Therapy and Early-Line CAR T-Cell Therapy Approvals Mark Shifting Standards in Multiple Myeloma

With upfront quadruplet induction therapy solidified as the standard of care (SOC) in multiple myeloma irrespective of cytogenetic risk status, research efforts are increasingly focused on the feasibility and safety of moving chimeric antigen receptor (CAR) T-cell therapies into earlier lines of treatment and identifying the optimal role for bispecific antibodies, according to Minoo Battiwalla, MD, MS, who adds that there has been a significant expansion of FDA indications for CAR T-cell therapies in this disease.

In April 2024, the FDA approved ciltacabtagene autoleucel (cilta-cel; Carvykti) in the second-line setting for the treatment of patients with lenalidomide (Revlimid)–refractory disease and idecabtagene vicleucel (ide-cel; Abecma) for patients who are triple-class exposed in the third-line setting.^1,2 Although these agents have previously been used in the fifth-line setting, patients have experienced diminished toxicities and improved survival outcomes when they receive them earlier in treatment.

“We also have a lot of work to do in exploring novel combinations and maintenance strategies after these immunotherapies,” Battiwalla said in an interview with OncLive^® regarding a State of the Science Summit on hematologic oncology, which he chaired. “We are going to have a lot of active clinical investigations trying to find the appropriate combinations and sequencing strategies to extend the duration of survival.”

In the interview, Battiwalla discussed the impact of earlier-line FDA approvals for CAR T-cell therapies on treatment outcomes, highlighted the widespread adoption of quadruplet induction therapy in patients with transplant-eligible multiple myeloma, and emphasized the need for more effective therapies for the high-risk and transplant-ineligible populations. Battiwalla serves as director of blood cancer outcomes research at Sarah Cannon Research Institute in Nashville, Tennessee.

OncLive: What critical advances have shaped the evolving treatment paradigm in multiple myeloma within the last year?

Battiwalla: Over the past year, we have seen a significant uptick in approvals for multiple myeloma, which is always a dynamic disease in that respect. We have seen widespread adoption of quadruplet induction therapy for patients with transplant-eligible myeloma. This was initially hinted at by [data from] the phase 2 GRIFFIN trial [NCT02874742] and subsequently confirmed by [findings from] the phase 3 Perseus trial [NCT03710603] presented at the 2023 American Society of Hematology Annual Meeting. [These data] confirmed that upfront quadruplet induction therapy should be the SOC for all comers with transplant-eligible multiple myeloma, irrespective of cytogenetic risk status. [Another] big change has been an emphasis on consolidation after transplant for such patients; [this] usually [involves] 2 cycles of the quadruplet regimen.

How have the FDA approvals for cilta-cel and ide-cel in earlier lines of treatment impacted outcomes?

CAR T-cell therapy was confined to the fifth-line setting, [and] the expected median survival was extended [in that setting for patients treated] with ide-cel and cilta-cel—[the median overall survival was 19.4 months for patients treated with ide-cel who had previously received 3 regimens]. These very effective treatments are now moving from the fifth line to earlier-line settings.

In April 2024, the FDA approved cilta-cel in the second-line setting for patients with lenalidomide-refractory [disease] and ide-cel in the third-line setting for patients who are triple-class exposed. Interestingly, some of the toxicities we see in the fifth-line setting [with these CAR T-cell agents] are somewhat diminished in the earlier-line setting where the disease burden is lower.

What unmet needs in multiple myeloma remain to be addressed?

Myeloma remains a disease of catastrophic manifestations. We are doing much better today [treating patients] with standard-risk disease—the big unmet need remains for patients with high-risk disease. To some extent, in the transplant-eligible population, we can blunt the impact of at least a single cytogenetic high-risk abnormality by using a quadruplet approach, [and] the impact on double cytogenetic high-risk abnormalities remains undefined. We clearly need more effective therapies, especially in that space.

The transplant-ineligible population, which is currently served very well with the combination of the anti-CD38 [monoclonal antibody daratumumab (Darzalex) plus] lenalidomide and dexamethasone, could also benefit from some of the advances made in the transplant-eligible space, such as the earlier involvement of CAR T-cell therapy. With cilta-cel demonstrating reduced toxicity in the second-line setting compared with the fifth-line setting, this brings those patients under [consideration for earlier treatment with] CAR T-cell therapy and other immunotherapies. The other unmet need is that bispecific antibodies need to find a home, probably in the earlier-line setting.

What are future research directions in this space?

We are continuing to see innovations, particularly [for] immunotherapy, with the identification of novel targets. [We have] trials involving CAR T-cell [products that] simultaneously direct against BCMA and CD19, which could kill off an earlier precursor cell in the myeloma spectrum of cells. Novel [agents] such as that are very exciting. GPRC5D has proved to be a very attractive target with the introduction of the bispecific antibody talquetamab-tgvs [Talvey]. Targeting [GPRC5D] and other such surface molecules with CAR T-cell therapy is not far behind [in development as well]. We have a lot of excitement ahead of us [with these investigations].

References

1. Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. News release. Johnson & Johnson. April 6, 2024. Accessed June 12, 2024. https://www.jnj.com/media-center/press-releases/carvykti-is-the-first-and-only-bcma-targeted-treatment-approved-by-the-u-s-fda-for-patients-with-relapsed-or-refractory-multiple-myeloma-who-have-received-at-least-one-prior-line-of-therapy
2. US FDA approves Bristol Myers Squibb and 2seventy bio’s Abecma for triple-class exposed relapsed or refractory multiple myeloma after two prior lines of therapy. News release. Bristol Myers Squibb and 2seventy bio, Inc. April 5, 2024. Accessed June 12, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-FDA-Approves-Bristol-Myers-Squibb-and-2seventy-bios-Abecma-for-Triple-Class-Exposed-Relapsed-or-Refractory-Multiple-Myeloma-After-Two-Prior-Lines-of-Therapy/default.aspx