Cilta-Cel Induces Impressive ORR in Relapsed/Refractory Multiple Myeloma

Ciltacabtagene autoleucel (cilta-cel; Carvykti) demonstrated strong overall response rate (ORR) and progression-free survival (PFS) results in patients with relapsed or refractory multiple myeloma in the CARTITUDE-1 trial (NCT03548207), according to Thomas Martin, MD. He presented updated findings from the phase 1/2 study during the 2021 ASH Annual Meeting and Exposition.

“They were some of the best results ever reported in a relapsed and refractory myeloma population,” Martin said. “There were 97 patients involved in the trial, and only 2 patients did not respond. One of the patients was assessed to have unmeasurable disease at baseline, and therefore, could not be assessed for response. That patient is 2 years down the road and in remission. It was an unbelievable response.”

In March 2022, the FDA approved cilta-cel, a novel B-cell maturation antigen (BCMA)-directed genetically modified autologous CAR T-cell therapy, for use in adults with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.¹ The decision was based on findings from CARTITUDE-1.

In an interview with OncLive^®, Martin, clinical professor of medicine in the adult leukemia and bone marrow transplantation program and associate director of the myeloma program, University of California, San Francisco, discussed updates from the CARTITUDE-1 trial, as well as the future of CARs and bispecific T cell engagers in multiple myeloma.

OncLive^®: What was the rationale of the study investigating cilta-cel in relapsed or refractory myeloma?

Martin: The CARTITUDE-1 study involved a novel CAR T-cell therapy for relapsed/refractory multiple myeloma, cilta-cel. Cilta-cel is unique in that it has 2 single-domain binding antibodies that bind to BCMA. The intracellular signaling domain was 4-1BB and CD3-ζ.

We presented updated results from phase 2, which evaluated patients who had relapsed/refractory myeloma and received [a median of] 6 prior lines of therapy; 88% of them were triple-class refractory, so this was a heavily pretreated population.

The 1-year median follow-up data has been published and it showed a response rate that was about 97%. The median PFS had not been reached. [Moreover], 24% of patients had high risk cytogenetics [and] 20% of them had extramedullary disease—13% of those were extramedullary soft tissue plasmacytomas and 6% were bone-only plasmacytomas. One hundred percent of them were triple-class exposed.

The study was to prove that this single infusion of cilta-cel could provide deep and durable responses in this relapsed and refractory patient population.

Could you speak to the results yielded from the CARTITUDE-1 study?

They were some of the best results ever reported in a relapsed and refractory myeloma population. The 1-year results were published, where the ORR was 97%. Essentially, 67% of patients at 1 year had achieved a stringent complete response [CR].

This was a 2-year follow-up and the ORR was 97.9%. There were 97 patients involved in the trial, and only 2 patients did not respond. One of the patients was assessed to have unmeasurable disease at baseline, and therefore, could not be assessed for response. That patient is 2 years down the road and in remission. It was an unbelievable response.

The other thing we were looking at was median PFS. At 1 year, a median PFS was not reached. At 2 years, the rate of PFS was 60.5%, so a median was still not reached at 2 years of follow up, which is amazing. The rate of stringent CR had increased…to 83%. These were all stringent CRs. These were all deep responses, which is amazing in a population that was so heavily pretreated. These are unprecedented results.

I also showed data on minimal residual disease [MRD] negativity and how that correlated with survival. Sixty-one percent of the patients were evaluable for MRD negativity, and 92% achieved MRD negativity. For those who are MRD-negative sustained for 6 months or more, the 2-year PFS rate was 91%. For those who had sustained MRD negativity for 12 months or more, the 2-year PFS rate was 100%. In both of those groups the overall survival was 100%.

One of the important parts of this is that we need to further interrogate those populations to pick out biomarkers or characteristics that might predispose patients to having such great responses.

What are the next steps?

Currently for [these] patients, there are not many drugs and that is our unmet medical need. Going forward, [our goal] is to get this therapeutic to these patients. [Furthermore], cilta-cel is now being tested as part of frontline therapy, as well as early relapse. The early relapse studies include a randomized phase 3 trial utilizing cilta-cel vs a standard-of-care relapsed/refractory regimen. That study is fully enrolled and hopefully we'll see data from that study sometime in the next 2 to 3 years. The frontline study will take longer for those data to mature.

What are the key takeaways from this study?

The key takeaway from this is that patients who had relapsed/refractory multiple myeloma in the past, with each successive line of therapy, the PFS would get shorter and shorter and shorter. This is the start of a new era where the PFS gets dramatically longer with this line of therapy, which is amazing.

The future is bright for all patients with relapsed/refractory myeloma, and it includes CAR T-cell therapeutics. But there are several other therapeutics being investigated, including the T-cell engaging antibodies, for which data look quite exciting.

Reference

1. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. News release. March 7, 2022. Accessed May 3, 2022. https://bit.ly/3MLqS2p