ODAC Decisions Confirm Benefit of Ide-Cel and Cilta-Cel in Earlier Line R/R Myeloma Therapy

Positive voting decisions from the recent FDA Oncologic Drugs Advisory Committee (ODAC) meetings on idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti) have reinforced the use of the CAR T-cell therapies in earlier lines of therapy shifting the myeloma treatment paradigm, according to Kenneth C. Anderson, MD, who added that the continued monitoring of overall survival (OS) will be important.

“With the CAR T-cell therapy approvals [of ide-cel and cilta-cel] put together, it’s difficult to compare the 2 agents because they’re in the setting of patients who have had different amounts of prior treatment,” Anderson explained in an interview with OncLive®. “The patients who received ide-cel are representative of those who have had triple-class exposure, which is more common earlier in myeloma treatment. Nonetheless, both approvals will result in CAR T-cell therapy being moved earlier to treat patients.”

In March 2024, the ODAC voted 8 to 3 that the benefits of ide-cel outweigh its risks for the treatment of adult patients with relapsed/refractory multiple myeloma who have received an immunomodulatory drug (IMiD), a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Additionally, an 11 to 0 vote by the committee determined that the benefits of cilta-cel do outweigh its risks for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an IMiD, and who are refractory to lenalidomide (Revlimid).¹ Cilta-cel also received approval from the FDA in April 2024 for this indication.²

Data from the phase 3 CARTITUDE-4 trial (NCT04181827) revealed that patients treated with cilta-cel (n = 208) achieved a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs standard-of-care pomalidomide (Pomalyst) plus bortezomib (Velcade) and dexamethasone (PVd) or daratumumab (Darzalez) plus pomalidomide and dexamethasone (DPd; n = 211; HR, 0.26; 95% CI, 0.18-0.38; P < .0001).³

Additionally, updated findings from phase 3 KarMMA-3 trial (NCT03651128) showed that, at a median follow-up of 30.9 months (range, 12.7-47.8), prespecified sensitivity analyses adjusting for crossover showed an improvement in OS for patients who received ide-cel (n = 254) vs standard-of-care (SOC) regimens (n = 132). The median OS was 41.4 months (95% CI, 30.9-not reached [NR]) vs 23.4 months (95% CI, 17.9-NR), respectively (HR, 0.69; 95% CI, 0.45-1.09).⁴

In the interview, Anderson, the Kraft Family Professor of Medicine at Harvard Medical School as well as director of the LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, Massachusetts, expanded on PFS and OS data from both trials. He also highlighted top takeaways from the ODAC decisions and emphasized the importance of monitoring patients for secondary malignancies.

OncLive: What was the most important takeaway from the ODAC decision regarding the use of cilta-cel in relapsed/refractory multiple myeloma?

Anderson: Cilta-cel was first FDA-approved in patients who had received 4 or more prior treatments where it achieved remarkable results [with a] 98% ORR [at a 27.7-month median] follow-up. This is unprecedented activity in far-advanced myeloma.

The recent decision was in patients with lenalidomide refractory myeloma [who] had received 1 prior line of therapy including a proteasome inhibitor and IMiD. It was a uniform endorsement for cilta-cel to be used in that setting [based on data from CARTITUDE-4]. Cilta-cel was compared with DPd or PVd, and the HR [for PFS] was 0.26—the median PFS was NR in the cilta-cel arm vs 11.8 months in the standard of care therapy arm. The median OS was NR in either arm, although it was higher at 79% vs 66% at 2 years in favor of cilta-cel [vs SOC].

It’s exciting that this brings this earlier modality to patients [who received] only 1 prior treatment. Only approximately a quarter of these patients had been exposed to CD38 monoclonal antibodies as part of their initial treatment. It is common nowadays in both transplant-eligible and transplant-ineligible patients to receive daratumumab as part of their initial treatment—in the patients who receive transplant it’s often daratumumab [given with] bortezomib, lenalidomide, and dexamethasone, and in the non-transplant patients daratumumab [is typically given with] lenalidomide, and dexamethasone. I mention that because the fact that most patients didn’t receive daratumumab [in this study] is not standard practice, at least in North America.

There were concerns about some early deaths in this trial in the cilta-cel arm.The issue there was that patients died having been randomly assigned to cilta-cel before receiving the cilta-cel therapy; in all likelihood, this was related to a number of factors including bridging therapy.

This is a very exciting approval, [but] secondary cancers are [also] a concern. They were roughly the equivalent in both arms at [4.3% vs 6.7% for cilta-cel vs SOC, respectively]. But overall, the overwhelming benefit is for the use of cilta-cel earlier in the course of disease.

What was the key takeaway from the ODAC decision on ide-cel in relapsed/refractory multiple myeloma?

Ide-cel was similarly approved by the FDA, first in patients who had received 4 or more prior treatments, and now has been moved up [to earlier lines for] patients who have had 2 or more lines of therapy [and] have been triple-class exposed. That includes [treatment with] an IMiD, proteasome inhibitor, and CD38 monoclonal antibody. It is exciting in the sense that there was a 51% reduction in the likelihood of [disease progression or] death—the HR is 0.49 in favor of ide-cel in this context [according to data from KarMMA-3].

The response rate was higher for ide-cel than SOC, and in this trial the comparison was with 5 different FDA-approved SOC regimens. The ORR was 71% for ide-cel vs 42% for SOC [with] complete response [CR] rates of 39% vs 5%, [respectively]; the DOR was 14.8 months vs 9.7 months, [respectively]. There was no OS advantage because crossover was allowed in this trial. This is a very important approval.

What contributed to the difference in the ODAC voting margins for the 2 CAR T-cell therapies?

I don’t know for sure why the vote was different, [but] I would mention that the results in patients who received 4 or more prior therapies treated with cilta-cel are superior to those noted with ide-cel. In these 2 more recent decisions, where earlier patients are being treated, there was a crossover in the ide-cel arm which was not present in the cilta-cel study. As a consequence, no OS advantage was demonstrated in the ide-cel study, which could have contributed to the difference in the approval voting for these 2 modalities.

What were some issues raised by ODAC regarding the OS data for both ide-cel and cilta-cel?

In the ide-cel trial, there was crossover allowed so there was no OS advantage demonstrable. In the cilta-cel study, the OS median was NR in either the cilta-cel or the SOC therapy arm. In both cases, therefore, OS needs to be continually followed both for efficacy but also for adverse effects. Secondary cancers have been raised as a concern. Overwhelmingly, the benefit is in favor of using CAR T-cell therapy, but we need to monitor [patients] very carefully as we get more experience with both of these CAR T-cell therapies.

The CARTITUDE-4 trial treated patients with very early myeloma [as] they had only received 1 prior treatment and only a quarter of the patients had been exposed to a CD38 monoclonal antibody. We know in myeloma that we can extend OS markedly with already available treatments. Therefore, we need to follow the CARTITUDE-4 trial very carefully to ensure that there are no efficacy or safety issues identified with [cilta-cel] with further follow-up.

What can be said about the risk of second primary malignancies with CAR T-cell agents, especially with the recent boxed warnings added to labels?

The risk of secondary cancers in patients with myeloma is [approximately] 10%. Recently, the FDA has put out a black box warning related to secondary primary malignancies in patients who have received CAR T-cell therapy. This rarely can involve CAR T cells contained within the secondary malignancies, such as T-cell lymphoma. We need to follow patients very carefully and monitor for the development of secondary malignancies. Importantly, the benefits overwhelmingly outweigh the very rare risk of secondary cancers that we’ve identified at least to date.

Is there anything else you’d like to add on the ODAC decisions?

The FDA and ODAC have been central to the progress to date in the treatment of myeloma that has completely transformed the paradigm and improved outcomes for patients with myeloma and their families. On April 12, 2024, the ODAC unanimously voted to include minimal residual disease-negative CR as an end point for accelerated approval in myeloma, which will ensure that we have continued rapid approval of novel agents [allowing] patients access to these new treatments more quickly.

References

1. March 15, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/watch?v=VSjdGeeXb40
2. 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 5, 2024. Accessed April 22, 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
3. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379
4. Abecma delivers sustained progression-free survival versus standard regimens in earlier lines of therapy for relapsed and refractory multiple myeloma based on longer-term follow-up from KarMMa-3. News release. Bristol Myers Squibb. December 11, 2023. Accessed April 22, 2024. https://news.bms.com/news/corporate-financial/2023/Abecma-Delivers-Sustained-Progression-Free-Survival-Versus-Standard-Regimens-in-Earlier-Lines-of-Therapy-for-Relapsed-and-Refractory-Multiple-Myeloma-Based-on-Longer-Term-Follow-up-from-KarMMa-3/default.aspx