PFS Benefit of Ide-cel in Myeloma Maintained in Higher-Risk Population
During a live event, Samuel M. Rubinstein, MD, discussed the efficacy and safety outcomes from the KarMMa-3 trial.
Samuel M. Rubinstein, MD, MSCI
Patients with relapsed multiple myeloma can receive a variety of options based on which agents they have received in prior lines of therapy, but now oncologists are looking toward the approved chimeric antigen receptor (CAR) T-cell therapies, particularly for patients whose disease relapses rapidly. During a Case-Based Roundtable event in Durham, North Carolina, Samuel M. Rubinstein, MD, MSCI, associate professor of medicine at UNC School of Medicine in Chapel Hill, shared the most current results from CAR T-cell trials and discussed a case where patients would be eligible after 2 prior lines of therapy. Participating oncologists discussed their current approach to referring patients for CAR T-cell therapy and what roadblocks they see at referral before Rubinstein explored the efficacy and safety data in greater depth to identify the benefits and risks of this approach.
Targeted OncologyTM: What led to the approval of idecabtagene vicleucel (ide-cel; Abecma) after 2 prior lines of therapy for multiple myeloma?
Samuel M. Rubinstein, MD, MSCI: The trial supporting ide-cel for relapse after 2 to 4 lines of therapy was the KarMMa-3 trial [NCT03651128]. This trial took patients who had had 2 to 4 prior regimens of myeloma-directed therapy. They had to have an immunomodulatory agent [IMiD], a proteasome inhibitor [PI] and daratumumab [Darzalex], although they did not have to be refractory to all those agents. They had to be refractory to the last regimen, but that didn't necessarily need contain all or even one of those drugs. Patients were randomly assigned 2:1 to get ide-cel with optional bridging therapy [vs standard of care]. A number of patients got no bridging therapy. They got a single ide-cel infusion with escalating doses of 150, 300, and 450 million cells. The FDA approved dose is 450 million cells, so that's the relevant group to pay attention to. Those randomly assigned to the control arm received investigators choice of one of those 5 regimens: daratumumab, pomalidomide [Pomalyst], and dexamethasone; daratumumab, bortezomib [Velcade], and dexamethasone; ixazomib [Ninlaro], lenalidomide [Revlimid], and dexamethasone; carfilzomib [Kyprolis] plus dexamethasone; or elotuzumab [Empliciti], pomalidomide, and dexamethasone, and they continued that until progression. Upon progression, those patients could cross over to get ide-cel. The primary end point was progression-free survival [PFS] with other standard secondary end points.
[Nearly] all patients were refractory to some IMiD; for most patients that was lenalidomide.1 Over 70% of patients were refractory to a PI, and 90% of patients plus were refractory to anti-CD38 monoclonal antibody. The majority of patients who were treated on the KarMMa-3 trial were truly triple-class refractory, which is most of the patients who are having early relapses in 2025. Most of them got 2 to 4 lines of therapy within 4 years, [which is] a high-risk group. Two-thirds were triple class refractory, and almost 100% were refractory to daratumumab.
What are the updated efficacy data from this trial?
The updated PFS is from the [2024] American Society of Hematology Annual Meeting.2 The median PFS for ide-cel is 13.8 months vs 4.4 months for the control arm. When I first digested this information, the part that was most striking to me was how poorly the patients on control arm do. That includes some daratumumab-based regimens, and carfilzomib/dexamethasone is a pretty effective doublet that has had a median PFS of 15 to 20 months in trials. On this study, with a largely daratumumab-refractory population, the median PFS is 4 months—a little less than I thought it was going to be, and ide-cel significantly improved on that with an HR of 0.49 [95% CI, 0.38-0.63]. Overall survival [OS] is a little early [to read out], but we do not see a statistically significant advantage in OS. Keep in mind that patients treated on the control arm could cross over to get ide-cel on progression, which informs how you interpret the OS data.
Within the first 6 months, you do see some increased hazard of death. This is a theme that emerges with all CAR T-cell therapy studies, where you do get a bit more death early because you're having to bridge patients, hold therapy, and you have some toxicity that results in death. In the first few months of therapy, the standard arms tend to do better in terms of OS. In the long run, the CAR T product arm crosses [the control arm on the Kaplan-Meier curve]. You see the same phenomenon with ciltacabtagene autoleucel [Carvykti] in its trials, and you see a similar phenomenon with immune checkpoint inhibitor trials in solid tumors.
Responses are clearly better with the ide-cel arm compared with the standard arm, 70% vs 42% overall response, respectively.3 Most of the responses with ide-cel were very good partial responses or better; 60% plus percent of patients got a very good partial response or better. MRD negativity was achieved by 35% vs 2% in the ide-cel vs standard-of-care arms, respectively, and that is by next-generation sequencing with a threshold of 10-5. PFS2 [second progression-free survival] was also significantly better for those who received ide-cel, so you get benefit in the first line, and then it can take longer to have the second line of progression as well.
What adverse events (AEs) were reported in the KarMMa-3 trial?
They are getting a therapy that has risk of cytokine release syndrome [CRS] and ICANS [immune effector cell–associated neurotoxicity syndrome], which is not a risk associated with any regimens in the control arm.1 Patients experienced a lot of CRS and ICANS in the ide-cel arm. Most of it is grade 1 or 2; the probability of grade 3 CRS was quite low, at 4%. Grade 3 ICANS [requires admission to] the intensive care unit and multiple different agents to treat, and often intubation for airway protection, but that severity of ICANS was quite low at 7 patients, or 3% of the population, and only 15% got ICANS at all. A lot of the neurologic events are things like headache or transient confusion, which is sometimes related to other things that happen to these patients besides ICANS. [CRS and ICANS] are not happening on the control arm.
There was infection because we're lymphodepleting patients by giving them a B-cell maturation antigen–directed therapy, which is toxic to normal plasma cells, but there was a similar rate of infection and infectious morbidity on the ide-cel arm to the control arm.If you look at the landscape of relapsed myeloma regimens with triplets, these are patients who have been getting plasma cell–directed therapy for years. They have very dysfunctional immune systems due to the disease as well, so the baseline rate of infection in patients with multiple myeloma is very high. Any time you're interpreting infectious data in a myeloma trial, especially in a relapsed myeloma trial, you need to keep that in mind. There was a small increase in the probability of grade 3 infectious events with ide-cel vs standard of care, 24% vs 18%, but for the benefit of almost a year of PFS, in my opinion, it’s probably worth it.
DISCLOSURES: Rubinstein previously reported consulting with Janssen, Sanofi, Roche Diagnostics, and EUSA Pharma.
