Earlier Use of Ide-Cel May Increase Benefit for Patients With High-Risk R/R Myeloma

Krina K. Patel, MD, MSc

The substantial benefit seen with idecabtagene vicleucel (ide-cel; Abecma) across multiple high-risk, triple-class–exposed subgroups of patients with relapsed/refractory multiple myeloma supports continued efforts to expand and improve access to the CAR T-cell therapy in earlier lines of treatment, according to Krina K. Patel, MD, MSc.

Findings from a post-hoc analysis of high-risk subgroups of patients treated in the phase 3 KarMMa-3 trial (NCT03651128) were reported at the 2023 EHA Congress. Ide-cel was shown to elicit clinically meaningful improvements in overall response rate (ORR) and progression-free survival (PFS) vs standard of care (SOC) regimens, irrespective of baseline high-risk disease characteristics. Ide-cel elicited an improvement in PFS vs SOC in subgroups of patients with cytogenetic abnormalities (HR, 0.61), Revised International Staging System (R-ISS) stage III disease (HR, 0.86), high tumor burden (HR, 0.60), extramedullary plasmacytoma (EMP; HR, 0.40), and triple-class–refractory disease (HR, 0.46).

The agent’s toxicity profile was also manageable across subgroups, and toxicity findings from this analysis were consistent with those of the overall population, and data from previous studies.¹

Based on prior data from KarMMa-3, the FDA has accepted a supplemental biologics license application for the approval of ide-cel in patients with relapsed/refractory multiple myeloma who previously received an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.²

“I try to get my patients who are [most] in need the novel therapy first. With SOC CAR T-cell therapy, where it is approved in the fifth line or beyond, most patients who are high risk at diagnosis can't make it to that fifth line. There is a need to get this [therapy] earlier [in the treatment course],” said Patel, who is an associate professor in the Department of Lymphoma/Myeloma, in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, in Houston.

In an interview with OncLive^®, Patel expanded on the importance of evaluating outcomes for treatment with ide-cel in patients with relapsed/refractory multiple myeloma with different high-risk characteristics, key findings from the high-risk subgroup analysis of the KarMMa-3 trial, and how shifting ide-cel to earlier lines of therapy could improve outcomes for both high- and standard-risk patients in this space.

OncLive: What was the rationale for analyzing the outcomes with ide-cel in patients with high-risk features enrolled onto the KarMMa-3 trial?

Patel: KarMMa-3 was our first randomized study of BCMA-specific CAR T-cell therapy for multiple myeloma. It was a monumental moment where we [saw] data that showed that CAR T-cell therapy did much better than our SOC options.

When KarMMa-3 came out, a lot of my high-risk patients went onto the trial. We wanted to do this analysis, because we found out that the majority of patients [enrolled on the trial] were in one of these high-risk categories. It's important to highlight that our patients are different in multiple myeloma. [Additionally], we have new treatments such as monoclonal antibodies, IMiDs, and next-generation PIs, but we give them earlier now. When patients are relapsing in their third or fourth line, they're [considered] higher risk compared with patients in the past who [may have] only received a couple drugs and, over time, got some of these other novel therapies. We don't know the resistance pattern for myeloma.

This study highlighted that high-risk cytogenetics are not the only thing we should be looking at for patient outcomes. That's why we wanted to [identify] other categories that we should be looking at for patients. Hopefully, this [analysis] lays the foundation for the future for [identifying treatment options for] patients who are high risk early vs clonal evolution and resistance patterns [that develop] over time that make patients high risk later on in their treatment trajectory.

Please expand on the trial design of KarMMa-3, as well as the patient population included in the study.

KarMMa-3 was a 2:1 randomized study [of the] CAR T-cell therapy [ide-cel] as a third, fourth, or fifth line of therapy. Patients had to be [previously] exposed to an anti-CD38 antibody, which was a bit different than some of the other studies. In the SOC arm, [patients were randomly assigned to] daratumumab [Darzalex], pomalidomide [Pomalyst] and dexamethasone; daratumumab, bortezomib [Velcade], and dexamethasone; ixazomib [Ninlaro], lenalidomide [Revlimid], and dexamethasone; carfilzomib [Kyprolis] and dexamethasone; or elotuzumab [Empliciti], pomalidomide, and dexamethasone. [These were] mostly options approved in the United States and in other countries because this was an international study.

[The study looked] at an intention-to-treat [ITT] population, which is important. There are patients who we collect for apheresis who we cannot get to CAR T-cell therapy because of the time it takes to make the cells. It usually only takes about 4 weeks, but, during that time, especially for patients with more aggressive disease, they might not be able to make it to the actual cell infusion. [The ITT population included] all those patients who potentially didn't make it to the CAR T-cell infusion.

Could you briefly provide some background on the previously reported findings from KarMMa-3?

The median PFS was 13.3 months for patients who got ide-cel vs 4.4 months for those patients who got any SOC regimen [in the ITT population]. The hazard ratio was 0.49, [translating to a] 51% reduction in the risk of progression or death from myeloma if patients received ide-cel. [That was a] significant hazard ratio for an ITT population.

What high-risk categories were included in this subgroup analysis?

We looked at the data set to investigate [which] patients potentially did not do as well [on ide-cel] as our median in the ITT population. In the end, this study was not powered to look at this analysis. This is a post-hoc evaluation to see [the potential influence of] high-risk features, and this warrants further prospective investigation.

We looked at classical high-risk cytogenetics, [including] 17-P deletion, t(4;14), and t(14;16). We do have information on patients with 1q amplification, but [there were not] enough data [regarding] copy numbers that were increased. [Accordingly], we didn't include that in the analysis.

[We also looked at patients with] R-ISS stage III myeloma. The way R-ISS staging was developed, it was [meant to be assessed] only at diagnosis. However, every trial requires us to give [patients] their [R-ISS] stage prior to going into a treatment for relapsed/refractory myeloma. It can sometimes be hard to find what the R-ISS stage was at diagnosis, and we don't want patients to not be able to [participate in a study] because we did not have that [data]. Therefore, we look at R-ISS staging, and patients who have R-ISS stage III disease tend to have a more disease burden. Their beta-2 and lactate dehydrogenase levels might be elevated, and they might also have high-risk cytogenetics. We realized that this patient group likely had a few different high-risk characteristics. It also had the lowest number of patients, so the data [should be] taken with a grain of salt.

Patients with high tumor burden—those who had more than 50% bone marrow involvement—[were analyzed]. We don't have a great way of [evaluating] high tumor burden with a PET scan or an MRI, so that was not incorporated in this [study], and [high tumor burden here] was just based on bone marrow.

Another category is extramedullary myeloma. We know that patients who have soft tissue involvement tend to not do as well with some of our SOC options. Unfortunately, we don't have data separating paramedullary lesions, meaning something attached to a bone with soft tissue extension, vs true extramedullary liver lesions or lung lesions, but we're still able to look at them all together.

The other [category] was triple-class–refractory disease. Because we now treat patients with triplets and quadruplets up-front or in the second line, our patients are getting all the different classes of drugs early. They get better PFS during that time, so they get more time in remission. However, by the third line, they've seen almost all our [standard] drugs. Patients who are refractory to an anti-CD38 antibody, an IMiD, or a PI don't do well with anything else that's been available. We looked at that data to see how these patients did with ide-cel vs SOC options.

What did the analysis reveal about the effect of high-risk characteristics on response rates with ide-cel vs standard of care?

These were smaller numbers in terms of patient populations in these subgroups, but every high-risk characteristic subgroup did much better [with ide-cel] than [with] SOC. The high-risk cytogenetics [subgroup had] the [longest median PFS of] 11.9 [months with ide-cel] vs 4.2 months [with SOC].

The R-ISS stage III disease [subgroup] had the lowest number of patients, with only 31 on ide-cel and 14 on the standard regimen. [The] median PFS [in this group was] 5.2 months with ide-cel vs 3.0 months [with SOC], and a hazard ratio of 0.86. In that group, we wondered if [R-ISS stage] could become a biomarker. CAR T-cell therapy is different from most of our other therapies because it's not an off-the-shelf [agent], and bridging therapy [is often required]. As a general rule, patients who respond to bridging therapy and have myeloma that is stable or improving do better in terms of efficacy and toxicity compared with patients who have disease that is increasing going into CAR T-cell therapy. Patients with R-ISS stage III have high disease burden and other high-risk potential characteristics. [The question is], should we try to [reduce] myeloma for those patients during that bridging period or apheresis before they go on to CAR T-cell therapy to maximize benefit? This trial didn't show that, but gives us a question to ask, [and a potential way to] improve outcomes for that especially high-risk group.

What should be known about the agent’s safety profile and effect on quality of life in the context of this trial?

Treatment-related mortality and safety are also very important. For KarMMa-3, we thankfully didn't see an increased safety risk when [administering ide-cel] earlier. People thought that patients [might] experience more adverse effects [AEs] if T cells were more naive and hadn't been beaten up like we saw in some of the checkpoint inhibitor trials in myeloma.

We actually saw less cytokine release syndrome [CRS] on average, and no major high-grade CRS [events]. [We also] didn't see any parkinsonism or any of those [neurological AEs]. Overall, [the agent] seems safe, but we want to make sure it is safe for all patients long term, especially for our standard-risk patients, who have other treatment options.

There's [also] some quality-of-life data [for] KarMMa-3 showing that patients do better in regard to quality of life in all different categories when they're getting ide-cel vs continuous SOC options. [Considering those data], we want to get this to our standard-risk patients too, if that's going to improve not just the quantity but quality of their life.

Ide-cel is currently under review for potential FDA approval in earlier lines of therapy for patients with multiple myeloma. What could the ability to access this therapy early in the treatment course mean for this patient population?

This is something that most of us are very excited about. We know that our standard-risk patients will do better than our high-risk patients. Anecdotally, my [standard-risk] patients on this trial are doing better for even longer. Hopefully, we'll have more studies [of ide-cel] with standard-risk patients in the future, but we know that they're going to benefit [from this therapy] even more. Maybe those are the patients we can finally be able to functionally cure.

[However], when it comes to access, we are already not getting enough slots for patients who are in the fifth line. We run out of everything fast, so I'm excited for [this potential option in early lines], but there's a huge need to improve how we can get these slots to allow patients to access this [therapy]. This backlog does not just go on at the academic centers, but at our community centers. There is a lot more work to be done. This is a great start for our high-risk patients, but this is something that we need to look at for all our patients.

How did ide-cel affect soluble BCMA levels vs SOC regimens in these high-risk subgroups, and how might this measure have clinical utility going forward?

The other translational piece of this study was looking at soluble BCMA levels. We were able to show that most patients on both arms had similar levels of soluble BCMA early. We cleared it at a much better level with ide-cel for all the high-risk groups compared with SOC. [BCMA levels] slowly came back at progression, and it was still at lower levels compared with those who progressed on the SOC arm. [This indicates that ide-cel could] potentially change biology to a less aggressive form [of multiple myeloma].

Again, these are early questions, but the data are intriguing, and we’re excited to look at them further. In general, soluble BCMA has also helped us with [identifying] the amount of tumor burden. [Those data] were presented at the 2023 ASCO Annual Meeting. It might be a great biomarker for the future, and I'm excited to hopefully be able to use [it] with these novel therapies.

Dr Patel reports receiving research funding from AbbVie, Allogene, Arcellx, Bristol Myers Squibb, Celgene, Cellectis, Janssen, Nekta, Poseida, Precision Bio, Takeda; she has worked as a consultant or in an advisory role for AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Curio Sciences, Janssen, Karyopharm, Legend Biotech, Merck, Oncopeptides, Pfizer, and Precision Bio.

References

1. Patel K, Rodriguez-Otero P, Manier S, et al. Idecabtagene vicleucel (ide-cel) vs standard regimens in patients with triple-class–exposed (TCE) relapsed and refractory multiple myeloma (RRMM): a KarMMa-3 analysis in high-risk subgroups. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S195.
2. Regulatory applications accepted across three regions globally for Abecma for earlier use in adults with triple-class exposed relapsed and/or refractory multiple myeloma. News release. Bristol Myers Squibb. April 17, 2023. Accessed April 17, 2023. https://news.bms.com/news/details/2023/Regulatory-Applications-Accepted-Across-Three-Regions-Globally-for-Abecma-for-Earlier-Use-in-Adults-with-Triple-Class-Exposed-Relapsed-andor-Refractory-Multiple-Myeloma/default.aspx