BLOG: Autologous stem cell transplantation for myeloma in the CAR-T era
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Multiple myeloma is the most common indication for autologous stem cell transplantation worldwide.
Upfront treatment of multiple myeloma results in prolongation of PFS, and a greater proportion of patients achieve deep responses after ASCT than alternative consolidation.
However, OS is similar even if ASCT is deferred and performed at relapse, although this strategy is often underutilized in practice.
In the past 2 years, BCMA-targeted chimeric antigen receptor T-cell therapy has emerged as a therapeutic modality that can produce deep durable responses even among patients with multiple relapsed or refractory multiple myeloma.
This naturally has generated enthusiasm to explore CAR-T earlier in the disease course given the possibility that remissions after CAR-T could be even longer in the upfront multiple myeloma setting.
How should we think about the upfront CAR-T question, and what studies should we be designing?
The ability of CAR T cells to produce measurable residual disease (MRD)-negative remissions is superior to almost any other therapeutic regimen in multiple myeloma. However, studies comparing MRD negativity after ASCT vs. after CAR-T in the upfront setting can lead to premature and misleading conclusions.
PFS or the duration of first remission remains the primary benefit of ASCT, which is a well-established, safe and accessible therapy.
Data from Gay and colleagues suggested that, despite similar MRD negativity rates, patients who received non-ASCT consolidation tend to relapse earlier. Therefore, a PFS benefit needs to be the primary comparison for such studies.
The ideal patient for studies of upfront CAR-T would be a patient with high-risk multiple myeloma who is underserved by all of our recent advances in the field, and for whom MRD clearance is a desirable therapeutic goal.
Should our strategy be a synergistic one for high-risk multiple myeloma using ASCT and CAR-T sequentially, or should it be an either/or approach tested in a randomized clinical trial?
Although de-escalation of therapeutic steps is a desirable goal, it may again be premature and shortsighted to design head-to-head studies without exploring potential synergistic approaches.
Enrollment is underway for nonrandomized studies exploring the role of CAR T-cell therapy instead of ASCT for patients with multiple myeloma. The KarMMa 4 trial of idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio) will include patients with high-risk disease, and the CARTITUDE-2 study of ciltacabtagene autoleucel (Janssen, Legend Biotech) will include standard-risk and high-risk cohorts.
The Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) also is initiating two multicenter phase 2 clinical trials to evaluate idecabtagene vicleucel in the post-ASCT context to augment suboptimal responses (less than very good partial response) after ASCT or as additional consolidation for high-risk multiple myeloma after ASCT.
The most recent BMT-CTN State of the Science Symposium recommended that the network undertake studies that explore the use of CAR-T and bispecific antibodies in sequential fashion after ASCT in high-risk multiple myeloma.
References:
- Garderet L, et al. Biol Blood Marrow Transplant. 2020;doi:10.1016/j.bbmt.2020.04.016.
- Gay F, et al. J Clin Oncol. 2021;doi:10.1200/JCO.2021.39.15_suppl.8002.
- Heslop HE, et al. Transplant Cell Ther. 2021;doi:10.1016/j.jtct.2021.08.016.