ASCT or CAR T as first-line therapy for MM?

Although autologous stem cell transplant (ASCT) is still the frontline therapy for patients with multiple myeloma (MM), CAR T-cell therapies have demonstrated high efficacy rates in later treatment lines. Prof. Salomon Manier (Lille University Hospital, France) compared the value of ASCT and CAR T-cell therapies for the treatment of patients with MM.

“We do not have data from phase 3 trials comparing ASCT to CAR T-cell therapy in patients with MM,” Prof. Manier started his presentation [1]. “Therefore, we do not yet know which is the better option. We can, however, speculate on this topic using the currently available data.”

ASCT has shown to deliver an additional 1 to 2 year progression-free survival when added to a standard-of-care therapy [2–5]. The data does not demonstrate a benefit of ASCT on overall survival. “However, when we look at the IFM2009 trial, we can see that 76% of the patients who relapsed in the control arm received delayed ASCT, confounding the overall survival data,” added Prof. Manier [1,3]. Furthermore, additional ASCT is associated with higher minimal residual disease (MRD)-negativity rates (10^-6) than the standard triple therapy of lenalidomide, bortezomib, and dexamethasone (VRd) alone (29.8% vs 20.4%; P=0.01) [3]. Similarly, higher 1-year persistent MRD-negativity rates (10^-5) were reported for carfilzomib, lenalidomide, dexamethasone (KRd) plus ASCT than for KRd alone (90% vs 78%).

“What can we expect from CAR T-cell therapies in terms of MRD negativity?” asked Prof. Manier. The KarMMa trial, investigating idecabtagene vicleucel (ide-cel) in patients with MM in the late-stage setting, showed an MRD-negativity (10^-5) rate of 48% for participants who were treated with the recommended dose of ide-cel [6]. Also, in the phase 1b/2 CARTITUDE-1 trial, ciltacabtagene autoleucel (cilta-cel) displayed an MRD-negativity rate of 91.8% in patients with MM who received 6 prior lines of therapy and were evaluable for MRD [7]. The MRD-negativity rate was 58% if the complete study population was considered. “Then we have the DUAL Fast CAR T cells, targeting BCMA and CD19,” continued Prof. Manier. “A phase 2 study evaluating this option in a heavily pre-treated patient population showed that 100% of the participants who were evaluable for MRD (27 out of 28) reached MRD negativity” [8].

Prof. Manier commented that the results from these trials do not come from intention-to-treat populations but from patients who actually received CAR T-cell therapies. The KarMMa-3 trial (n=386) did provide results from an intention-to-treat population. The included participants had received 2 to 4 prior lines of therapy and were randomised 2:1 to ide-cel or a standard regimen, resulting in a clear progression-free survival benefit for patients who were treated with ide-cel (13.3 months vs 4.4 months; HR 0.49; P<0.0001) [9]. In total, 20% of the patients reached a complete response or better plus MRD negativity (10^-5). “Furthermore, emerging data is showing that early CAR T-cell therapy is likely to result in better responses than when this type of therapy is administered in later lines [10,11],” said Prof. Manier.

The phase 3 CARTITUDE-6 trial (NCT05257083), comparing ASCT and CAR T-cell therapy head-to-head in the frontline, will provide more insights. “Since a high tumour burden is a risk factor for severe cytokine release syndrome (CRS), the results of this trial may show us that frontline CAR T-cell therapy reduces the rate of severe CRS compared with administering CAR T-cell treatment in later lines of therapy,” added Prof. Manier.

1. 1. Manier S. CAR-T versus ASCT in Myeloma. JS03-2, European Society for Blood and Marrow Transplantation (EBMT) 49^th Annual Meeting, 23–26 April 2023, Paris, France.
   2. Attal M, et al. N Engl J Med 1996;335(2):91–97.
   3. Attal M, et al. N Engl J Med 2017;376:1311–1320.
   4. Richardson PG, et al. N Engl J Med 2022;387:132–147.
   5. Gay F, et al. Lancet Oncol. 2021;22(12):1705–1720.
   6. Raje NS, et al. Session 635, ASH 2020, 5­–8 December.
   7. Usmani SZ, et al. Journal of Clinical Oncology 2021; no. 15_suppl (May 20, 2021) 8005–8005.
   8. Du J, et al. Journal of Clinical Oncology 2022; no. 16_suppl (June 01, 2022) 8005–8005.
   9. Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002–1014.
   10. Cohen AD, et al. JCI. 2019;129(6):2210–2221.
   11. Garfall AL, et al. Blood Adv. 2019;3(19):2812–2815.

 

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Posted on 3 May, 20233 May, 2023