ASCT or CAR T cell 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, and emerging data suggest that perhaps it should be considered for earlier lines of treatment.

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 stated [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 been 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 (RVd) 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 [1]. The phase 2 KarMMa trial, investigating idecabtagene vicleucel (ide-cel) in participants 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 participants with MM who received 6 prior lines of therapy and were evaluable for MRD [7]. The MRD-negativity rate was 58% when 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” [1,8].

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 participants 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 participants 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,” said Prof. Manier [1,10,11].

The phase 3 CARTITUDE-6 trial (NCT05257083), comparing head-to-head in the frontline ASCT and CAR T-cell therapy following DRVd, 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. 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. Abstract 635, ASH 2020, 05–08 December.
7. Usmani SZ, et al. J. Clin. Oncol. 2021;39(15)_suppl:8005–8005.
8. Du J, et al. Clin. Oncol. 2022; 40(16)_suppl:8005–8005.
9. Rodríguez-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 14 June, 202315 February, 2024