With two recently approved chimeric antigen receptor T therapies targeting B-cell maturation antigen, this novel platform has altered the treatment paradigm for heavily-pretreated patients with multiple myeloma.
Ever since high-dose melphalan with autologous stem cell transplantation (ASCT) became standard-of-care for multiple myeloma (MM), many have sought a replacement. Part of the reason is the historical toxicity of ASCT; however, advances in supportive measures have significantly improved transplant-related morbidity and mortality, thereby allowing it to expand to wider populations and to be performed in the ambulatory setting.1-3 Perhaps, in part, the desire to find an alternative to ASCT stems from the perceived lack of refinement of the continued use of myeloablative chemotherapy for a disease in which clinicians have many highly effective novel agents and cellular/immunotherapies.
Nowhere is this circumstance more apparent than at the imminent collision of ASCT with chimeric antigen receptor (CAR) T-cell therapy. With two recently approved CAR T therapies targeting B-cell maturation antigen (BCMA), this novel platform has altered the treatment paradigm for heavily-pretreated patients with MM. The logical progression is to investigate if CAR T-cell therapy can challenge and supplant ASCT (with or without maintenance therapy) as a principal component of frontline MM therapy.
At the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022), Amrita Krishnan, MD, Director of the Judy and Bernard Briskin Center for Multiple Myeloma Research, professor, Department of Hematology & Hematopoietic Cell Transplantation, and chief, Division of Multiple Myeloma, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Cancer Center will debate this topic with Saad Z. Usmani, MD, MBA, FACP, chief, myeloma service, Memorial Sloan Kettering Cancer Center, New York, New York.
Krishnan is in favor of ASCT followed by maintenance therapy, but Usmani believes that CAR T-cell therapy will replace it. The hurdles that CAR T-cell therapy must overcome to replace ASCT are substantial, not only because of the proven efficacy of ASCT compared with other therapies but also because of ASCT’s toxicity profile, the known effectiveness of subsequent therapies, and the favorable financial burden in comparison with CAR T-cell therapy. The debate will be September 29, 2022, at 1:58 pm during the meeting’s Multiple Myeloma session.
Evidence Supports Autologous Stem Cell Transplantation as the Current Standard for Frontline Consolidation
In the era predating novel MM therapies, the MRC Myeloma VII trial (NCT00002599) and an Intergroupe Francophone du Myélome (IFM; IFM2009) trial demonstrated an overall survival (OS) benefit of ASCT-based frontline therapy compared with prolonged nonmyeloablative conventional chemotherapy.4,5 The subsequent introduction of highly effective novel therapies led to similar studies comparing transplant and nontransplant frontline strategies (Table 16,7,8). The IFM 2009 study examined lenalidomide-bortezomib-dexamethasone (RVD) induction followed by ASCT vs RVD for 8 cycles without ASCT, with both arms receiving 1 year of lenalidomide maintenance.6,7 Although the primary end point of progression-free survival (PFS) was superior in the transplant arm, OS has remained statistically comparable. It results in part from the increased utilization of ASCT at first relapse among the nontransplant cohort (76.7%), but also the expansion of novel and immunotherapies available as salvage options. This study established that ASCT could be performed in the front line or at first relapse without sacrifice.
More recently, the phase 3 DETERMINATION study (NCT01208662) compared similar cohorts with those of IFM2009, with both arms receiving maintenance lenalidomide until progression or intolerance.8 Overall, the findings were similar to IFM2009 with superior PFS and comparable OS between cohorts. Notably, however, among patients with high-risk cytogenetics, ASCT yielded a particularly superior median PFS (55.5 months vs 17.1 months) and 5-year OS (63.4% vs 54.3%). To date, only a minority of patients at first relapse have received a subsequent ASCT (28%), although this proportion is expected to increase with longer follow-up.
Current State of CAR T as a Standard Therapy for Advanced Myeloma
CAR T therapy has revolutionized the treatment of advanced, relapsed/refractory MM, with the addition of 2 approved agents, idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti); others are in clinical development.9 Ide-cel, in the pivotal phase II KarMMa trial (NCT03361748), yielded a median PFS of 8.6 months in a heavily pretreated patient population.10,11 At a median follow-up of 28 months in a similarly refractory cohort from CARTITUDE-1 (NCT03548207), the median PFS of cilta-cel had not yet been reached at the last analysis, with a 2-year PFS of 60.5% (Table 2).12,13 Responses with these cellular therapies are deep, especially with cilta-cel, for which recent highlights reported 55% sustained minimal residual disease (MRD) negativity (10-5) for 12 months or more, correlating with a 79% 2-year PFS.
Although ide-cel and cilta-cel are now established as a standard therapy option for eligible patients with triple-class refractory MM, data on earlier use are immature. CARTITUDE 2 (NCT04133636), a multiarm exploratory phase 2 trial, has reported early results from deploying cilta-cel in patients with 1 to 3 prior lines of therapy (cohort A) and patients with early relapse after 1 line of therapy (cohort B), both with complete response (CR) rates exceeding 80% and 6-month PFS rates exceeding 90%.14,15 However, the most provocative arm is exploring substitution of cilta-cel for ASCT as consolidation (Cohort E), which has yet to report findings. KarMMa-4 is similarly examining ide-cel for frontline consolidation in high-risk populations in lieu of ASCT.16 Although results of these studies will yield some insight into the feasibility of CAR T replacing ASCT, they are not powered to answer that question. The upcoming international phase III CARTITUDE-6/EMN trial (NCT05257083), however, will directly compare ASCT with cilta-cel, both following daratumumab plus RVD induction, in a study powered to assess coprimary end points of PFS and sustained MRD-negative CR (10-5 for ≥12 months).
The Imminent Collision between CAR T-cell Therapy and ASCT
CARTITUDE-6, and others pitting CAR T-cell therapy against ASCT as consolidation, will be required to answer questions beyond comparative efficacy. Whereas the cellular component of ASCT is solely for hematopoietic rescue, to date, the impact of intensive induction therapy on CAR T-cell therapy production, expansion, and function remains unclear, both from the standpoint of potential T-cell impairment and reduced in vivo antigenic stimulation.17
The toxicity profile of consolidative ASCT is well established and generally confined to the acute setting. Among 15,999 patients reported to the Center for International Blood and Marrow Transplant Research who received high-dose melphalan with ASCT between 2013 and 2017, 100-day nonrelapse mortality was 0% in those younger than 70 years and 1% among those 70 years or older.1 Among published studies, BCMA CAR T therapy has led to acute, life-threatening toxicities as well as delayed or prolonged adverse events such as cognitive and motor neurotoxicity, second primary malignancies, and delayed hematopoietic recovery.10,12 Although mitigation efforts have reduced immune-related toxicities, and fewer prior therapies will theoretically result in more resilient immune and hematopoietic systems, this residual robustness of the autologous CAR T-cell therapy cells could potentially raise the risk of immune-related toxicity in a relatively treatment-naïve population.
Although ASCT with maintenance has long been the standard, substantial evidence exists demonstrating the efficacy of subsequent therapies after relapse.6 Frontline CAR T studies must also demonstrate that early use of CAR T-cell therapy does not impair therapies deployed after relapse, including stem cell collection and ASCT; therefore, PFS2 (time to second objective disease progression) and OS are imperative secondary end points.
High-dose melphalan with ASCT does have a transient negative impact on quality of life (QOL) metrics.18 Pivotal BCMA CAR T-cell therapy studies reported improvements in QOL, although many patients had advanced, symptomatic disease and the studies lacked control groups.19 Whether CAR T-cell therapy can meaningfully improve QOL among patients with controlled disease relative to standard of care remains to be seen.
Beyond PFS, all of the abovementioned end points (toxicity, QOL, OS, PFS2) are needed to gauge the relative efficacy and cost-effectiveness of these 2 modalities.20 With an established median PFS exceeding 5 years, a survival benefit among those with high-risk cytogenetics, manageable and predictable toxicity, and total treatment cost representing a fraction of that of CAR T-cell therapy, ASCT with maintenance is unlikely to be overtaken as frontline consolidation. Unless CAR T can effectively cure a substantial proportion of patients with MM, it would best serve patients as a complement to ASCT after relapse or potentially for those with suboptimal response to ASCT.