The depth and durability of responses seen with these CAR T-cell therapies in refractory myeloma is unprecedented and raises again the question of the role of up-front autologous stem cell transplant in the era of immune therapies, including CAR T-cell therapies.
The treatment of multiple myeloma has evolved substantially in the last 3 decades with the introduction of multiple novel therapies and improvement in survival for patients.1 Up-front consolidation with high-dose chemotherapy and autologous stem cell transplant (ASCT) after initial induction therapy has remained the standard of care for patients over this time.2 The introduction of novel therapies such proteasome inhibitors and immunomodulatory drugs with high response rates led to the reassessment of the role of up-front ASCT.3 Two recent randomized trials (NCT01208662, NCT01191060) have demonstrated significant progression-free survival (PFS) benefit with up-front compared with delayed ASCT even with modern induction therapies.4,5 However, notably with median of 8 and 6 years of follow-up, overall survival has not been reached in either of the studies.
The development of BCMA-directed therapies including autologous CAR T cells is a new chapter in the remarkable progress for myeloma.1,6 There are now two different autologous BCMA CAR-T cell therapies for the treatment of relapsed or refractory myeloma patients with 4 or more prior therapies.7-9 This includes idecabtagene vicleucel (ide-cel; Abecma®; Bristol Myers Squibb; 2SeventyBio), which has an overall response of 73% in relapsed and refractory myeloma, with 33% of patients achieving a complete response or better.7 The median duration of response (DOR) was 10.7 months and median PFS was 8.8 months. Ciltacabtagene autoleucel (cilta-cel; Carvykti™; Janssen, Legend Biotech) similarly showed an overall response of 98% and complete response or better in 82.5% of relapsed and refractory myeloma patients. The median DOR and PFS were not reached, with 54.9% of patients progression-free at a median follow-up of 27 months.9 The depth and durability of responses seen with these CAR T-cell therapies in refractory myeloma is unprecedented and raises again the question of the role of up-front ASCT in the era of immune therapies, including CAR T-cell therapies.
Lessons From CD19 CAR T-Cell Therapies for Diffuse Large B-Cell Lymphoma (DLBCL)
Similar to multiple myeloma, ASCT is an important treatment option for patients with DLBCL, particularly as second line treatment. The development of BCMA-targeted CAR T cells for multiple myeloma has generally followed the trajectory of CD19 CAR T cells for B-cell malignancies. There are now 3 different CD19 CAR T cells: axicabtagene ciloleucel (axi-cel; Yescarta®; Kite Pharmaceuticals), tisagenlecleucel (tisa-cel; Kymriah®; Novartis), and lisocabtagene maraleucel (liso-cel; Breyanzi®; Bristol Myers Squibb), approved for the third-line treatment of DLBCL.10 More recently, 3 randomized trials (NCT03391466, NCT03570892, and NCT03575351) compared treatment with CD19 CAR T cells to ASCT as a second line of treatment, and 2 of these 3 trials have shown a significant benefit in terms of event-free survival (EFS), and both studies also show a trend toward improved overall survival.11-13 These results have led to the US FDA approval of axi-cel and liso-cel for patients with refractory DLBCL after 1 prior line of therapy.
Moving BCMA CAR T-Cell Therapies to Earlier-Line Treatment in Multiple Myeloma
Based on the deep and durable responses with BCMA CAR T-cell therapies in advanced myeloma, 2 randomized trials have now completed accrual in earlier lines of treatment. The KARRMA-3 trial (NCT03651128) evaluated ide-cel compared with standard-of-care combination treatments in myeloma patients after 2 to 4 prior treatments. While the full results are not yet available, recent reports suggest the trial met its primary objective, demonstrating a statistically significant improvement in PFS with ide-cel.14 A similar trial (CARTITUDE-4; NCT04181827) has completed accrual and compares cilta-cel to standard-of-care triple-drug combination in patients with relapsed myeloma and 1 to 3 prior lines of treatment.15 These studies will hopefully establish the role of autologous CAR T-cell therapies in earlier lines of treatment for multiple myeloma.
Can CAR T-Cell Therapies Replace ASCT in Myeloma?
While the efficacy of ASCT is clear, there are substantial logistical challenges and potential short- and long-term side effects, including the risk of transplant-related mortality, second primary cancers, and infections. In the last 2 decades, every time a new class of treatment has emerged for myeloma, physicians and patients have questioned the need for up-front ASCT; despite this, ASCT has continued to remain the standard of care for transplant-eligible myeloma patients. However, with the introduction of CAR T-cell therapies, which provide deep and durable responses in advanced and refractory multiple myeloma and arguably the highest rates of complete responses noted with any treatment for myeloma, we believe it is reasonable to hope that CAR T-cell or other T-cell engaging therapies could potentially replace up-front ASCT as a standard treatment for many patients. Indeed, there are ongoing randomized trials that address this very important question; for instance, CARTITUDE-6 is a global phase 3 trial comparing cilta-cel and ASCT in patients receiving initial induction therapy with daratumumab (Darzalex®; Janssen), bortezomib (Velcade®; Takeda), lenalidomide (Revlimid®; Bristol Myers Squibb), and dexamethasone (DVRd).16 The availability of these therapies has the potential to change the natural history of this disease and improve outcomes for our patients.
"[W]ith the introduction of CAR T-cell therapies, which provide deep and durable responses in advanced and refractory multiple myeloma and arguably the highest rates of complete responses noted with any treatment for myeloma, we believe it is reasonable to hope that CAR T-cell or other T-cell engaging therapies could potentially replace up-front ASCT as a standard treatment for many patients.” – Sham Mailankody MBBS, and Saad Z. Usmani, MD, MBA