Will CAR-T Therapy Replace Transplant in Myeloma and Lymphoma?

Over half a century ago, Bob Dylan released The Times They Are a-Changin’ as a generational anthem of his era. The song’s title is quite applicable to the fields of transplantation and cellular therapy in 2022 – to an extent. T-cell redirecting immunotherapies such as chimeric antigen receptor T-cell (CAR-T) therapy are rapidly expanding as effective options for both myeloma and lymphoma. On the other hand, alkylator-based conditioning for autologous stem cell transplantation (ASCT) has remained largely stagnant for almost 40 years.

Bob Dylan crooned in his now-famous ballad that “the order is rapidly fading, and the first one now will later be last.” Will CAR-T and ASCT switch places as lines of therapy in the next 5 years?

On Monday, April 25, 2022, a satellite symposium to the 2022 Tandem Meeting was held titled 'Autologous Stem Cell Transplantation for Myeloma and Lymphoma will be Replaced by T-Cell Re-directing Immunotherapies within the Next 5 Years – Yes or No?’

Ahead of this session, ASTCT reached out to the 4 invited panelists to get their takes on some of the most immediate unanswered questions in their respective fields. They included:

Myeloma, advantage to CAR-T: Kwee Yong, PhD, FRCP, FRCPath, University College London

Myeloma, advantage to ASCT: Saad Usmani, MD, MBA, Memorial Sloan Kettering

Lymphoma, advantage to CAR-T: Anna Sureda, MD, PhD, Institute Catala d’Oncologia

Lymphoma, advantage to ASCT: Gunjan Shah, MD, Memorial Sloan Kettering

MYELOMA – What type and magnitude of data would be needed to convince you that B-cell maturation antigen (BCMA)–directed CAR-T therapy is superior to frontline ASCT?

Dr. Yong: The gold standard evidence would be from a randomized controlled trial (RCT): for example, an improvement in sustained measurable residual disease (MRD) negativity (2 years, at least 10-5 level), of the order of 15-20%. This could serve as a surrogate measure of longer-term outcomes such as progression-free survival (PFS) and second PFS (PFS2). Having said that, evidence from an RCT is only part of the story. Real-world data (which will take longer to accrue) are needed before the true benefit of CAR-T therapy is revealed. Access and resource implications will also determine how “superior” a therapy really is.

Dr. Usmani: We would need to see, at the very least, a significant increase in the rate of sustained MRD negativity (at 10-6 sensitivity for at least 2 years) with a defined duration of therapy. A profound PFS benefit would also convince me. While PFS2 and overall survival (OS) are ideal, we have to be pragmatic because these data will take a decade to mature and the field will have moved on by then.

MYELOMA – Can ASCT and T-cell redirecting therapies be metaphorical friends and not foes? Do you foresee a world where, instead of the two vying for the same spot, they are used in tandem for certain patients?

Dr. Yong: This is an attractive option, and it will allow us to harness the unique benefit of each modality while combining their immunotherapeutic effects. That being said, it will not be suitable for all-comers the way that ASCT is currently considered the standard of care for fitter, newly diagnosed patients. We need clinical trials to inform us of the safety and true benefit of these approaches, and how to select patients in a risk-stratified way.

Dr. Usmani: This is quite possible. Ongoing trials investigating this strategy have focused on high-risk patients in some way, and ASCT followed by CAR-T or bispecific antibodies may end up being helpful for these subgroups. That being said, we need to see the efficacy and safety of these strategies in clinical trials first.

LYMPHOMA – In the past year, two large trials have shown improved outcomes with CAR-T therapy instead of ASCT in relapsed/refractory large B-cell lymphoma (R/R LBCL). Why are, or aren’t, these results practice-changing?

Dr. Sureda: The long-term outcome of patients with primary refractory and early-relapse LBCL with the use of salvage chemotherapy followed by ASCT is quite poor, with PFS not higher than 20%. Both ZUMA-7 and TRANSFORM have demonstrated that CAR-T therapy can significantly improve event-free survival, which was the primary endpoint in both trials. Without any doubt, these results will establish CAR-T cells as the new standard of care in this high-risk group.

Dr. Shah: It’s worth noting that the BELINDA trial of tisagenlecleucel (tisa-cel, Kymriah®) did not meet its primary endpoint. But ZUMA-7 and TRANSFORM are definitely practice-changing for the right population. Two unanswered questions remain. First, does this approach make sense for all patients, or just the patient population enrolled in ZUMA-7 and TRANSFORM? Second, is it logistically feasible to proceed with CAR-T therapy in all such patients?

LYMPHOMA – Based on the results of ZUMA-7 and TRANSFORM, are there any patients with R/R LBCL for whom you would still recommend ASCT rather than CAR-T?

Dr. Sureda: The trials we’re discussing focused on primary refractory disease and early relapses. Late relapses were not included in the trials; these patients have a better prognosis with salvage therapy and ASCT, and I do not think this concept is going to be changed by the positive results of ZUMA-7 and TRANSFORM. In addition, these trials do not solve the question of whether CAR-T is better than the standard of care in patients who respond to second-line salvage chemotherapy. ASCT might still be an adequate option for these patients.

Dr. Shah: Not all patients with early relapses or refractoriness to first-line therapy will be able to proceed to CAR-T logistically. Some patients have rapidly growing disease and require immediate therapy. Waiting for insurance clearance and slot availability for leukapheresis before proceeding to salvage chemotherapy might not be practical. These types of patients were generally not enrolled on the CAR-T arms of the studies being discussed. And of course, CAR-T therapy is not yet available in most of the world.

These answers only scratch the surface of what will end up being a lively debate on April 25. Interested in learning more? As Bob Dylan himself might have said about our a-changin’ times: