Maximilian Merz, MD

EHA25: Key Findings in Multiple Myeloma

Question

In your view, what studies presented during the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress have practice-changing implications for the treatment of multiple myeloma?

Answer

The IKEMA study (ClinicalTrials.gov Identifier: NCT03275285) showing for the first time superiority of carfilzomib-dexamethasone (Kd) in combination with the CD38 antibody isatuximab compared with Kd with regard to response rates and progression-free survival (PFS) has, in my opinion, direct implications for day-to-day care.¹ This is the first phase 3 trial showing efficacy of isatuximab in combination with a [proteasome inhibitor]. Isatuximab was approved for relapsed/refractory myeloma in combination with pomalidomide-dexamethasone based on the results from the ICARIA-MM trial (ClinicalTrials.gov Identifier: NCT02990338).² With the current results, we see for the first time superiority of an isatuximab-containing regimen with a [proteasome inhibitor]. This broadens the spectrum of the respective agent. Furthermore, the updated results from early B-cell maturation antigen (BCMA)-targeted immunotherapies, including chimeric antigen receptor (CAR) T cells, are promising but need longer follow-up and later-stage trials to show whether the encouraging results will change our practice in the future.

Question

Was the finding from SWOG-1211 at EHA25³ — that the addition of elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) induction and maintenance in newly diagnosed multiple myeloma did not improve outcomes — surprising? Why or why not?

Answer

It was a bit surprising seeing no differences in PFS, especially because elotuzumab was applied during maintenance therapy. We saw in the past that elotuzumab in combination with RD needs some time to unfold its action. It just shows us that high-risk patients are a special population with unmet needs. Nevertheless, it is a great to finally see trials designed to target this specific population. It will be exciting to see further results from trials like the CONCEPT study (ClinicalTrials.gov Identifier: NCT03104842) of [isatuximab, carfilzomib, lenalidomide, and dexamethasone] in high-risk patients that were presented by [Katja Weisel, MD, of the University of Hamburg-Eppendorg, Germany,] at EHA and other trials using quadruplet therapies in high-risk patients.⁴

Question

Proteasome-based therapy in the maintenance setting of newly diagnosed multiple myeloma: Time to progression was significantly prolonged with ixazomib in the phase 3 TOURMALINE-MM4 trial (ClinicalTrials.gov Identifier: NCT02312258).⁵ What did the researchers conclude about the effect of the drug on overall survival? Was this conclusion surprising?

Answer

Overall survival (OS) data are not mature at this time to conclude on the efficacy of ixazomib to prolong OS in transplant-ineligible patients. However, this is a very important endpoint, especially in maintenance trials, because for the current standard of care (lenalidomide), several trials and a meta-analysis led by [Philip L. McCarthy, MD, of the Roswell Park Comprehensive Cancer Center in Buffalo, New York,] demonstrated an overall survival benefit compared with observation/placebo.⁶ Therefore, longer follow-up for the TOURMALINE-MM4 trial is needed.

Question

In the IKEMA trial in relapsed/refractory multiple myeloma, it was determined that the addition of isatuximab to Kd provided a “superior, statistically significant improvement” in PFS with “clinically meaningful improvement in depth of response,” and it was suggested that the combination could represent a possible new standard of care for patients in this setting. What do we know about the addition of isatuximab on overall survival in this population?

Answer

In the ICARIA-MM trial of isatuximab-pomalidomide-dexamethasone compared to pomalidomide-dexamethasone in relapsed/refractory multiple myeloma, an early OS analysis showed a trend towards prolonged OS without reaching statistical significance. Therefore, longer follow-up is needed for both trials (IKEMA and ICARIA-MM) to see whether the very promising results of long-lasting, deep remissions and longer PFS with isatuximab translate into prolonged OS in relapsed/refractory multiple myeloma. This is also very important since OS benefits have been shown for daratumumab combinations, the other CD38 antibody, in comparable populations of relapsed/refractory multiple myeloma.

Question

There have been encouraging data on the use of chimeric antigen receptor T-cell (CAR-T) therapies in relapsed/refractory multiple myeloma (eg, KarMMA,⁷ CARTITUDE-1⁸). Despite the promising developments with these adoptive cell therapies, what are your concerns about their use, if any?

Answer

The latest results from [the American Society of Hematology, the American Society of Clinical Oncology], and EHA show that CAR-T cells are here to stay in multiple myeloma. However, there are still a lot of unanswered questions for future trials: How should we assess treatment response? Is minimal residual disease-negativity after CAR really comparable to minimal residual disease-negativity after conventional therapy? Do we need to incorporate imaging to rule out extramedullary progression that occurs more often in heavily pretreated patients? Can we identify biomarkers that predict response (eg, BCMA expression/serum levels)? What are modes of resistance to CAR-T cells? And finally, should we move CARs to earlier lines, especially to treat high-risk patients? These and many more open questions need to be answered to define the clinical value of CAR therapy of myeloma in the future.