Case series | How do I treat patients who have relapsed after quadruplet regimen in the first-line in multiple myeloma?

The Multiple Myeloma Hub spoke with Paul Richardson, Dana-Farber Cancer Institute, Boston, US. We asked, How do I treat patients who have relapsed after quadruplet regimen in the first-line in multiple myeloma (MM)?

In this interview, Dr Paul Richardson, shares his approach to treating patients with newly diagnosed MM who become refractory to daratumumab and other quadruplet regimens in the first-line. He discusses second-line treatment strategies following the failure of quadruplet therapies, including the emergence of novel treatment options such as CAR T-cell therapies, bispecific antibodies, and other immunotherapies in earlier lines. Dr Richardson also emphasizes the importance of personalizing treatments based on patient factors, such as age, fitness, and treatment history, highlighting both established and emerging therapies for relapsed MM.

Key points

• The prevalence of quadruplet therapy in the first-line treatment of MM has increased. There have been promising data observed with lenalidomide-bortezomib-dexamethasone (RVd) in combination with daratumumab or isatuximab.
• These quadruplet therapies have shown efficacy in both transplant-eligible and -ineligible patients.
• BCMA-directed immunotherapies, such as CAR-T cell therapies, were initially developed for and have resulted in previously unseen efficacy in the treatment of heavily pretreated MM.
  • However, the indication for CAR T-cell therapies has been expanding, with many trials investigating cilta-cel and ide-cel in earlier lines of therapy. 
  • Ide-cel was most recently approved for the treatment of triple-class-exposed relapsed/refractory MM based on data from the phase III KarMMa-3 (NCT03651128) trial.
• Bispecific antibody therapies have also shown promise in clinical trials in early relapsed disease; however, are not currently approved in this indication. 
• Older and frail patients may not be candidates for CAR T-cell therapies or bispecific antibodies. However, alternative therapies include:
  • Chemotherapy-based approaches, such as cyclophosphamide combinations
  • Pomalidomide-based treatments
  • Melflufen
• Pomalidomide remains an option for patients in early relapse, in particular when combined with other agents such as elotuzumab, proteasome inhibitors, or dexamethasone.
• Selinexor has also shown promise in relapsed disease, particularly when combined with bortezomib and dexamethasone, based on data from the BOSTON (NCT03110562) trial.
• For patients who are naïve to proteasome inhibitors after first-line treatment, bortezomib, ixazomib, or carfilzomib-based therapies are key options.
• Carfilzomib may be used for patients who have progressed after VRd or daratumumab, especially in combination regimens.
• Treating early relapsed disease after the failure of quadruplet therapies is more challenging as myeloma disease biology can become more aggressive in this instance.