Practical Considerations for Early Relapsed/Refractory Multiple Myeloma in the Canadian Landscape in 2025

Abstract

Multiple-class drug combinations have long been integral to the management of multiple myeloma (MM). This has led to significant advances in myeloma survival with agents such as lenalidomide and daratumumab moving to frontline therapy. Therefore, relapse therapy requires rational sequencing strategies to prioritize effective regimens with each treatment line without compromising access to subsequent lines.

At first relapse, most transplant-eligible patients would have undergone RVd (lenalidomide, bortezomib, dexamethasone) induction with subsequent consolidative high-dose therapy with autologous stem cell rescue and Len (lenalidomide) maintenance. For transplantineligible patients, frontline therapy with DRd (daratumumab, lenalidomide, dexamethasone) has become the standard of care until myeloma progression or drug intolerance. With the increasing adoption of quadruple therapy in frontline treatment, a significant proportion of patients will soon be multi-class exposed or refractory at early relapse, including exposure to daratumumab, lenalidomide, and bortezomib.

This shift necessitates careful consideration of treatment sequences based on available regimens, which include previous treatment responses, cytogenetic and molecular risk profiles (e.g., high-risk versus standard-risk disease), disease kinetics at relapse, and the potential benefit of therapies with novel mechanisms of action. Achieving and maintaining sustained minimal residual disease (MRD) negativity is also critical, as patients in this category consistently experience better outcomes, regardless of cytogenetic risk or line of therapy.