Evolution of Multiple Myeloma Treatment Paradigms and Relapse Management

Dr. Nooka traces the 15-year evolution of multiple myeloma therapy from doublet regimens to current quadruple combinations. Initially, treatments included doublet therapies, progressing to triplet regimens (VRd, VCd, VTd), and now to quadruple regimens incorporating CD38 antibodies with steroids. This progression has dramatically improved complete response (CR) rates: thalidomide-dexamethasone achieved 4% CR rates, lenalidomide induction increased this 10-fold, and current four-drug regimens reach 80% CR rates post-transplant.

The introduction of minimal residual disease (MRD) testing at the 10^-6 threshold represents a paradigm shift, allowing measurement of 1 myeloma cell among a million bone marrow cells. This deeper response assessment translates into survival advantages and represents the pathway toward potential cure by increasing the proportion of patients achieving and sustaining MRD negativity.

For 2026, Dr. Nooka advocates that quadruple therapy should be standard for all patients, including transplant-eligible, ineligible, and even frail patients, as dose-reduced 4-drug regimens prove more efficacious than 3-drug alternatives. This aggressive frontline approach creates new challenges at relapse, as patients have been exposed to multiple effective agents.

Using the PERSEUS trial as an example, patients progressing at 18 months while receiving daratumumab and lenalidomide maintenance represent a fundamentally different population than those relapsing after 7 years on single-agent lenalidomide. For early progressors on dual maintenance, Dr. Nooka would immediately consider BCMA CAR-T therapy as the most effective available option.

He emphasizes the importance of bone marrow biopsies at every relapse to assess cytogenetic evolution, as patients acquire additional abnormalities with each progression. Next-generation sequencing provides comprehensive genetic profiling beyond traditional FISH, enabling personalized treatment decisions based on emerging high-risk features and biological changes driving disease progression.