Minimal Residual Disease (MRD) testing is gaining prominence in multiple myeloma research, offering a more sensitive measure of treatment response and long-term outcomes. Recent clinical trials and regulatory considerations are highlighting MRD negativity as a crucial endpoint in evaluating new therapies.
The Significance of MRD in Multiple Myeloma
MRD testing utilizes advanced techniques like next-generation flow cytometry and next-generation sequencing to detect minimal levels of disease that conventional methods might miss. Surbhi Sidana, MD, MBBS, vice chair of the American Society of Hematology’s Committee on Communications and associate professor of medicine at Stanford University, explains that MRD testing is "a more sensitive technique to detect disease that cannot be detected by conventional technologies."
Historically, myeloma was evaluated through monoclonal proteins, free light chains in the blood and urine, and the percentage of plasma cells in the bone marrow. However, MRD testing allows for the detection of disease at levels undetectable by these traditional methods.
Regulatory and Clinical Trial Advancements
The FDA's Oncologic Drugs Advisory Committee (ODAC) is considering MRD as a surrogate endpoint for drug approval, indicating a potential shift in how new myeloma treatments are evaluated. This move could accelerate the approval process for therapies that demonstrate high rates of MRD negativity.
Several recent clinical trials have focused on MRD negativity as a primary or secondary endpoint. The CEPHEUS trial, presented at the IMS 2024 meeting in Brazil, used MRD negativity as its primary endpoint. The IMROZ trial (NCT03319667) also demonstrated higher MRD negativity rates with quadruplet induction therapy, although its primary endpoint was progression-free survival (PFS).
Impact of MRD Dynamics on Clinical Outcomes
A retrospective analysis of 220 newly diagnosed multiple myeloma (NDMM) patients, who underwent flow cytometry-based MRD tests at multiple time points after therapy initiation, showed that achieving MRD negativity significantly improved both progression-free survival (PFS) and overall survival (OS) (P < 0.0001 for both). The study also found that maintaining MRD negativity for at least 12 months was associated with an 83% reduction in the risk of progression or death (95% CI, 0.09-0.34; P < 0.0001) and a 69% reduction in the risk of death (95% CI, 0.13-0.76; P = 0.0098).
Loss of MRD negativity was associated with poor PFS (hazard ratio [HR] 0.01, 95% CI 0-0.06, P < 0.0001) and OS (HR 0.03, 95% CI 0-0.24, P = 0.0008). Notably, 70% of patients who lost MRD negativity had high-risk cytogenetic abnormalities (HRCAs). The predictive value of MRD status was independent of baseline risk factors, such as high-risk cytogenetic abnormality, International Staging System (ISS), or Revised (R-)ISS staging.
The Future of MRD in Myeloma Treatment
The increasing emphasis on MRD negativity in clinical trials and regulatory decisions underscores its importance as a prognostic marker and a potential surrogate endpoint for drug approval. As MRD testing becomes more integrated into clinical practice, it is expected to play a crucial role in tailoring treatment strategies and improving outcomes for patients with multiple myeloma.
