CD38 Antibody Exposure vs. Refractoriness and MRD Negativity as Treatment Goal

Dr. Nooka clarifies the critical distinction between CD38 antibody exposure and refractoriness, which significantly impacts treatment selection. CD38 antibody exposure refers to patients who received these agents as part of induction therapy but remain sensitive to them, representing the majority of current patients. This differs fundamentally from CD38 antibody refractoriness, where patients progress while actively receiving daratumumab maintenance therapy. The refractory population represents less than 5% of patients encountered in practice, and for these patients, Dr. Nooka would avoid daratumumab-bispecific combinations.

However, since CD38 antibody exposure is now standard of care for both transplant-eligible and ineligible populations in 2026, virtually all patients should be considered for teclistamab-daratumumab combinations, as the vast majority remain CD38-sensitive despite prior exposure.

Dr. Nooka emphasizes minimal residual disease (MRD) negativity at the 10^-6 threshold as the primary treatment goal for all patients, but particularly crucial for high-risk populations. He distinguishes between modifiable and non-modifiable risk factors: cytogenetics represent unchangeable disease biology, whereas MRD status is modifiable through enhanced immune-based approaches. Converting MRD-positive patients to negative status through available treatments provides optimal outcomes.

The hierarchy of outcomes demonstrates that standard-risk MRD-negative patients perform best, followed by high-risk MRD-negative patients, then standard-risk MRD-positive patients, with high-risk MRD-positive patients showing the poorest outcomes. This ranking emphasizes that achieving MRD negativity in high-risk patients can improve their outcomes substantially, making it a more critical goal than in standard-risk populations.

Multiple large-scale studies across all myeloma patient populations, including newly diagnosed transplant-eligible, transplant-ineligible, relapsed, and refractory patients, consistently demonstrate that MRD negativity correlates with superior progression-free survival and overall survival. A meta-analysis by the International Myeloma Working Group encompassing nearly 8,000 patients confirmed this benefit across all subsets, establishing MRD negativity as the universal treatment target that should drive therapeutic adaptation decisions.