In Multiple Myeloma, Minimal Residual Disease (MRD) Is an Early Predictor of Progression and Is Modulated By Maintenance Therapy with Lenalidomide

Background. Minimal residual disease (MRD) detection by multi-parameter flow cytometry (MFC) and real time quantitative PCR (RQ-PCR) is highly predictive of outcome in multiple myeloma (MM) patients (pts). Less is known on the ability of maintenance therapy to modulate MRD levels. The primary end-point of this study was to monitor MRD during maintenance therapy and to evaluate the impact on outcome.

Patients and Methods. In the RV-MM-EMN-441 study (NCT01091831), after induction and consolidation pts received maintenance therapy with either Lenalidomide alone (R) or Lenalidomide-Dexamethasone (RD) until progression. Pts achieving at least very good partial response (VGPR) after induction/consolidation treatment were eligible for the MRD sub-study. MRD analysis was performed on bone marrow (BM) samples at diagnosis, after consolidation, after 3 and 6 courses of maintenance, and thereafter every 6 months until progression. MFC complete remission (CR) was defined by <1E-04 monoclonal plasmacells (PCs). Molecular-CR was defined by <1E-05 according to EuroMRD guidelines. MFC and molecular progression were defined by confirmed 25% increase of malignant plasma cells.

Results. MRD sub-study included 50 pts with a median age of 57 years (range 40-65). After consolidation 34/50 (68%) pts achieved VGPR, 16/48 (32%) achieved CR according to IMWG criteria (Rajkumar et al. Blood 2011). After a median follow-up of 44 months, 22/50 (44%) progressed and 7/50 (14%) deaths were recorded, with a 4-year PFS of 49% and 4-year OS of 87%.

In the MFC analysis 19/50 pts (38%) achieved MFC-CR after consolidation, while other additional 7/50 pts (14%) achieved MFC-CR during maintenance. Among pts who achieved MFC–CR (< 1E-04), 7/26 (27%) pts progressed after a median of 30 months; among those who did not reach MFC–CR, 15/24 (62%) pts progressed after a median of 26 months (p=0.009). In 18/19 pts MFC-progression anticipated clinical relapse of a median of 9 months. In 1/19 pts, clinical extra-medullary progression anticipated MFC-progression.

A molecular marker was identified in 25/50 pts (50%); 4/25 pts (16%) achieved molecular-CR after consolidation, while other additional 3/25 pts (20%) achieved molecular-CR during maintenance. Among pts who achieved molecular–CR (<1E-05), 2/7 (28%) pts progressed after a median of 34 months; among those who did not reach molecular–CR, 11/18 (61%) pts progressed after a median of 30 months (p=0.15). In 12/13 pts molecular-progression anticipated clinical relapse of a median of 8 months. In 1/13 pts, clinical extra-medullary progression anticipated molecular-progression.

Conclusions. Lower MRD values, both with MFC and RQ-PCR procedures, predict better outcome. 30% of patients achieved MFC-CR (7/26) or molecular-CR (3/7) during maintenance therapy suggesting that MRD levels can be modified by maintenance. MRD progression anticipates clinical relapse of approximately 8 months.