Minimal Residual Disease Monitoring During Maintenance In Multiple Myeloma Patients
Authors: Rocci Alberto , Gambella Manuela , Omedè Paola , Drandi Daniela , Gay Francesca , Patriarca Francesca , Cavallo Federica , Petrucci Maria Teresa , Tommaso Caravita , Benevolo Giulia , Pescosta Norbert , Oliva Stefania , Offidani Massimo , Montefusco Vittorio , Liberati Anna Marina , Falcone Antonietta Pia , Ballanti Stelvio , Spadano Tonino , Guglielmelli Tommasina , Musto Pellegrino , Zambello Renato , Di Raimondo Francesco , Ladetto Marco , Boccadoro Mario , Palumbo Antonio 
Published: October 2019

Abstract

Background
The quality of response and the residual disease after treatment are important prognostic factors in several hematological diseases including multiple myeloma (MM). Several papers demonstrated that the deeper the response after treatment, the longer the survival. However few data are available on the monitoring of minimal residual disease (MRD) during the maintenance therapy in transplant eligible MM patients.

Aims
to evaluate the role of maintenance therapy in reducing MRD and the role of monitoring the response to predict clinical relapse.

Patients and Methods
newly diagnosed MM patients enrolled in the RV-MM-EMN-441 trial (NCT01091831) and achieving at least a very good partial response (VGPR) after consolidation were included in the study. Patients received 4 Lenalidomide-Dexamethasone (RD) courses as induction, Cyclophosphamide to mobilize bone marrow stem cells (BMSC) and then were randomized to receive 6 cycles of Cyclophosphamide-Lenalidomide-Dexamethasone (CRD) or Autologous Stem Cell Transplantation (ASCT) with Melphalan 200 mg/m2. All patients received maintenance therapy with Lenalidomide (R) or Lenalidomide-Dexamethasone (RD) until relapse. MRD analysis was performed in a single laboratory (University of Turin, Italy) using flow cytometry according to European Myeloma Network guideline (Rawstron AC, Haematologica 2008). Samples of bone marrow (BM) were collected at diagnosis, after consolidation, after 3 and 6 courses of maintenance and then every 6 months until clinical relapse. The samples were considered MRD +ve if ≥ 0.01% of PC were detected. Immunophenotypic (IF) relapse was defined as an increase of ≥ 25% in the amount of malignant plasma cells in BM compared to the previous determination.

Results
Fifty patients (27 female/23 male) with a median age of 57 yrs (40-65) entered the study. According to ISS, 27 patients were stage I, 15 stage II and 8 stage III. Fish risk profile was standard in 31 patients, high in 11 and not available in 8. Twenty-five patients received CRD as consolidation and 25 underwent ASCT. The median follow-up was 28.6 months. After consolidation 16 (32%) patients achieve a complete response (CR) and 34 (68%) a VGPR. MRD was negative in 19/48 (40%) patients, of which 12 received ASCT (out of 23, 52%) and 7 received CRD (out of 25, 28%). Patients receiving ASCT showed a lower value of residual cells (median 0.08%, range 0 – 1.00) compared to patients receiving CRD (median 0.5%, range 0 – 2.9%, p=0.0134). The lower MRD value was achieved after consolidation in 31 patients (62%), after 3 courses of maintenance in 6 patients (12%) and after 6 or more courses of maintenance in 13 patients (26%). The increase in quality of response was observed primarily in patients receiving CRD: the average amount of residual plasma cells in bone marrow was 71/uL after induction, lowering to 51/uL after 6 and 12 courses of maintenance therapy. Nine patients clinically relapsed after an average time of 25.6 months from the beginning of the therapy and in all patients this was anticipated by immunophenotypic relapse.

Conclusion
1) consolidation therapy with ASCT determines a deeper response compared to CRD; 2) maintenance therapy can improve the quality of response, in particular in patients not receiving ASCT; 3) Immunophenotypic relapse anticipate the clinical relapse. These results suggest the possible role of MRD monitoring to better assess the response to therapy also during maintenance and as marker of early relapse.

Disclosures:
Ladetto: Celgene: Research Funding, Speakers Bureau; Janssen Cilag: Research Funding, Speakers Bureau; Mundipharma: Research Funding, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.