Minimal Residual Disease Evaluation Using 8-Color Flow Cytometry Predicts Risk of Relapse in High-Risk and/or Young Myeloma Patients Who Receive Bortezomib Consolidation after Frontline Tandem Transplantation

Introduction: Multiple myeloma (MM) remains incurable with standard therapies. Allogeneic stem cell transplantation (alloSCT) is the only curative treatment for these patients. We hypothesized that bortezomib (BTZ) consolidation after tandem autologous stem cell transplantation (ASCT) and nonmyeloablative (NMA) alloSCT could improve quality of response while decreasing relapse and cGVHD. We also sought to determine prospectively the predictive value of bone marrow minimal residual disease (MRD) evaluation using a highly sensitive flow cytometry assay. Methods: Newly diagnosed myeloma (NDMM) patients ≤65 years with high-risk (HR) features (based on cytogenetics, ISS 3 or plasma cell leukemia) or ≤50 year regardless of risk status with an 8/8 HLA matched donor are eligible to participate in this prospective trial. After a BTZ-based induction and ASCT, outpatient NMA alloSCT is performed with either fludarabine and cyclophosphamide (sibling donor) or fludarabine and TBI 2 Gy (unrelated donor) followed by peripheral blood stem cells. GVHD prophylaxis consists of tacrolimus and MMF. BTZ is initiated on day +120 post-alloSCT at 1.3 mg/m2 every 2 weeks for 1 year. Response evaluation is based on IMWG criteria. Bone marrow MRD evaluation is performed on 10x106 nucleated cells with highly sensitive (≥10-5) next-generation flow cytometry using the 8-color EuroFlow protocol (CD45, CD38, CD138, CD56, CD19, CD27, CD81, CD117, CyIgκ and CyIgλ) before alloSCT, before BTZ and every 3 months for 2 years. Immunophenotypic complete response (iCR) is defined as stringent CR in addition to 2 consecutive negative MRD results. aGVHD and cGVHD are evaluated prospectively. Results: As of June 29th 2018, 37 patients have been enrolled with a median age of 53 (range: 35-64) years. ISS 3 is found in 43% and HR cytogenetics in 54% (5% del17p, 14% t(4;14), 22% gain 1q21 and 14% >1 HR cytogenetics). Induction consisted of CyBorD (81%) or VTD (19%) for a median of 4 (range: 4-7) cycles. Median times from induction to ASCT and from ASCT to alloSCT were 5.8 and 4.4 months, respectively. Sibling and unrelated donor transplants were performed in 43% and 57%, respectively. KPS and HCT-CI were 90 (range 80-100) and 1 (range 0-3), respectively. Median follow-up is 21 (range 0-39) months after alloSCT. Of enrolled patients, 34 have started BTZ and received 92.5% of planned doses, with no dose reduction needed for toxicity. Observed grade ≥3 non-hematologic toxicities possibly/related to BTZ incl