Myeloma Canada Research Network (MCRN)-001 Trial Utilizing Bortezomib (btz)-Based Induction, Enhanced Conditioning with IV Busulfan + Melphalan (BuMel) and Lenalidomide (len) Maintenance in Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplant (ASCT): A National Canadian Study Evaluating Achievement of Minimal Residual Disease (MRD) Negativity and Involved Serum HevyliteTMÂ chain (HLC) Normalization

• Published in: Blood Vol. 126; no. 23; p. 1982
• Main Authors: Reece, Donna, Piza Rodriguez, Giovanni, Pantoja, Mariela, White, Darrell, Venner, Christopher P., Stakiw, Julie, Sebag, Michael, Comeau, Terrance, Song, Kevin, Roy, Jean, Minuk, Leonard, Tay, Jason, Kukreti, Vishal, Trudel, Suzanne, Anca, Prica, Tiedemann, Rodger, Chen, Christine, Paul, Harminder
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 03.12.2015
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V126.23.1982.1982

As therapy for MM improves, methods more sensitive than conventional serum/urine electrophoresis/immunofixation are required to optimally evaluate response. Our phase 2 multi-center clinical trial, conducted in 10 Canadian centers, utilized serial bone marrow aspirate (BMA) samples for MRD analysis by 8-color multiparameter flow cytometry (MFC), along with serum Hevylite assay of the involved heavy light chains (HLC), to assess responses after ASCT and during maintenance therapy. After btz-based induction therapy (usually CyBorD), pts without progression received enhanced conditioning with BuMel (IV busulfan 3.2 mg/kg days -5 to -3 or days -6 to -4 + melphalan 140 mg/m2 day -2 or day -3) followed by ASCT on day 0. On day 100 post-ASCT, lenalidomide (len) 10 mg/day was commenced, escalated to 15 mg/day after 3 cycles if appropriate, and continued until progression. BMA and serum samples were shipped centrally for MRD and Hevylite analysis before induction therapy, before ASCT, on day 100 post-ASCT, every 3 mos for the 1st year and every 6 mos until progression. From 03/2013 - 07/2015, 122 newly diagnosed pts provided BMA samples for MRD analysis. To date, 70 pts (target 78), have completed induction therapy and undergone ASCT; 8 others provided pre-induction samples and are expected to be enrolled. 44 of the 122 (36%) who provided BMA samples did not proceed to BuMel due to: poor samples-4 pts (3.2%); MM not confirmed-3 pts (2.5%); prior therapy-1 pt (0.8%); death during induction-1 pt (0.8%); consent withdrawal/opted for standard conditioning-19 pts (15.6%); and no ASCT-16 pts (13.1%; 8 were unfit, 4 had comorbidities, 2 progressed, 1 failed mobilization and 1 received tandem ASCT for high-risk MM). Median follow-up is 17.4 mos (range: 6.3-25.6). Median age is 57 (34-69); 64% are male. Median serum β2-microglobulin level is 3.07 mg/L (1.5-20) and albumin 37 g/L (2.8-48.1); 31 pts have ISS stage I; 18 stage II; 15 stage III MM and 6 have missing data. Ig subtype includes IgGκ in 30 (43%), IgGλ in 14 (20%), IgAκ in 8 (12%), IgAλ in 9 (13%), κ in 5 (7%); λ in 1 (1%) and missing data in 3 pts (4%). Post-ASCT, 14 SAEs have occurred: Grade 3 atrial fibrillation (2), acute kidney injury (3), increased creatinine (1), upper respiratory infection (2), febrile neutropenia (2), bacteremia (1), hypoxia (1) and lung infection (1) and Grade 4 sepsis (1). There have been no ASCT-related deaths; 4 pts have progressed. The best conventional Ig response post-induction in the 66 pts with available data is CR in 5 (7.6%), VGPR in 25 (38%), PR in 31 (47%), MR in 4 (6%) and SD in 1 (1.5%). The Ig response at day 100 in the 60 evaluable pts includes CR in 10 (17%), VGPR in 30 (50%), PR in 18 (30%), MR in 1 (1.5%) and SD in 1 (1.5%). MRD negativity improved from 18/67 (27%) after induction to 22/60 (37%) at day 100 (Table 1). Among evaluable pts, 83.3% of those after induction and 68.2% of those at day 100 who were MRD-negative had normal involved HLC ratios, while 42.6% and 51.5% of those who were MRD-positive, respectively, had normal ratios. Table 1Response Rates by Conventional Serum/Urine Parameters and Marrow Flow Cytometry for MRDMRD Negativity by Conventional Ig Response#EvaluableNormalHevylite ratio(# normal /evaluable)(%)#MRDNegative(%)CRVGPRPRMRSDMissingTotalMRD(-)TotalMRD(-)TotalMRD(-)TotalMRD(-)TotalMRD(-)TotalMRD(-)After Induction6715/18 (83.3%)18 (27%)54259315401010Day 100 Post-ASCT6015/22 (68.2%)22 (37%)1043016182101000 Conclusions: 1) IV BuMel conditioning + ASCT was well-tolerated with few SAEs and no ASCT-related deaths; 2) at day 100 post-ASCT, 97% had achieved ≥ PR (≥ VGPR in 67% and CR in 17%); 3) MRD negativity rates improved from 27% to 37% after ASCT; 3) conventional Ig and MRD responses were often discordant as only 40% of CR pts were MRD-negative at day 100; 4) the majority of MRD-negative patients also had normalization of their involved HLC ratios; 5) further F/U is required to determine the rate of achievement of MRD negativity during maintenance therapy; relationships between conventional Ig response, MRD status and involved HLC ratio; and long-term outcomes with this approach. Reece:Janssen: Consultancy, Honoraria, Research Funding; Osuka: Honoraria, Research Funding; Merck: Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Off Label Use: Lenalidomide maintenance after autologous stem cell transplantation. White:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Venner:Amgen: Honoraria; Celgene: Honoraria, Research Funding; J&J: Honoraria, Research Funding. Sebag:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Song:Celgene: Honoraria; Otsuka: Honoraria; Janssen: Honoraria. Tay:Celgene: Honoraria; Janssen: Honoraria. Kukreti:Janssen: Honoraria; Celgene: Honoraria. Trudel:Amgen: Honoraria, Speakers Bureau; Oncoethix: Research Funding; BMS: Honoraria; Novartis: Honoraria; Celgene: Equity Ownership, Honoraria, Speakers Bureau; Trillium Therapeutics Inc.: Research Funding. Anca:Janssen: Honoraria; Celgene: Honoraria. Tiedemann:Janssen: Honoraria; Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding; Millennium: Research Funding; Janssen: Honoraria.