title: Reducing Treatment-Related Mortality Did Not Improve Outcomes of Allogeneic Myeloablative Hematopoietic Cell Transplantation for High-Risk Multiple Myeloma: A University of Michigan Prospective Series.
abstract: Despite the ongoing advent of more effective immunomodulators and proteasome inhibitors, multiple myeloma (MM) remains incurable and no effective therapy is available for advanced aggressive disease. Although allogeneic (Allo) hematopoietic cell transplantation (HCT) has a curative potential, the outcomes remain poor because of high treatment-related mortality (TRM), mostly due to regimen-related toxicities and graft-versus-host disease (GVHD) in case of myeloablative conditionings, high relapse rate in case of reduced-intensity or nonmyeloablative regimens, and possibly other unknown MM-specific issues. In an attempt to improve TRM, without compromising conditioning intensity, we prospectively explored the feasibility and efficacy of a myeloablative but reduced-toxicity conditioning regimen, consisting of fludarabine and busulfan (FluBu4; fludarabine 40 mg/m(2)/day and busulfan 3.2 mg/kg/day i.v. × 4 days) in 22 patients with high-risk or advanced refractory MM. The majority (14 of 22, 64%) had prior autologous HCT. The median HCT-specific comorbidity index score was 3 (range, 0 to 6), with 46% having a Karnofsky performance score < 80%. Ten patients had unrelated donors, 3 of whom were 7/8 HLA-loci matched. GVHD prophylaxis was tacrolimus and methotrexate in 20 (91%). Most patients had active MM at transplantation, with a partial response in 12 of 22 (46%) and stable disease in 1 of 22 (4.5%). All 22 patients tolerated the FluBu4 conditioning well, without early toxic deaths or graft failure. Common regimen-related toxicities included mild to moderate mucositis (18 of 22, 82%) and mild transient liver function abnormality (9 of 22, 41%). There were no grade 4 toxicities but grade 3 mucositis occurred in 7 of 22 patients (32%). The cumulative incidence of severe, grades III and IV acute GVHD at day 180 was 23% (95% confidence interval [CI], 10% to 47%) and that of chronic GVHD was 68% (95% CI, 46% to 88%). The cumulative incidences of TRM at 100 days, 1 year, and 3 years were 9% (95% CI, 2% to 33%), 19% (95% CI, 7% to 44%), and 29% (95% CI, 13% to 55%), respectively. Two TRMs were due to idiopathic pneumonia syndrome and 1 was due to cirrhosis. They all had decreased pre-HCT corresponding organ function, with HCT-specific comorbidity index scores of > 3. With a median follow-up of 58.7 (range, 39 to 82) months, the cumulative incidences of relapse at 1 and 3 years were 37% (95% CI, 20% to 61%) and 50% (95% CI, 29% to 75%); those for 1-year and 3-year overall survival (OS) were 58% (95% CI, 40% to 83%) and 29% (95% CI, 15% to 57%), respectively, and those for the 1-year and 3-year progression-free survivals (PFS) were 40% (95% CI, 23% to 67%) and 15% (95% CI, 5% to 42%), respectively. In summary, the use of the myeloablative FluBu4 conditioning Allo-HCT for high-risk MM resulted in decreased TRM, compared with that of Allo-HCT using conventional myeloablative regimens; however, the relapse rate was high, including in those developing moderate-to-severe chronic GVHD. This suggested a less robust graft-versus-myeloma effect against high-risk MM, thus resulting in poor PFS and OS. Nonetheless, the FluBu4 regimen may be used as a lower-TRM platform to combine with other strategies, eg, addition of an MM-targeted agent and/or maintenance therapy with these agents, to decrease relapse or progression in patients with high-risk MM.
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan. Electronic address: pawarode@med.umich.edu.
authors.forename: Attaphol
authors.initials: A
authors.lastname: Pawarode
authors.affiliation: Blood and Marrow Transplantation and Cell Therapy Program, University of Alabama at Birmingham, Alabama.
authors.forename: Shin
authors.initials: S
authors.lastname: Mineishi
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
authors.affiliation: Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Braun
authors.affiliation: Blood and Marrow Transplantation Program, The University of Tennessee, Memphis, Tennessee.
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Khaled
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Sung W
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: John M
authors.initials: JM
authors.lastname: Magenau
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Harris
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: James A
authors.initials: JA
authors.lastname: Connelly
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Kitko
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Parkin
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Goldstein
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Yanik
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: John E
authors.initials: JE
authors.lastname: Levine
authors.affiliation: The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: James L
authors.initials: JL
authors.lastname: Ferrara
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Couriel
mesh_terms: D000368:Aged; D064591:Allografts; D005260:Female; D006086:Graft vs Host Disease / Q000401:mortality* / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006784:Hospitals, Teaching; D006801:Humans; D008297:Male; D008824:Michigan; D008875:Middle Aged; D009101:Multiple Myeloma / Q000401:mortality* / Q000628:therapy*; D011446:Prospective Studies; D012307:Risk Factors; D019172:Transplantation Conditioning
keywords: Allogeneic; Busulfan; Fludarabine; Multiple myeloma; Myeloablative; Prospective; Reduced toxicity