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The treatment of advanced and poor-risk multiple myeloma (MM) is still a major challenge and no therapy has proven to be curative or effective long term. Although allogeneic HCT has curative potential, the outcomes remain poor due to high treatment-related mortality (TRM) after full-intensity conditioning, high relapse rate after reduced-intensity regimens and possibly other disease-specific issues. Under an IRB approved protocol at the University of Michigan, we enrolled 22 patients onto a phase 2 trial exploring the feasibility and efficacy of an intermediate-intensity conditioning with fludarabine and busulfan x 4 (FluBu4) [fludarabine 40mg/m2/day and busulfan 3.2 mg/kg/day IV x 4 days], followed by allogeneic HCT between 2008 and 2011. Eligible patients included those with high-risk MM, defined as unfavorable cytogenetics [t(4;14), t(14;16), t(14;20), -13, -17p] or early relapse post autologous HCT. The median age was 54 years (range, 45-70 years). The majority (64%) had prior autologous HCT. The median HCT-specific comorbidity index (HCT-CI) score was 3 (0-6), with 46% having a Karnofsky performance score ≤80%. Donor types [total (match+mismatch)] were 12 (10+2) related and 10 (7+3) unrelated. GVHD prophylaxis was tacrolimus / methotrexate in 20 (91%). Disease status was complete response in 3 (14%), very good partial response in 6 (27%), partial response in 12 (54%) and stable disease in 1 (4.5%).
All 22 patients tolerated the conditioning regimen without early toxic deaths or graft failure. Common regimen-related toxicities (RRT) include mucositis (19, 86%) and mild transient liver function abnormality (13, 59%). Grade 3-4 mucositis occurred in 9 patients (41%). Cumulative incidence of grade II-IV acute GVHD was 48% (95% confidence interval [CI]; 29-72%), grade III-IV acute GVHD was 23% (95%CI; 10-47%) and chronic GVHD at 1 year was 55% (95%CI; 34-78%). Cumulative incidences of relapse at 1 and 3 years were both 29% (95% CI; both 14-55%) and TRM at 100 days, 1 and 3 years were 9% (95%CI; 2-33%), 19% (95%CI; 7-44%) and 33% (95%CI; 17-59%), respectively. Of note, TRM was due to idiopathic pneumonia syndrome in 2 (9%) and cirrhosis in 1 (4.5%). All had a marginal HCT-CI score of 3, 4 and 6 pre-HCT. With a median follow-up of 9.5 months (range, 2-38 months), the 1- and 3-year overall survival was 61% (95%CI; 43-87%) and 33% (95%CI; 17-64%), and the 1- and 3-year progression free survival was 40%(95%CI; 23-67%) and 15% (95%CI; 5-42%) [Figure]. In summary, allogeneic HCT using an intermediate-intensity FluBu4 conditioning for high-risk MM is safe and feasible, with similar TRM, compared with the published reduced-intensity experience. Although disease recurrence continues to be a major issue, this regimen is a promising platform to combine the benefit of a graft-versus-myeloma effect with new maintenance strategies, in order to maximize the chance of a long-term remission in poor-risk MM patients.
