Tandem Autologous-Nonmyeloablative (NMA) Allogeneic(Allo) Transplant (Tx) in Newly Diagnosed Multiple Myeloma (MM) Leads to Improved Survival When Compared to Conventional Allogeneic Transplant

Despite various strategies involving autologous Tx and use of newest drugs with anti-MM activity such as bortezomib and lenalidomide, very few patients with MM currently achieve long-term remission. Allo Tx theoretically remains an attractive option due to evidence of graft-versus-MM activity supported by small series of patients with long-term (>10 years) complete remissions (CR) following myeloablative Tx, the association between chronic graft-versus-host disease (Gvhd) and CR, and response in 20–30% of relapsed patients following donor leucocyte infusion. However, to date, the ideal strategy using Allo Tx remains uncertain. Early studies using myeloablative regimens have been associated with high (30–50%) mortality rates and late relapses have been observed despite Gvhd. Low (10–22%) reported mortality in NMA regimens is hampered by reduced CR and higher progression rates compared to ablative regimens. Additionally, long-term outcome following NMA transplant remains unclear. In this present study, we sought to compare outcomes of 2 sequential cohorts of patients with MM who underwent Allo Tx in our institution. Between 01/01 and 10/07, patients with newly diagnosed stage II–III MM were invited to participate in a phase II prospective study consisting of vincristine, adriamycine and decadron x 4 cycles followed by autologous blood stem cell Tx with melphalan 200 mg/m². Within 3 months post autologous Tx, enrolled patients received outpatient NMA Allo Tx from a 6/6 HLA matched sibling donor with a conditioning of fludarabine 30 mg/m² and cyclophosphamide 300 mg/m² for 5 days, followed by infusion of >4 x 10⁶ CD34+ cells/kg. Gvhd prophylaxis was chosen to take advantage of low incidence of acute Gvhd and putative protective effect of chronic Gvhd: tacrolimus 3 mg bid was started on day (D)-8 then tapered off by D+100, with mycophenolate mofetil 1000 mg bid D+1 to D+50. Our NMA cohort was compared to MM patients who underwent full myeloablative Allo Tx between 06/90 and 01/01, mostly (N=29) with TBI; marrow was used in 54% and all received short course CSA/MTX. A total of 73 patients received NMA Tx (M/F: 43/30, median age 54 years, 73% stage III) and were compared to 39 patients with myeloablative Tx (M/F: 24/15, median age 47 years, 64% stage III). The incidence of grade II–IV acute Gvhd was significantly higher in the myeloablative group (30.7% vs 6.8%; p=0.0004); in contrast, as expected, chronic Gvhd was more frequent at 3 years following NMA Tx (90% vs 59.4%; p=0.0001). At 4 years, transplant related mortality (TRM) following myeloablative Tx was 50% compared to 17% in the NMA group (p=0.0001). Median (range) follow-up in NMA and myeloablative cohorts were 28 (3.5–82.9) and 37 (0.5–139) months, respectively. Kaplan-Meier estimates of overall survival (OS) at 2 (87% vs 59%; p=0.001) and 5 years (67% vs 44%; p=0.001) are significantly better in the NMA cohort. Similarly, disease free survival (DFS) at 2 (87% vs 48.5%; p=0.0001) and 5 years (67% vs 41%; p=0.0001) are also significantly better with the NMA Tx. In conclusion, our sequential auto-NMA Tx protocol is more effective to control MM than myeloablative Tx with significantly less TRM, better OS and DFS. These results might be explained by less advanced disease and higher incidence of chronic Gvhd in the NMA cohort. Future strategies should focus on reducing the relapse rate and incidence of extensive chronic Gvhd while preserving the graft versus MM effect.