We investigated the feasibility of HLA-matched unrelated donor (URD) HCT in pts with advanced stage, poor-risk multiple myeloma after nonmyeloablative conditioning. Nineteen pts, median age 52 years (range, 28–65), were treated between 5/2000 and 2/2004. Eight pts had known complex cytogenetic abnormalities including Δ13. At study entry, 12 pts had relapsed or refractory disease after a previous autologous HCT, 5 pts had refractory disease following multiple standard chemotherapy regimens, and 2 pts achieved a partial remission (PR) after standard chemotherapy. Before URD HCT, 10 pts underwent a planned high dose autologous HCT (Melphalan 200 mg/m2) to provide cytoreduction a median of 85 days prior to URD HCT, including 4 pts with relapsed/refractory disease after a prior autologous HCT. Three pts were in complete remission (CR) immediately prior to URD HCT. Nonmyeloablative conditioning consisted of fludarabine (30 mg/m2 x 3 days) and 2 Gy total body irradiation followed by PBSC grafts from URDs matched for HLA-A, −B, −C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Durable engraftment was achieved in 18 of 19 pts. One pt had graft rejection at day +56 and received a second successful nonmyeloablative HCT from another URD. Acute GVHD occurred in 13 (68%) pts and was exclusively grades II and III in 11 and 2 pts, respectively. Chronic extensive GVHD occurred in 12/17 (70%) of evaluable pts. After allografting, 9 pts (47%) were in CR and 3 (16%) in PR, for an overall response rate of 63%. Four pts (21%) died of progressive disease and 4 pts (21%) died of non-relapse causes at a median of 5.3 months. The 2-year overall survival, progression-free survival and non-relapse mortality was 62%, 51% and 24%, respectively. The median follow-up was 25 months. Eleven of 19 pts (58%) were alive, 6 (32%) in CR, 1 (5%) in PR, 2 (10%) with stable disease (SD) and 2 (10%) with relapse after initially achieving CR. Of the 10 pts who underwent a planned high dose autologous HCT for cytoreduction followed by nonmyeloablative URD HCT, 8 were alive: 6 CR, 1 SD, 1 relapse. Of the 9 pts who underwent nonmyeloablative URD HCT without planned autologous HCT, 3 were alive: 1 PR, 1 SD and 1 relapse. Of the 12 pts who entered the study with relapsed/refractory disease after a previous autologous HCT, 5 were alive: 2 CR, 1 PR, 1 SD, 1 relapse. In summary, URD HCT after nonmyeloablative conditioning is feasible with relatively low non-relapse mortality and provides a high response rate for pts with relapsed or refractory multiple myeloma, including pts with disease relapse following an autologous HCT. The data suggest that a treatment strategy consisting of two sequential transplants (1) intensive cytoreductive therapy with autologous HCT followed by (2) nonmyeloablative URD HCT, may be highly effective for treating pts with poor risk, chemotherapy-refractory multiple myeloma or after relapse following autologous HCT.
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