T-Cell Depleted Allogeneic Hematopoietic Stem Cell Transplantation with Busulfan, Melphalan, and Fludarabine Conditioning Followed by Post Transplantation Donor Lymphocyte Infusions for Patients with Relapsed Multiple Myeloma and High-Risk Cytogenetics

Abstract 1992

Allogeneic hematopoietic stem cell transplantation (allo HSCT) is a curative therapy for patients (pts) with multiple myeloma, but conventional allo HSCT has been associated with unacceptably high rates of mortality. Non-myeloablative allo HSCT has resulted in high rates of acute and chronic graft-versus-host disease (GvHD) and progression. We report results of a pilot study of 13 pts, using T-cell depleted allo HSCT (allo TCD HSCT) from HLA compatible (matched related = 8, matched unrelated = 3, and mismatched unrelated = 2) donors. All 13 pts had relapsed myeloma within 12 mos following auto HSCT, and 12/13 pts also had high-risk cytogenetics at diagnosis [t(4;14), t(14;16), del17p by FISH and/or del13q by karyotyping]. All pts achieved at least a partial response from preceding chemotherapy or second auto HSCT. Pts underwent allo TCD HSCT with busulfan (0.8mg/kg × 10 doses), melphalan (70mg/m² × 2 days), fludarabine (25mg/m² × 5 days) and rabbit ATG (2.5mg/kg × 2 days). T-cell depletion was performed by positive CD34 selection (Isolex) followed by rosetting with sheep erythrocytes, achieving < 10³CD3+/kg for all grafts. All pts engrafted promptly (median d+11, range d+10 to +12). Pts were eligible to receive low doses of donor lymphocyte infusions (DLI) (5×10e⁵ – 1×10e⁶ CD3+/kg) no earlier than 5mos post allo HSCT.

9/13 pts are alive and now 19–45months (mos) post TCD HSCT. Four pts are in complete remission (CR) at 19, 22, 33 and 39mos following allo TCD HSCT. Two of these pts reentered CR following DLI. Two pts had stable VGPR for 24 and 26mos before progression and reentered VGPR following treatment with Rev/Vel/Dex (RVD) + DLI; they are now 36 and 45mos post TCD HSCT. Two pts with refractory myeloma, who were transplanted with residual 16% and 10% plasma cells in marrow, achieved CR for 8 and 12mos post allo TCD HSCT before they developed progression. Following salvage chemotherapy + DLI, these pts are 20 and 21mos post transplant, respectively. One pt remained in CR for 9mos post TCD HSCT before progression with soft tissues plasmacytomas. With salvage radiation + chemotherapy, the pt is now 20mos post TCD HSCT. The 1 and 2 year probability estimates for overall survival and progression free survival with their 95% confidence intervals are: 1-yr OS 0.69 (95% CI: 0.48, 1.0); 2-yr OS 0.69 (95% CI: 0.48, 1.0); 1-yr PFS 0.46 (95% CI: 0.26, 0.83), 2-yr PFS 0.35 (95% CI: 0.15, 0.78).

12/13 pts were without signs of GvHD, but one pt had possible superimposed gut GvHD following fulminant C diff colitis. Four pts died early post TCD HSCT (between 2–6 mos), due to oseltamivir-resistant H1N1 infection (N=1); respiratory failure secondary to infection of unknown etiology (N=1), status epilepticus (N=1), and acute cerebral hemorrhage (N=1).

In summary, these results demonstrate that long-lasting disease control can be achieved with TCD HSCT in pts with multiply relapsed and refractory myeloma including those with high-risk cytogenetics. Administration of calculated, low dose donor lymphocyte infusions can induce complete remission without inducing GvHD. Pts who failed to respond to standard chemotherapy pretransplant responded to reuse of this therapy post TCD HSCT. Based on these results, we are performing a phase II clinical trial at Memorial Sloan-Kettering Cancer Center for pts with relapsed multiple myeloma following auto SCT who had high-risk cytogenetics at diagnosis or at relapse as well as for patients with high-risk cytogenetics in the upfront setting following preceding auto SCT.