Novel Drug Combinations and Donor Lymphocyte Infusions Allow Prolonged Disease Control in Multiple Myeloma Patients Relapsing after Allogeneic Transplantation

Abstract

Although allogeneic stem cell transplantation (allo-SCT) is curative for only a minority of patients with multiple myeloma (MM), patients who relapse after allo-SCT can experience long-term survival, suggesting a synergy between antimyeloma drugs administered after allo-SCT and donor T cells. We retrospectively evaluated the outcome of MM patients reported to the Gruppo Italiano Trapianto Midollo Osseo e Terapia Cellulare (GITMO) network who underwent allo-SCT between 2009 and 2018, to identify predictors of long-term outcome in the whole population (242 patients) and predictors of prolonged overall survival (OS) after relapse in the subgroup of relapsed patients (118 patients). In the whole population, at a median follow-up of 40.9 months after allo-SCT, the median duration of OS and progression-free survival (PFS) were 39.4 and 19.0 months after allo-SCT, respectively. The cumulative incidence of nonrelapse mortality (NRM) was 10.3% at 1 year and 27.6% at 5 years. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 19.8%, and the 5-year cumulative incidence of moderate or severe chronic GVHD was 31.8%. In the multivariate model, older age at transplantation (P = .020), receipt of >2 lines of therapy before allo-SCT (P = .003), and transplantation from an unrelated or haploidentical donor (P = .025) were significant factors associated with reduced OS. Relapse after allo-SCT occurred in 118 patients (59%) at a median of 14.3 months (interquartile range, 7.2 to 26.9 months). Twenty patients (17%) received only steroids, radiotherapy, or supportive care; 41 (35%) received 1 line of salvage treatment; 23 (19%) received 2 lines of salvage treatment; and 34 (29%) received 3 or 4 lines of salvage treatment. Nine patients were treated exclusively with chemotherapy, 9 received at least 1 salvage treatment including immunomodulating agents, 43 patients were treated with at least 1 rescue therapy including proteasome inhibitors, and 37 patients received at least 1 salvage treatment including monoclonal antibodies (33 with daratumumab, 1 with elotuzumab, 1 with isatuximab, and 2 with belantamab). The median OS of relapsed patients was 38.5 months from allo-SCT and 20.2 months from relapse. In multivariate analysis, OS after relapse was significantly prolonged in patients with a longer time to relapse after allo-SCT (time to relapse 6 to 24 months, P = .016; time to relapse ≥24 months, P < .001) and in those who had received at least 3 lines of salvage treatment (P < .036) and donor lymphocyte infusion (DLI) (P = .020). In this study, patients who underwent transplantation in early phases of disease and with an HLA-identical sibling donor had the best chance of long-term survival. Late relapse after allo-SCT, multiple courses of salvage treatment, and an association with DLI could allow for long-term disease control in patients who experienced relapse after allo-SCT.

Keywords: Allogeneic stem cell transplantation; Immunomodulating agents; Monoclonal antibodies; Multiple myeloma; Proteasome inhibitors.