The stepchild in myeloma treatments: is allogeneic transplantation not so bad after all?

摘要

In this edition of Haematologica , two papers from the US and Germany report on the long-term follow up of patients with multiple myeloma (MM) treated with reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (HCT).~(~(1),~(2)) Given the armamentarium of highly effective agents and a pipeline of novel therapeutic options, including chimeric antigen receptor T (CAR-T) cells, many hemato-oncologists believe that there is no longer a role for allogeneic HCT in the treatment of MM. Despite remarkable improvements in outcomes with novel drugs, these advances have not yet translated into cure of the disease, even when combined with high-dose chemotherapy and autologous HCT. Patients eventually relapse and die of their underlying disease. The two reports by Maffini et al . and Greil et al . both show that long-term survival, and potentially a cure, can actually be achieved in a proportion of myeloma patients by an allogeneic HCT, a treatment outcome that so far has not been observed with any other therapeutic strategy.Maffini et al . present the long-term clinical outcomes of 244 patients who underwent allogeneic HCT following non-myeloablative conditioning with fludarabine and total body irradiation (TBI) between 1998 and 2016. In this study, more than half the patients had a chemotherapy-based induction with vincristine-doxorubicin-dexamethasone (VAD), whereas after 2006 mostly immunomodulatory / proteasome inhibitor triplet regimens were given. The majority of patients (86%) received tandem autologous-allogeneic treatment upfront, while 14% had failed previous autologous HCT. After high-dose melphalan and autologous HCT, 26% of patients were in a complete remission (CR), 19% in a very good partial remission (VGPR), 38% in a partial remission (PR), and 17% had progressive disease. Best responses following allogeneic HCT were: CR in 46%, VGPR in 17%, PR in 20% of patients [overall response rate (ORR) 83%], and 17% failed to achieve a response. With a median follow up of 8.3 years (range, 1.018.1), 5-year overall survival (OS) and progression-free survival (PFS) rates were 54% and 31%, respectively, and 10-year OS and PFS rates were 41% and 19%, respectively. Non-relapse mortality was low with 2% at day +100 and 14% at five years, The rate of acute graft- versus -host disease (GvHD) was acceptable (33% grade II, 11% grade III / IV), while the cumulative incidence of chronic GvHD was 46%. The key findings of this study were: i) that patients with disease that was refractory to induction and those with high-risk biological features experienced shorter OS and PFS, while among standard-risk patients the median OS was not reached, and the median PFS was 6.5 years. High-risk patients experienced a median OS of 8.4 years with a PFS of 2.5 years; ii) patients who proceeded to tandem HCT after a previously failed autologous HCT had poor outcomes with a median OS of 1.2 years and a median PFS of 0.4 years; iii) those patients who achieved negativity for minimal residual disease (MRD) had a significantly lower relapse rate as compared with MRD-positive (MRD~(+)) patients, indicating that marrow sampling for MRD assessment post HCT is an important tool to guide treatment decisions.