Daratumumab as Maintenance After Peripheral Blood Stem Cell Transplantation From HLA-identical or Haploidentical Family Donor in the Treatment of Refractory or Relapsed Multiple Myeloma: a Phase 2 Trial

Allogeneic stem cell transplantation in patients with multiple myeloma (MM) Outcomes for patients with MM who are resistant to proteasome inhibitors (bortezomib) and immunomodulatory drugs (lenalidomide, thalidomide) are dramatically poor. The median expected overall survival (OS) in these patients is 9 months. New drugs such as pomalidomide or carfilzomib, when used in monotherapy, can only offer a median progression free survival (PFS) of 3.8 months and OS of 11.9 and 13.4 months, respectively.

Allogeneic stem cell transplantation (allo-SCT) remains the most reasonable treatment option, apart from palliative care, in patients with refractory or relapsed MM. No other strategy is able to offer any chance of cure for a patient at this stage. However, in the context of standard myeloablative (MAC) allo-SCT, results are limited in terms of feasibility in the larger patients' population who is in need, and by both a relatively high relapse incidence (RI) and especially high non-relapse mortality (NRM). Also, in the last decade, the advent of reduced intensity conditioning (RIC) allo-SCT and the improvement in supportive care management regarding infectious complications allowed a significant reduction of NRM. RIC expanded the transplant option to those patients who are ineligible for standard MAC allo-SCT either because of age or because of pre-existing comorbid conditions. While NRM is over 40% with MAC, relapse incidence remains high with either RIC or MAC. The major reason for treatment failure after allo-SCT for MM has become relapse, which is between 38% and 55%. Median PFS ranges from 10% to 32%. Thus, strategies to prevent relapse after allo-SCT for MM remain an unmet medical need.

Post-transplant maintenance therapy Consolidation/maintenance post-transplantation for MM has demonstrated to not only upgrade but also deepen the response, which translates into improved PFS. Studies investigated immunomodulatory drugs, thalidomide or lenalidomide, as maintenance therapy after allo-SCT. The observed activation of natural killer and regulatory T cells induced by immunomodulatory drugs provides an attractive rationale for its use post-transplant. But some concerns are raised by a high rate of graft-versus-host disease (GVHD) induction. In the prospective HOVON 76 trial, 43% patients stopped lenalidomide maintenance because of development of GVHD, 17% patients because of other adverse events, and 17% patients because of progression. Thus, lenalidomide maintenance after RIC allo-SCT in MM patients is not feasible, mainly because of the toxicity and the induction of acute GVHD.

Daratumumab, a human IgG1 monoclonal antibody that binds CD38-expressing malignant cells with high affinity and induces tumor cell death, has recently shown promising results in a phase 2 trial. Daratumumab was well tolerated, median PFS was 3.7 months and median duration of response was 7.4 months in patients who were refractory to both proteasome inhibitors and immunomodulatory drugs. Our first pilot experience, based on 3 patients with refractory MM suggests that Daratumumab maintenance is feasible. No grade 3-4 toxicities were observed. None of the patients experienced GVHD. After a median follow-up of 12 months, none of these patients relapsed. Thus, Daratumumab appears to be the ideal candidate to propose immunotherapy maintenance and reinforce the post-transplant immunomodulation strategy.

Prophylactic donor lymphocyte infusions Given that relapsed or refractory patients are at very high risk of relapse, prophylactic donor lymphocyte infusion (pDLI) is a promising approach to prevent relapse after allo-SCT. pDLI can improve remission status in 54% of the patients and result in 5-year PFS of 79%. The incidence and severity of acute GVHD remains manageable.