Haploidentical transplantation in patients with multiple myeloma making use of natural killer cell alloreactive donors

Abstract

Disease relapse is an important problem after allogeneic stem cell transplantations in multiple myeloma (MM). To test the hypothesis that natural killer (NK) cell alloreactivity in the setting of a haploidentical stem cell transplantation (haploSCT) can reduce the risk of myeloma relapse, we performed a small prospective phase 2 study in which we transplanted poor-risk MM patients using a killer cell immunoglobulin-like receptor (KIR)-ligand mismatched haploidentical donor. Patients received bone marrow grafts after reduced-intensity conditioning, with post-transplantation cyclophosphamide (PTCY) graft-versus-host-disease (GVHD) prophylaxis. The primary endpoint was 1.5-year progression-free survival (PFS); stopping rules were installed in case interim results made a benefit of 50% PFS at 1.5 years unlikely. After inclusion of 12 patients, of which 9 were evaluable for the primary endpoint, all patients relapsed within a median time of 90 days. All except 1 patient showed engraftment, with a median time to neutrophil recovery of 18 (12–30) days. The study was prematurely terminated based on the predefined stopping rules after the inclusion of 12 patients. With this small study, we show that in chemo-resistant myeloma patients, NK cell KIR-mismatch is not superior to conventional alloSCT. This strategy, however, can serve as a platform for new treatment concepts. Clinical Trial Registry: NCT02519114

Allogeneic Stem Cell Transplantation in Multiple Myeloma

“…Of note, the number of haploidentical transplantations for the treatment of hematological malignancies has increased in the last years and it seems effective with tolerable toxicity, especially with post-transplantation GvHD-prophylaxis with cyclophosphamide. There are few data about haploidentical allo-SCT in MM, but small retrospective studies show that it is feasible with moderate TRM- and similar PFS-rates as compared to allo-SCT with HLA-matched donors [ 56 , 57 , 58 , 59 , 60 ].…”

The Role of Allogeneic Stem Cell Transplantation in Multiple Myeloma: A Systematic Review of the Literature

“…They included both observational studies (n = 15) and randomized control trials (n = 1) with moderate-to-high quality based on the conducted bias assessment. The findings of these studies are summarized in Table 3 [ 25 - 40 ].…”

“…Both allogeneic and autologous SCTs offer beneficial treatment options for eligible MM patients. The first-line treatment for newly diagnosed, transplant-eligible patients is high-dose pharmacotherapy with auto-hematopoietic cell transplant (HCT); however, conditions for treatment are stringent and concerns in previous studies involving auto-HCT involve high-risk cytogenetics (poor risk MM), including post-treatment time to relapse [ 25 , 31 ]. A small prospective study by Van Elssen et al assessed if killer cell immunoglobulin-like receptor (KIR)-ligand mismatched haploidentical (haplo) bone marrow transplant (BMT) combined with post-transplant cyclophosphamide (PTCy) improves survival in poor-risk chemo-resistant MM, which, in this study, was not superior to conventional allo-HCT [ 25 ].…”

“…The role of pharmacotherapy is exigent in allowing transplant intervention to take place. Nevertheless, new drug therapies are constantly evolving the landscape of treatment: the study by Van Elssen et al describes haplo-BMT in MM may be a possible platform for future immunotherapeutic strategies utilizing the KIR-ligand mismatch; however, not necessarily with post-transplantation cyclophosphamide [ 25 ]. Immunoparesis was assessed by Eisfeld et al in the context of post-transplant survival, in that it may aid as a gauge for post-allogeneic transplantation mortality [ 27 ].…”

“…A study by Bryant et al evaluated a cohort of CD34+ allo-HCT recipients with relapsed refractory MM and their pre-allo-HCT variables [ 26 ]. An important adverse pre-allo HCT variable was the pre-salvage stage II-III International Staging System (ISS), which resulted in relapse and poorer survival [ 25 ]. However, radioimmunotherapy (RIT) combined with reduced-intensity conditioning (RIC) in patients who responded to pre-salvage therapy before allo-HCT saw a benefit in progression-free and overall survival [ 30 ].…”