Assistant Attending Memorial Sloan Kettering Cancer Center New York, New York, United States
Introduction: Despite recent advances in the therapeutic landscape of multiple myeloma (MM), a subgroup of patients with poorer than expected outcomes, remains at a high risk of rapid progression and death. Allogeneic hematopoietic cell transplantation (alloHCT) is considered for select patients in this subgroup with some success. Immune checkpoint blockade (ICB) has the theoretical potential to enhance the effectiveness of the alloHCT, but concerns of an unrestrained immune system causing graft versus host disease (GVHD) or allograft rejection has tempered the enthusiasm for testing these strategies to prevent or delay relapse after alloHCT. Given the lower probability of GVHD with CD34+selected alloHCT, we explored if adding ipilimumab (ipi), a CTLA-4 blocking antibody after CD34+selected alloHCT would be safe and effective in a phase I trial.
Methods: Patients with RRMM in remission who had a 10/10 matched donor underwent conditioning with busulfan, melphalan, fludarabine, and rabbit ATG followed by an ex-vivo CD34+selected alloHCT. If in remission at day 100, patients then received ipi 3 mg/kg every 3 weeks for 4 doses followed by once every 3 months for 4 doses unless limited by DLT or disease relapse. Preventive and supportive care was as per institutional standards. The trial was approved by MSK institutional review board.
Results: Between July 2021-July 2022, three patients enrolled prior to study closure for slow enrollment; 1 of these patients progressed prior to day 100 and was not eligible for treatment with ipi. The 2 patients who received ipi were male and aged 61 and 63. Patient 1 had 8 prior lines of treatment including 2 autologous HCT and patient 2 having 9 prior lines including 2 autologous HCTs and BCMA CAR T cells. Patient 1 received 5 doses of ipi before progressing at 309 days after alloHCT. Patient 2 received 3 doses of ipi prior to progression at 160 days after alloHCT. Neither of the two patients had GVHD or rejection of allograft. Patient 1 developed an ipi-associated rash that resolved with topical steroids and pericarditis related to a parainfluenza respiratory infection. We performed high-dimensional multicolor flow cytometry of peripheral blood and bone marrow before and after alloHCT, that showed expansion of T cells after alloHCT. At time points closer to relapse there were increased myeloid-derived suppressor cells and numbers of PD-1 expressing T cells.
Conclusions: Our study suggests that ICB with ipi can be used after CD34+selected alloHCT without GVHD or allograft rejection in select patients. Further studies are needed to understand if the expanding T cell subsets participate in graft versus myeloma effects and into mechanisms that affect the durability of ICB therapy. Our trial underscores the significance of meticulous patient selection for ICB after alloHCT as a strategy to delay relapse of MM in platforms with low GVHD potential.
