Hyperbaric Oxygen (HBO) Effects on Blood Count Recovery and Post-Transplant Outcomes Following High-Dose Therapy and Autologous HSPC Transplantation for Multiple Myeloma: An Updated Analysis of the Multicenter Phase II Randomized Clinical Trial

Background By reducing systemic erythropoietin (EPO) levels, in vivo studies showed that hyperbaric oxygen (HBO) promoted homing of transplanted umbilical cord hematopoietic stem/progenitor cells (HSPC) to the bone marrow. In a pilot study, we demonstrated that HBO in autologous HSPC transplantation (auto-HSPC) was well tolerated. Time to absolute neutrophil (ANC) recovery was correlated with HBO-mediated reduction in EPO levels. Methods In this phase II multicenter clinical trial, patients with multiple myeloma (MM) receiving high-dose melphalan and auto-HSPC were randomized 1:1 between HBO and no HBO. HBO was given as 100% oxygen, 2.5 ATA for a total of 90 min, on Day 0, 6 hours before cell infusion. The study's primary objective was to evaluate the effect of HBO on blood count recovery, filgrastim use, blood transfusions, and length of hospitalization (LOH). We also examined 1-year progression-free survival. Exploratory objectives included HBO effects on EPO and IL-15 measured at several time points (pre-conditioning, Day 0 pre-HBO, 6- and 8-hours following HBO, and Days 1-3, 7 and 15 post-transplant). In addition, we explored HBO effects on Day 15 lymphocyte subset recovery. Results A total of 99 patients were enrolled, with 52 randomized to HBO. Baseline characteristics were well balanced except for cell dose, with higher odds that patients with lower cell dose were treated with HBO. There was insufficient evidence of a difference between the two groups regarding time to neutrophil recovery, filgrastim use, blood transfusions, or LOH. Patients randomized to receive HBO were 1.7 (95% CI: 1.1-2.7) times more likely to have lymphocyte recovery (ALC) to > 0.5 k/µL by any given day compared to control. EPO levels (only URMC patients, n=75) were lower for HBO versus placebo on Day 1 (p = 0.02), but there was insufficient evidence of a difference at other time points. Regarding immune reconstitution, IL-15 levels were not significantly different between the two groups. We observed higher median NK cell count at Day 15 in the HBO arm (246 vs. 183), but this was not statistically significant (p=0.59). On the other hand, there was significant improvement in the HBO arm in the case of CD-4 (384 vs. 271, p=0.020) and CD-8 cell subsets (194 vs. 115, p=0.045), with borderline evidence of an improvement in CD-3 cell subset (610 vs 386, p=0.06). Figure-1A summarizes immune-reconstitution of different subsets. 1-year progression-free survival was not significantly different between the two arms (91.3% versus 92.6%, Figure-1B). Conclusions HBO resulted in lower EPO levels at Day +1 of auto-HSPC, translating to faster ALC recovery with improved CD-4 and CD-8 cell subsets recovery. Single HBO treatment did not impact 1- year progression-free survival. A pilot study (NCT04862676) is ongoing to determine if multiple HBO treatments can keep EPO levels low beyond Day +1 and impact outcomes.