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

Background: In vivo studies showed that hyperbaric oxygen (HBO) promoted the homing of transplanted umbilical cord hematopoietic stem/progenitor cells (HSPC) to the bone marrow by reducing systemic erythropoietin (EPO) levels. In a pilot study, we demonstrated that HBO was well tolerated in autologous HSPC transplantation (auto-HSPC). 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, in a single treatment on Day 0, 6 hours before cell infusion. The study's primary objective was to evaluate the effects of HBO on blood count recovery, filgrastim use, blood transfusions, length of hospital stay (LOH), Day +100 and 1-year responses, and 1-year progression-free survival (PFS). Exploratory objectives included HBO effects on EPO and IL-15 measured at several time points and on Day 15 NK cell and T-cell subsets recovery. Results: A total of 99 patients were enrolled, with 52 randomized to HBO. Baseline characteristics were well balanced, except for cell dose, which showed higher odds that patients with lower cell doses were treated with HBO. There was insufficient evidence of a difference between the two groups regarding time to neutrophil recovery, use of filgrastim, blood transfusions, or LOH. Patients randomized to receive HBO were 1.7 (95% CI: 1.1-2.7) times more likely to have recovery of absolute lymphocyte count (ALC) to > 0.5 k/µL by any given day compared to control. EPO levels were significantly lower in HBO versus placebo only on Day 1 (p = 0.02). We observed a non-significant increase in median NK cell count at Day 15 in the HBO arm (246 vs. 183 cells/µL p=0.59). There was significant improvement in CD-4 (384 vs. 271 cells/µL, p=0.020) and CD-8 cell subsets (194 vs. 115 µL, p=0.045), with borderline improvement in CD-3 cell subset (610 vs 386 cells/µL, p=0.06), in the HBO arm. Day +100 response analysis showed that the HBO cohort had a complete response (CR) + stringent CR (sCR) + minimal residual disease negative (MRD-) CR in 25/52 (48.1%, 95% CI 34%-62%), while non-HBO cohort had a CR + sCR + MRD- CR in 12/46 (26.1%, 95% CI 14.3%-41.1%), which was statistically significant (P=0.049). The difference did not reach statistical significance when stratified by infused cell dose and pre-transplant disease responses (p=0.14). At one year, there were higher CR or better rates in the HBO arm compared to the non-HBO arm 51% vs 25.6% (p=0.02) after stratification by infuse cell dose and pre-transplant disease response. One-year PFS was not significantly different between the two arms (91.3% versus 92.6%). Conclusions: HBO resulted in lower EPO levels at Day +1 of auto-HSPC, translating to faster ALC recovery, improved CD-4 and CD-8 cell subset recovery, and improved 1-year post-transplant responses. Improvement in immune reconstitution might have positively improved post-transplant responses. Longer follow-up might be needed to see an impact on PFS. A pilot study (NCT04862676) is ongoing to determine if multiple HBO treatments can sustain low EPO levels beyond Day +1 and potentially influence outcomes.