Impact of gender on outcomes of patients with multiple myeloma undergoing autologous Haematopoietic stem cell transplant

Multiple myeloma (MM) is a common haematological malignancy, accounting for 1.8% of all new cases of cancer in the United States.1 The prevalence of MM is slightly higher in men compared to women, 8.8 versus 5.7 new cases per 100 000 persons per year, respectively, yet the impact of gender on outcomes of patients with MM remains unclear, with contradictory reports in the literature.2-4 Specifically, the impact of gender on outcomes after high-dose chemotherapy and autologous haematopoietic stem cell transplantation (AHCT) has not been studied in detail. We performed a single-centre retrospective study to evaluate the impact of gender on the outcomes of patients with MM undergoing AHCT. Adult MM patients who received upfront AHCT at MD Anderson Cancer Center between the years 2000 and 2021 were included. Fluorescence in situ hybridization (FISH) was used to identify high-risk cytogenetic abnormalities. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Associations between outcomes and variables of interest were evaluated using univariate and multivariable Cox proportional hazards (as indicated), regression analysis for PFS and OS, and Fine and Grey regression analysis for disease progression. Statistical significance was based on the 0.05 type I error level. Minimal residual disease (MRD) status on the bone marrow biopsy was evaluated using 8-colour next-generation flow cytometry with a sensitivity of 1/10−5 cells. We performed a subset analysis by age, with an age cut-off of 50 years. The primary endpoint was disease progression. A total of 2730 patients were included in the analysis, with a median age of 60 (range 25–83) years and 1610 (59%) were male. Most baseline characteristics were similar between the two genders, including the occurrence of high-risk chromosomal abnormalities (24% in females, 22% in males; p = 0.3). Overall, female patients more often had HCT-CI > 3 (26% vs. 22%, p = 0.02) and Karnofsky performance status (KPS) ≤ 80 (41% vs. 37%, p = 0.009) prior to AHCT (Table 1). There was no significant difference between the induction, conditioning or maintenance regimens between the two genders, and both had similar response rates, including MRD negative ≥ VGPR (37% in females and 35% in males, p = 0.5) prior to transplant. After AHCT, the median time to neutrophil engraftment (absolute neutrophil count of more than 500 × 106 cells/L for 3 consecutive days) was 11 days for both females and males. The median time to platelet engraftment (unsupported platelet count > 20 K × 109/L) was 14 days for females and 15 days for males. Both genders achieved similar rates of post-transplant day 100 ≥ VGPR (77% for females vs. 75% for males, p = 0.2), whereas a slightly higher proportion of females achieved ≥VGPR as the best post-transplant response (86% vs. 83%, p = 0.01) (Figure S1). 0.02 After a median follow-up among surviving patients of 53 (1–262) months, rates of disease progression were similar in both genders ([57%, 95% Confidence Interval (CI) 54–60] in females and [58%, 95% CI 55–61] in males; HR 0.9 [95% CI 0.9–1.1]; p = 0.7). There was also no significant difference in median PFS (41 [95% CI 38–45] vs. 40 [95% CI 37–43] months, p = 0.6) or OS (110 [95% CI 100–118] vs. 99 [95% CI 92–105] months, p = 0.3) between females and males in the entire cohort (Figure 1A,B). The 5-year non-relapse mortality (NRM) was similar in both genders: 4% (95% CI 3%–5%) in females and 4% (95% CI 3%–6%) in males (HR 0.9, 95% CI 0.6–1.3; p = 0.5). Detailed patient outcomes by gender in the entire cohort are provided in Table S1. In a subset analysis in patients aged <50 years (N = 437), the baseline characteristics were similar between females and males (Table S2), and both genders achieved similar rates of ≥VGPR at day 100 (78% vs. 74%; p = 0.31) and at best (86% vs 80%, p = 0.2) post-transplant response (Figure S2). Females <50 had a median PFS of 36 (95% CI 27–43) months, compared to 57 (42–67) months for males (HR at 60 months: 1.5, 95% CI 1.1–1.9; p = 0.005; Figure 1C), without a significant difference in OS (171 [116–193] months vs. 144 [119–208] months respectively; HR at 60 months: 0.9, 95% CI 0.6–1.6; p = 0.9) (Table S3). Multivariate analysis (MVA) showed that females aged <50 years had a significantly higher rate of progression (HR 1.5, 95% CI 1.1–1.9; p = 0.005, Figure 1D) irrespective of R-ISS stage (Figure S3). Predictive factors for reduced progression in MVA were achieving CR prior to transplant (HR = 0.5, 95% CI 0.3–0.7; p < 0.001). and use of post-transplant maintenance (HR = 0.5, 95% CI 0.4–0.7; p < 0.001). Type of conditioning regimen (melphalan vs. busulfan/melphalan-based) did not have a prognostic impact on disease progression in univariate analysis (HR 1.1, 95% CI 0.7–1.5; p = 0.7). The difference in PFS between genders was observed in both white and black MM patients (Figure S4). In the subset of patients aged ≥50 (N = 2293), most baseline characteristics were similar between the two genders, though more female patients had a lower performance score (KPS ≤ 80) at AHCT compared to males (43% vs. 38%; p = 0.01) (Table S2). In the ≥50 age group, females had slightly lower progression rates, without a statistical difference between genders (HR 0.9, 95% CI 0.8–1.0; p = 0.09). In this older age subset, females had numerically better survival outcomes, without reaching a statistical significance (Table S3). A study from the Surveillance, Epidemiology and End Results (SEER) database that included MM patients in the US up to 2006, suggested higher mortality rates among male patients compared to females (HR 1.50, 95% CI 1.49–1.51).3 On the other hand, post hoc analysis of the phase III MRC Myeloma IX clinical trial2 revealed inferior survival among female participants compared to males in univariate analysis, with a median overall survival (OS) of 44.8 versus 49.9 months (p = 0.02) respectively. However, in multivariate analysis, there was no significant survival difference. In that trial female patients more often had high-risk chromosomal abnormalities. Similarly, analysis of participants from the Myeloma XI Trial showed that women more often had high-risk cytogenetic features, without a difference in PFS or OS compared to men.5 Unlike the two aforementioned studies, in the current study, we did not observe a difference in the proportion of patients with high-risk chromosomal abnormalities between the two genders. A recent update from the combined SEER and Multiple Myeloma Research Foundation (MMRF) CoMMpass datasets4 showed that females had significantly better PFS and OS compared to males. Data for cytogenetic risk and the use of AHCT were not available for most patients. Importantly, not all patients underwent AHCT in these studies, whereas our cohort included only patients who underwent AHCT, which is considered standard of care for transplant-eligible patients with newly-diagnosed MM.6 A small single study conducted in Austria included 191 patients who underwent AHCT for MM between 1985 and 2017 and did not find a difference in outcomes between men and women.7 Although overall our results confirm these findings in the entire cohort, we did observe a significant gender difference in PFS in the subset of MM patients younger than 50. What could be the aetiology of inferior outcomes in female patients <50? There was no significant difference in baseline characteristics between females and males, including the R-ISS stage, or the occurrence of high-risk chromosomal abnormalities. Furthermore, the two groups received similar induction, conditioning and maintenance regimens, and achieved a similar depth of response prior to transplant, including MRD negative ≥VGPR. One potential explanation could be the hormonal difference. Oestrogen has been shown to promote the progression of MM by enhancing the immunosuppressive function of the myeloid-derived suppressor cells in the bone marrow, thereby inhibiting T-cell proliferation.8 We speculate that higher oestrogen levels in younger females might have contributed to a higher rate of progression. The impact of hormonal stimulation on tumour progression was recently demonstrated in patients with melanoma. Vellano et al. showed that testosterone was implicated in the worse recurrence-free survival in male patients treated with BRAF/MEK-targeted therapy through upregulation of the androgen receptor on tumoral cells.9 Moreover, inhibition of androgen receptor signalling improved outcomes in a murine model. Nonetheless, unmeasured differences in patient care at a younger age could also potentially explain the discrepancy in outcomes between genders. We acknowledge that our study has the limitations of a retrospective analysis, including patient selection, missing data and a relatively small number of patients in the subset analysis. Furthermore, there is potential for referral bias, since not all patients with newly diagnosed MM undergo upfront AHCT. In the registry study by Derman et al., females had a higher rate of referral to autologous HCT compared to males (54% vs 46%, p = 0009).4 To conclude, in this single-centre analysis of a large dataset of MM patients who received upfront AHCT, there was no significant difference in most baseline characteristics or survival outcomes between males and females. However, females <50 years of age had a significantly worse PFS compared to males. Additional research is required to explain this difference in outcomes, and our results and previous pre-clinical work raise the possibility that anti-oestrogen therapy could be studied in younger MM female patients. Oren Pasvolsky and MHQ conceived and designed the study. Oren Pasvolsky, Adeel Masood and Ali H. Mohamedi collected and assembled the data. Rima M. Saliba performed statistical analyses and interpreted the data. Oren Pasvolsky and Muzaffar H. Qazilbash analysed and verified the data. Mark R. Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Jeremy Ramdial, Yago Nieto, Hans C. Lee, Krina K. Patel, Partow Kebriaei, Sheeba K. Thomas, Donna M. Weber, Robert Z. Orlowski, Elizabeth J. Shpall and Richard E. Champlin verified and interpreted the data. All authors wrote and approved the article and are accountable for publication. The authors have no competing interests. Figure S1. Figure S2. Figure S3. Figure S4. Table S1. Table S2. Table S3. 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