Sex differences in outcomes in multiple myeloma

Abstract

Despite being perhaps the most fundamental distinction among human beings, the impact of sex on outcomes in multiple myeloma (MM) is unknown. Given that men are more likely to develop MM compared to women, and an analysis of all cancers using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program suggested possible worse MM survival for men than women,1 a comprehensive evaluation of sex differences in survival in MM is warranted. In an analysis of 1 960 MM patients enrolled in a phase III clinical trial, sex was associated with overall survival (OS) on univariate analysis (median OS 44·8 months female vs 49·9 months male, P = 0·02) but was not significant in multivariate analysis. Similarly, an analysis of the Myeloma XI trial found no sex differences in progression-free survival (PFS) or OS.3 In this report, we describe baseline characteristics and outcomes of patients with MM by sex using two large population-based datasets: the SEER dataset and the Multiple Myeloma Research Foundation (MMRF) CoMMpass dataset with clinical annotation. We used MM data for the period 2000–2017 from SEER 18 that covers about 27·8% of the United States population. We identified MM patients (n = 78,351) using the third edition of the International Classification of Diseases for Oncology (ICD-O-3) code 9732. We also obtained data from the MMRF CoMMpass study (NCT01454297), a prospective observational study of newly diagnosed MM patients initiated in 2011. Data relevant to treatment outcomes of 1 143 MM patients were collected, including pre-treatment demographics, International Staging System (ISS), baseline MM parameters, cytogenetics, induction regimen, autologous stem cell transplant (ASCT) and maintenance therapy use, PFS and OS. We defined OS as time from diagnosis until death from any cause. PFS was not available in SEER. In the MMRF data, PFS was defined as the time from the date of diagnosis until progression, death or the date of last follow-up. Survival curves were constructed using the Kaplan–Meier method and compared with the log-rank test. To examine the association between sex and outcomes, we first used Cox proportional hazards models to calculate age-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for PFS and OS. In all models, males served as the reference. Age at diagnosis as a continuous variable and categorical variable (<55, 55–69, 70+) generated similar findings. For SEER, basic multivariate models included age, race and diagnosis year (Table SI). For MMRF, basic multivariate models included age and established clinical prognostic factors including ISS, front-line ASCT and Eastern Cooperative Oncology Group (ECOG) performance status. High-risk cytogenetic abnormalities [defined as t(4;14), t(14;16), t(14;20), 1q gain and/or 17p deletion], gene expression profiling (UAMS70), estimated glomerular filtration rate (eGFR), treatment and race, were examined as potential covariates (Table SI), but were not found to change risk estimates by> 10%. The reported P values are two-sided. Statistical analyses were conducted in R v4·0.2 using the Survival package v3·1-12 (R Foundation for Statistical Computing, Vienna, Austria; https://cran.r-project.org). There were more males than females in both datasets: 55·5% males vs 44·5% females in SEER and 60·4% males vs 39·6% females in MMRF data. Although there were no significant differences between males and females with respect to baseline MM clinical characteristics (age, race, performance status, ISS, presence of high-risk cytogenetic abnormalities and induction treatment), females received front-line ASCT at a higher frequency compared to males (54% vs 46%, P = 0·009). OS and PFS were significantly better for females than males (Fig 1). The OS benefit persisted for females (SEER: HR = 0·92, 95% CI 0·90–0·94, P < 0·0001; MMRF: HR = 0·66, 95% CI 0·51–0·85, P < 0·0001) but was attenuated for PFS (MMRF: HR = 0·85, 95% CI 0·72–1·00, P = 0·06) after controlling for age, ISS, performance status and ASCT (Table I and Table SI). Point estimates for OS by sex in the SEER cohort were similar for patients diagnosed between 2000–2010 and 2011–2017, the time period during which the MMRF cohort was enrolled. These findings stand in contrast to previously published data from clinical trials that have suggested no difference in survival outcomes by sex. Though the afore-mentioned studies benefitted from more uniform treatment of patients under clinical trial conditions, they likely represent a subset of highly motivated and physically fit MM patients that could participate in such a trial. That biologic sex plays a role in MM outcomes poses a vexing problem and requires further investigation as to the reasons why. Factors related to long-term disease control may explain better OS and PFS for women; chiefly, that they may have healthier attitudes and behaviours and are more likely to engage in health-promoting behaviours after intensive treatment.4 It is also possible that male patients have more comorbidities at the time of MM diagnosis than females, and these comorbid conditions may contribute to poorer MM survival. There may be biologic underpinnings for sex differences in MM outcomes as well. Hormone-related pharmacokinetic variation, for example, has been demonstrated in lymphoma studies, where higher rituximab serum concentrations were associated with female sex and associated with remission quality of PFS.5 The cornerstones of anti-MM therapies involve immune-modifying drugs such as proteasome inhibitors, immunomodulatory imide drugs and corticosteroids. Thus, it is important to point out that there are clearly described sex differences in both innate and adaptive immune responses, including that males have higher frequencies of regulatory T cells (Treg) than their female counterparts.6 Increased Treg are associated with adverse clinical features and have an impact on MM progression.7 Depletion of Treg in the peri-ASCT setting of MM patients was shown to delay Treg recovery after ASCT and led to favourable outcomes in a pilot study of MM patients.8 Moreover, multiparametric flow cytometry of bone marrow samples from MM patients revealed that bone marrow Treg were lower in patients with long-term disease control than in symptomatic MM.9 This suggests that higher Treg frequencies in males may be responsible in part for inferior MM outcomes, though this requires further investigation. Our findings have implications with respect to the clinical care of MM patients. Specifically, clinical trials in MM must ensure adequate representation of both sexes. If frailty and/or lack of social-support mechanisms are in fact part of the underlying factors for sex differences, then pretreatment and on-treatment comprehensive geriatric assessment can be undertaken to maximize patient function which may allow for higher-intensity treatment and improved MM survival.10 For a distinction among human beings as old as time, much remains to be uncovered regarding the impact of sex on MM outcomes. This research was supported, in part, by the National Institutes of Health grant R01 CA223662 (BCC and WZ). We thank the Multiple Myeloma Research Foundation for making the CoMMpass registry available for analysis. BAD and BCC designed the research and provided oversight; SSL and MM performed statistical analysis; AJJ provided clinical advice; WZ helped with interpretation of data; BAD and BCC drafted the paper with input from all authors; and all authors read and approved the final manuscript. BAD, SL, MM, WZ and BCC declare no competing financial interests. AJJ declares: Honoraria — Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline; Abbvie, Janssen, Karyopharm Therapeutics, Millennium, Sanofi, Skyline Diagnostics, Takeda; Consulting or Advisory Role — Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, AbbVie, Janssen, Karyopharm Therapeutics, Millennium, Sanofi, Skyline Diagnostics, Takeda. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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