Mortality Trends in Multiple Myeloma after the Introduction of Novel Therapies in the United States
Authors: Nandakumar Bharat , Binder Moritz , Rajkumar S. Vincent , Kapoor Prashant , Buadi Francis K. , Dingli David , Lacy Martha Q. , Gertz Morie A. , Hayman Suzanne R. , Leung Nelson , Fonder Amie , Hobbs Miriam A. , Hwa Yi L. , Muchtar Eli , Warsame Rahma M , Kourelis Taxiarchis , Gonsalves Wilson I , Russell Stephen J. , Lin Yi , Siddiqui Mustaqeem A. , Kyle Robert A. , Dispenzieri Angela , Kumar Shaji 
Published: November 2021

Abstract
Background: There has been a steady improvement in the survival of patients with multiple myeloma (MM) due to better understanding of the pathophysiology, use of novel agents, and risk-adapted therapy. These improvements were largely observed in clinical trials and tertiary center populations and questions remain about the generalizability of these findings to patients in community settings. Here, we compared the experience of patients seen at Mayo Clinic, Rochester (MAYO) and those followed in the Surveillance, Epidemiology, and End Results Program (SEER), to gain a better understanding of current trends in survival.
Methods: We studied all patients with MM diagnosed between 01/2004 and 12/2018 seen at MAYO and those followed in SEER (18 registry research data 2000-2018, 11/2020 submission). For comparison with SEER, MAYO patients who were alive at the end of SEER follow-up (12/31/2018) were censored. For the estimation of relative survival, patients alive at the end of 2019 were censored to align with the published United States general population rate tables. Overall survival (OS) estimates were calculated using the method described by Kaplan and Meier. Multivariable-adjusted proportional hazards regression models were used to assess the association between the 5-year interval of diagnosis and overall survival. Expected OS estimates were calculated based on United States general population rate tables from the Human Mortality Database using a conditional approach. Standardized mortality ratios (SMR) were calculated by dividing the number of observed deaths by the number of expected deaths in age- and sex-matched general United States population controls. Linear regression models were fit to test for trends in SMRs over time.
Results: The median age at diagnosis was 3 years lower in patients seen at MAYO compared to patients followed in SEER. The proportion of patients 75 years and older at the time of diagnosis was higher in SEER (26.3%) compared to MAYO (15.3%). Median OS was 6.7 years (95% CI 6.3-7.1) for MAYO compared to 4.6 years (95% CI 4.5-4.7) in SEER (Figure 1). When stratifying OS by year of diagnosis (in 5-year-intervals: 2004-2008, 2009-2013, 2014-2018), improvements were seen in both patient populations over time, albeit to a greater extent in patients seen at MAYO (Figures 2 and 3). The results were consistent after adjusting for age and sex in both MAYO and SEER. There were improvements in OS across all three 5-year intervals and age groups in both patient populations. In MAYO, these improvements were most pronounced during the second 5-year interval for younger patients (&lt; 65 years) and more pronounced during the last 5-year interval for older patients (&gt; 65 years). In SEER, the improvements were more gradual across the three 5-year intervals, but it was noted that the relative improvements in younger patients were greater than in older patients during the last 5-year interval. Early mortality decreased over time in both patient populations: from 11% to 6% at MAYO and from 23% to 16% in SEER (Figure 4). To examine the observed improvements in the context of the survival trends of the general population, we stratified the SMRs by patient population, age at diagnosis, and year of diagnosis, and a lack of improvement in excess mortality was observed among older patients (&gt;75 years) in both populations over time (Figure 5). Three- and five-year overall survival estimates were higher in patients seen at MAYO compared to patients followed in SEER, but the survival advantage diminished with increasing follow-up time (Figure 6). On further sub-group analysis within MAYO patients, excess mortality was observed for all International staging system (ISS) stages and patients with high-risk (HR) cytogenetics. Stratifying the SMRs by age and risk group, decreases in excess mortality were most pronounced among older patients, particularly those with indolent disease (Figure 7).
Conclusions: Survival outcomes in MM continued to improve in both patient populations. These improvements were more pronounced in MAYO compared to SEER, which may be partially explained by differences in access to specialized care. The most pronounced improvements were observed among younger patients and those with favorable disease characteristics. Future efforts need to focus on improving therapies for patients with unfavorable disease characteristics and on increasing access to specialized care in community settings.
Figure 1 Figure 1.

Disclosures
Kapoor: Glaxo SmithKline: Research Funding; Takeda: Research Funding; Sanofi: Research Funding; Amgen: Research Funding; Sanofi: Consultancy; Pharmacyclics: Consultancy; Ichnos Sciences: Research Funding; BeiGene: Consultancy; Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy. Dingli: Alexion: Consultancy; Apellis: Consultancy; Janssen: Consultancy; Novartis: Research Funding; GSK: Consultancy; Sanofi: Consultancy. Gertz: Ionis Pharmaceuticals: Other: Advisory Board; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy. Lin: Novartis: Consultancy; Celgene: Consultancy, Research Funding; Juno: Consultancy; Takeda: Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Legend: Consultancy; Sorrento: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Dispenzieri: Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Research Funding; Oncopeptides: Consultancy; Alnylam: Research Funding; Pfizer: Research Funding. Kumar: Tenebio: Research Funding; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Bluebird Bio: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.