Temporal Trends in Multiple Myeloma Mortality and Their Relationship to Evolving Treatment Strategies: A Retrospective Analysis Using SEER Data

Temporal Trends in Multiple Myeloma Mortality and Their Relationship to Evolving Treatment Strategies: A Retrospective Analysis Using SEER Data | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Temporal Trends in Multiple Myeloma Mortality and Their Relationship to Evolving Treatment Strategies: A Retrospective Analysis Using SEER Data Navkirat Kahlon This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6624519/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Multiple myeloma (MM) is the second most common hematologic malignancy, accounting for approximately 2% of cancer-related deaths in the United States. Over the past five decades, therapeutic advancements, including novel drug approvals and intensified treatment strategies, have significantly transformed MM management. This study examines temporal trends in MM-specific mortality and their association with evolving therapeutic approaches. Methods: This retrospective cross-sectional study utilized the Surveillance, Epidemiology, and End Results (SEER) database to evaluate age-adjusted MM mortality rates from 1975 to 2022. Annual Percent Change (APC) was calculated using Joinpoint regression analysis to identify significant shifts in mortality trends. The timeline of FDA-approved MM treatments was reviewed to explore potential temporal associations with mortality reductions. Results: MM mortality increased from 1975 to 1994 due to limited treatment options. The introduction of autologous stem cell transplantation in 1994 correlated with a modest decline. A marked decrease in mortality was observed from 2002 to 2009 with the emergence of immunomodulatory drugs and proteasome inhibitors, followed by significant reductions between 2014 and 2022 with the approval of multiple novel therapeutic agents. Stagnant mortality trends between 2009 and 2014 coincided with a period of no new drug class approvals. Conclusion: MM-specific mortality in the U.S. has declined substantially over the past two decades, reflecting the impact of novel therapies and frontline treatment intensification. The findings highlight MM’s epidemiologic transformation into a more manageable chronic condition. Addressing disparities in healthcare accessibility and costs is crucial to ensuring equitable treatment benefits for all patients. Multiple myeloma epidemiologic trends mortality reduction therapeutic advancements FDA-approved treatments SEER database Figures Figure 1 Background Multiple Myeloma (MM) is characterized as a plasma cell malignancy arising from the uncontrolled proliferation of plasma cells within the bone marrow niche. Globally, MM is responsible for approximately 1% of cancer-related mortality, with its incidence having markedly increased by 126% from 1990 to 2016 [ 1 ]. Fortunately, remarkable progress has been made in the treatment of MM. The treatment modalities for MM before the 1990s were limited to conventional therapies, predominantly involving alkylating agents such as melphalan, corticosteroids, and combinations of vincristine, dexamethasone, and doxorubicin. However, the mid-1990s witnessed a pivotal shift in treatment paradigms, with the advent of Autologous Stem Cell Transplantation (ASCT) and high-dose chemotherapy demonstrating improved event-free survival when juxtaposed with standard chemotherapy regimens [ 2 ]. The past two decades have ushered in a new era in MM management, marked by the introduction and FDA approval of several novel therapeutic agents that can be sequenced for enhanced patient outcomes. Among these, proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (MAbs), selective inhibitors of nuclear export (SINEs), and chimeric antigen receptor (CAR) T-cell therapies, bispecific monoclonal antibodies (BsAbs) have emerged as critical components of contemporary treatment strategies. The mechanistic actions of these agents vary significantly; for instance, compounds such as Bortezomib and carfilzomib function by inducing endoplasmic reticulum (ER) stress, thereby activating antiproliferative signals and apoptotic pathways responsible for promoting cellular apoptosis [ 3 ]. In contrast, IMiDs such as thalidomide and lenalidomide exert their cytotoxic effects through diverse mechanisms, including the activation of pro-apoptotic factors, caspase activation, inhibition of transcription factors, and diminished cytokine production [ 4 ]. Similarly, MAbs such as daratumumab and elotuzumab, categorized as naked monoclonal antibodies, achieve their therapeutic effects by activating natural killer (NK) cells and enhancing antibody-dependent cellular cytotoxicity through the classical complement pathway [ 5 ]. Furthermore, BsAbs like teclistamab, which possess dual antigen-binding sites, have also been integrated into treatment protocols. In addition to the development of novel agents, the intensification of frontline therapy has been evident over the past three decades. Specifically, the routine adoption of ASCT since the mid-1990s and the preference for triplet therapy—combining an immunomodulatory agent, a proteasome inhibitor, and dexamethasone—over traditional doublet therapy have been pivotal since the mid-2010s in the United States [ 6 ]. Although MM remains an incurable malignancy, were reviewed. These trends are reported as Annual Percent Change (APC) with a 95% confidence interval (CI), using a two-sided p-value below 0.05 to determine significance. A Joinpoint regression model was used to determine the Annual Percent Change (APC) utilizing the Joinpoint Trend Analysis Software, Version 5.1, April 2024, National Cancer Institute [ 9 ]. The timeline and clinical benefit reported in clinical trials for FDA approvals of MM treatments during this period, to explore any temporal associations with MM mortality trends, was also reviewed. Methods Data Source This retrospective analysis is based on publicly available and de-identified SEER data. According to the Common Rule, institutional review board approval and patient consent were not required for the anonymized and publicly available data. This study analyzed long-term mortality rate trends of Multiple Myeloma from 1975 to 2022 using the Surveillance, Epidemiology, and End Results Program (SEER) database in the context of changing MM treatment paradigms. The SEER database, by the National Cancer Institute, is an open-access database that provides cancer statistics of the U.S. population. The SEER database contains patient information since 1973 and encompasses 48% of the United States population across 22 U.S. geographic areas. The SEER program is publicly available and uses de-identified patient data from the National Center for Health Statistics, Centers for Disease Control and Prevention, and US Mortality Files. Adult patients (18 years or older) diagnosed with MM from 1975 to 2022 were included [ 8 ]. Statistical Analysis The SEER database has mortality rates reported per 100,000 individuals age-adjusted to the 2000 US Standard Population. The data regarding MM mortality for the period from 1975 to 2022 were reviewed. These trends are reported as Annual Percent Change (APC) with a 95% confidence interval (CI), using a two-sided p-value below 0.05 to determine significance. A Joinpoint regression model was used to determine the Annual Percent Change (APC) utilizing the Joinpoint Trend Analysis Software, Version 5.1, April 2024, National Cancer Institute [ 9 ]. The timeline for FDA approvals of MM treatments during this period to explore any temporal associations with MM mortality trends was also reviewed. Results The age-adjusted U.S. myeloma mortality rate showed an increasing trend from 1975 to 1994 (APC, 1.43% [95% CI, 1.33–1.55]; P < .01. During this period, the available treatments, such as melphalan, provided no clinically meaningful benefit or improvement in overall survival outcomes. Melphalan was introduced in the 1950s, which was subsequently combined with corticosteroids. However, the clinical benefit of this regimen remained marginal over a three-decade span [ 10 ]. The pivotal shift in management emerged in the 1990s with the advent of high-dose melphalan (HDM) with autologous stem cell transplantation (ASCT). ASCT was introduced in upfront therapy to rescue the myelosuppression caused by high doses. This approach marked a significant improvement in patient outcomes, evidenced by a survival rate of 52% in the HDM plus ASCT group versus 12% in the conventional dose arm (P = 0.03) [ 11 ]. Following this innovation, a decrease in the MM-specific population mortality rate was observed between 1994 and 2002, with an APC of -0.70% (95% CI, -1.03 to -0.21; P = .02). A more significant decline in mortality rates was seen during 2002 to 2009, where an APC of -1.85% (95% CI, -2.78 to -1.50; P < .01) coincided with the introduction of two classes of novel agents i.e. PIs and IMiDs. Thalidomide was the first new effective drug to treat MM in decades. Even though thalidomide had been used off-label in the treatment of multiple myeloma since the late 1990s [ 12 , 13 ], its use became more widespread after the FDA officially approved it in 2006 for combination therapy with dexamethasone based on E1A00. The E1A00 study reported that the median PFS was 22.6 months in the thalidomide group versus 6.5 months in the dexamethasone-only group, demonstrating the significant and impressive efficacy of the combination therapy in newly diagnosed multiple myeloma patients. Despite these advancements, an overall survival benefit remained elusive at that time [ 14 ]. The emergence of proteasome inhibitors, particularly bortezomib, marked another milestone in MM therapy. The combination of doxorubicin and bortezomib demonstrated a modest improvement in time to progression in relapsed/refractory multiple myeloma in 2006. However, due to the small benefits and associated toxicities, doxorubicin is no longer used in clinical practice [ 15 ]. Bortezomib was the first FDA-approved as an induction treatment in 2007. Induction with bortezomib in combination with melphalan and prednisone was approved based on the results of the VISTA study. The study found that the median duration of response was significantly longer in the bortezomib group at 19.9 months, compared to 13.1 months in the control group. Additionally, the hazard ratio for overall survival was 0.61 for the bortezomib group (P = 0.008), indicating a notable survival benefit for patients treated with bortezomib [ 16 ].This marked a pivotal moment when treatments began showing overall survival benefits in clinical trials. During the period from 2009 to 2014, no new drug classes were introduced. This coincided with the stagnant MM-specific mortality rates (APC 0.52% [95% CI, -0.10 to 1.69]; p-value 0.10 during the period between 2009 and 2014, while no significant improvement in multiple myeloma (MM) mortality was noted, existing drug classes were further developed. This is exemplified by the FDA approval of carfilzomib, a selective PI in 2012 and pomalidomide, an IMiD in 2013 for relapsed/refractory cases based on their clinical efficacy [ 17 , 18 ]. From 2014 to 2022, a significant decline in MM-specific mortality was observed (APC − 2.08% [95% CI, -2.40 to -1.81]; P < .01), marking a substantial improvement compared to the preceding four decades. paralleling the introduction of numerous novel agents and combination therapies as well as the introduction of the concept of maintenance treatments. In 2015, the FDA approved three different drug combinations for relapsed/refractory multiple myeloma (MM). The first combination is panobinostat (a histone deacetylase inhibitor) with bortezomib and dexamethasone. Panobinostat received accelerated approval by the FDA based on phase 3 PANORAMA1 study. However, as the post-approval clinical research was not completed, the approval was later withdrawn in 2022 by the FDA [ 19 ]. The second combination is ixazomib (a proteasome inhibitor) with lenalidomide and dexamethasone. In the TOURMALINE-MM1 trial, patients were assigned to lenalidomide and dexamethasone with or without ixazomib. Patients from the ixazomib group showed improved median PFS of 20.6 months vs 14.7 months in the lenalidomide and dexamethasone alone group (HR, 0.74; P = .012) [ 20 ]. The third combination is elotuzumab (a monoclonal antibody) with lenalidomide and dexamethasone. Elotuzumab is the first monoclonal antibody used in the treatment of MM. It was approved in combination with lenalidomide plus dexamethasone in 2015 and also approved in combination with pomalidomide plus dexamethasone in 2018 based on the results from the ELOQUENT-2 and 3 studies, respectively. ELOQUENT-2 showed the median PFS was 19.4 months in the ERd group compared to 14.9 months in the Rd group, representing a 30% reduction in the risk of disease progression or death (HR, 0.70; P = 0.0004) [ 21 ].In addition, daratumumab, an anti-CD38 monoclonal antibody, was first granted accelerated approval in November 2015 as a monotherapy for relapsed/refractory MM in patients who had received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who were double refractory. In November 2016, the FDA expanded the approval of daratumumab for relapsed/refractory multiple myeloma to include its use in combination with standard regimens such as lenalidomide and dexamethasone (POLLUX trial) and bortezomib and dexamethasone (CASTOR trial). [ 22 , 23 ]. In the POLLUX (MMY3003) study, the median PFS was not reached in the trial group (Daratumumab plus lenalidomide and dexamethasone) and was 18.4 months in the control group (lenalidomide and dexamethasone only) with a median follow-up of 13.5 months. In the CASTOR (MMY3004) study, the median PFS in the trial arm (Daratumumab plus bortezomib and dexamethasone) was not reached, compared with a median PFS of 7.2 months in the control arm (bortezomib and dexamethasone alone at a median follow-up of 7.4 months. Later in 2019, daratumumab was approved for newly diagnosed MM based on the MAIA trial, which showed improved PFS. According to the results from this trial, a median PFS was not reached in the trial arm (Daratumumab in combination with lenalidomide and dexamethasone) compared to the median PFS of 31.9 months in the control arm (lenalidomide and dexamethasone) [ 24 ]. In 2017, Lenalidomide was approved by the FDA as maintenance therapy in patients with newly diagnosed multiple myeloma who had undergone autologous stem cell transplantation (ASCT). This approval was based on the CALGB 100104 trial in which TTP was 57.3 months in the lenalidomide arm compared to 28.9 months in the placebo arm (HR, 0.57; 95% CI 0.46–0.71; P < 0.0001). OS was also improved [ 25 ]. Selinexor, an NF-κB inhibitor, was approved by the FDA in 2019 for treating triple-class refractory multiple myeloma (MM). In a study involving its combination with dexamethasone, 26% achieved a partial response or better. The median response time was 4.1 weeks, with 39% of patients showing at least a minimal response. Additionally, the median overall survival was 8.6 months, and the median progression-free survival was 3.7 months. [ 26 ]. In 2020, the FDA granted accelerated approval to belantamab mafodotin-blmf as a monotherapy for the treatment of relapsed/refractory multiple myeloma (MM). This marked the first approval of an antibody-drug conjugate (ADC) for MM. The approval was based on the results from the pivotal phase 2 single-arm DREAMM-2 study, which demonstrated clinically meaningful and durable overall response rates [ 27 ]. In 2020, the FDA also approved a novel anti-CD38 monoclonal antibody named isatuximab, in combination with pomalidomide and dexamethasone, for the treatment of relapsed/refractory multiple myeloma (MM). This approval was based on the results from the phase 3 ICARIA-MM study. The combination therapy demonstrated an improved progression-free survival (PFS) of 11.53 months (95% CI: 8.94–13.9) compared to 6.47 months (95% CI: 4.47–8.28) in the pomalidomide and dexamethasone alone arm (HR: 0.596; 95% CI: 0.44–0.81; P = 0.0010) [ 28 ]. Additionally, in 2021, the FDA approved isatuximab in combination with carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. This approval was based on the results from the Phase 3 IKEMA trial, which showed an improved median progression-free survival (PFS) that was not reached in the trial arm (isatuximab with carfilzomib and dexamethasone) compared to a PFS of 20.27 months in the control arm (carfilzomib and dexamethasone alone) [ 29 ]. In 2021, the FDA approved idecabtagene vicleucel (ide-cel) as the first anti-BCMA CAR T cell therapy for relapsed or refractory multiple myeloma. This personalized immune cell therapy is manufactured using the patient’s white blood cells. The FDA approval was based on data from the pivotal Phase II KarMMa trial, which demonstrated unprecedented response rates in relapsed/refractory multiple myeloma [ 30 ]. In February 2022, the FDA approved ciltacabtagene autoleucel (CARVYKTI), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell immunotherapy, for the treatment of relapsed or refractory multiple myeloma. This approval was based on the results from the Phase 1b/2 CARTITUDE-1 study. The study demonstrated an overall response rate of 98% (95% CI, 92.7%-99.7%) with a stringent complete response rate of 78% (95% CI, 68.8%-86.1%) [ 29 ]. Teclistamab-cqyv, a bispecific BCMA-directed CD3 T-cell engager was approved for adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy in October 2022. The approval was based on the MajesTEC-1 study, which showed an overall response rate of 61.8% [ 32 ]. While clinical trials demonstrated PFS benefits over short durations, these effects translated into population-level mortality reductions. The cumulative real-world survival benefit observed was likely due to optimized sequencing of therapies, with clear temporal associations to the introduction and widespread use of new drug classes.real-world survival benefit observed was likely due to optimized sequencing of therapies. These results are summarized in Table 1 , Fig. 1 and Fig. 2. Table 1 Long-Term Trends in U.S. Age-Adjusted Mortality Rates, 1975–2022 and key developments Year Range Age Adjusted U.S. Myeloma Mortality Rate ; APC (%), 95% CI P-Value Interpretation Key Developments 1975–1994 1.43 (1.33, 1.55) < 0.01 Increasing No effective treatments available. Melphalan and corticosteroids used with marginal benefit. 1994–2002 -0.70 (-1.03, -0.21) 0.02 Decreasing Use of high dose melphalan with autologous stem cell transplantation. 2002–2009 -1.85 (-2.78, -1.50) < 0.01 Decreasing Introduction of immunomodulatory drugs and proteasome inhibitors. 2009–2014 0.52 (-0.10, 1.69) 0.10 No Statistically significant change No novel drug classes approved. 2014–2022 -2.08 (-2.40, -1.81) < 0.01 Decreasing Introduction of more novel drug classes like monoclonal antibodies, selective inhibitors of nuclear export (SINEs), CAR-T cell therapies, and bispecific antibodies Abbreviations: APC, annual percent change; %, percent; CI, Confidence interval Discussion This study provides a comprehensive analysis of multiple myeloma (MM)-specific mortality trends over the past five decades, demonstrating a strong correlation between the advent of modern therapeutic approaches, including novel pharmacological agents and the intensification of frontline treatments and population-level survival improvements. The novel therapies are reshaping the epidemiology of the disease Over the past five decades, MM treatment has undergone transformative shifts, beginning with alkylating agents and corticosteroids and progressing toward autologous stem cell transplantation (ASCT), immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (MAbs), selective inhibitors of nuclear export (SINEs), chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies (BsAbs). During 1975–1994, MM-specific mortality increased (APC 1.43%; p < 0.01) due to the limited efficacy of available treatments. However, between 1994–2002, the introduction of high-dose melphalan with ASCT contributed to a modest decline (APC -0.70%; p = 0.02). A more pronounced decline was observed during 2002–2009 (APC -1.85%; p < 0.01) with the integration of IMiDs and PIs, followed by 2014–2022, which demonstrated the most substantial decrease in mortality rates (APC -2.08%; p < 0.01) with the arrival of multiple new drug classes. While clinical trials primarily report progression-free survival (PFS) benefits, this study highlights that these short-term trial outcomes translated into long-term, real-world population-level mortality reductions. The sequencing and optimization of available treatments played a critical role in enhancing survival rates, even before overall survival (OS) improvements were fully established in clinical settings. Recent studies highlight significant global and regional disparities in MM trends. Globally, age-standardized incidence rates (ASIR) and mortality rates (ASMR) have risen over recent decades, with middle Socio-Demographic Index regions being particularly impacted [33, 34]. Europe demonstrates the highest ASIR and prevalence rates, reflecting advanced diagnostic capabilities [33]. However, mortality trends across European countries vary—some, like Sweden, report declines, whereas others, such as Bulgaria, show increases [34]. In North America, contrasting trends are evident; while overall mortality rates are reported to have increased in the region [33], data specific to the United States indicate declining mortality due to advancements in early detection, innovative treatments, and improved healthcare access [35, 36]. These findings underscore the need for region-specific strategies and the global dissemination of advanced therapies to address MM’s growing burden. Similar to MM trends of decreasing cancer-specific population mortality have been observed in other cancers, such as lung cancer and melanoma [36,37]. This is an exciting development, but it also highlights the rising cost of healthcare [38]. As survival rates improve, an increasing number of MM patients are expected to live longer, necessitating a shift in focus toward managing long-term treatment-related toxicities . The side effects associated with contemporary MM therapies—including neuropathy, cytopenias, cardiovascular risks, and immune dysfunction—pose significant challenges, particularly for those undergoing maintenance therapy or repeated lines of treatment. Ensuring multidisciplinary support and equitable access to survivorship care will be crucial for enhancing long-term quality of life for MM survivors. The strength of our study lies in its large, population-based sample derived from the publicly available SEER database, which is representative of the U.S. population. This dataset includes older and socioeconomically disadvantaged patients who are often underrepresented in randomized clinical trials, thereby enhancing the generalizability of our findings. However, several limitations must be considered. As a retrospective analysis, the study is susceptible to unaddressed confounders and selection bias inherent to the SEER database. Additionally, the SEER database lacks detailed clinical and chemotherapeutic data for individual patients, limiting our ability to assess specific treatment regimens. Variations in treatment protocols, adherence, and reporting inconsistencies may also introduce biases. Finally, the observational nature of this study precludes the definitive establishment of temporal relationships between therapeutic interventions and patient outcomes. Despite these limitations, our findings provide critical insights into MM-specific mortality trends and emphasize the impact of evolving treatment strategies on real-world population-level survival outcomes. Conclusion The declining MM-specific mortality rates over the past five decades highlight the profound impact of therapeutic innovations on patient survival. 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N Engl J Med 383(7):640–649. 10.1056/NEJMoa1916623 Chen S, Cao Z, Prettner K et al (2023) Estimates and projections of the global economic cost of 29 cancers in 204 countries and territories from 2020 to 2050. JAMA Oncol 9(4):465–472. 10.1001/jamaoncol.2022.7826 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6624519","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":454051383,"identity":"7dc0cf4b-94ab-4294-9293-463716c4c7c2","order_by":0,"name":"Navkirat Kahlon","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-1115-2029","institution":"Mass General cancer Center at Wentworth Douglass hospital","correspondingAuthor":true,"prefix":"","firstName":"Navkirat","middleName":"","lastName":"Kahlon","suffix":""}],"badges":[],"createdAt":"2025-05-09 03:05:48","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6624519/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6624519/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82850217,"identity":"60465a5a-8247-4080-aedb-a509e0bcae03","added_by":"auto","created_at":"2025-05-16 03:07:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":265252,"visible":true,"origin":"","legend":"\u003cp\u003eLong-Term Trends in U.S. Age-Adjusted Mortality Rates, 1975-2022 \u003cbr\u003e\n Abbreviations: APC, annual percent change; %, percent\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6624519/v1/0d82a7eae1741c79e3f7a951.png"},{"id":82851316,"identity":"f36ce32d-6d7b-4708-8ec7-3ba56b9f44e1","added_by":"auto","created_at":"2025-05-16 03:23:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":569455,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6624519/v1/d23e623c-e213-47db-87b6-720030f689ed.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eTemporal Trends in Multiple Myeloma Mortality and Their Relationship to Evolving Treatment Strategies: A Retrospective Analysis Using SEER Data\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eMultiple Myeloma (MM) is characterized as a plasma cell malignancy arising from the uncontrolled proliferation of plasma cells within the bone marrow niche. Globally, MM is responsible for approximately 1% of cancer-related mortality, with its incidence having markedly increased by 126% from 1990 to 2016 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Fortunately, remarkable progress has been made in the treatment of MM.\u003c/p\u003e \u003cp\u003eThe treatment modalities for MM before the 1990s were limited to conventional therapies, predominantly involving alkylating agents such as melphalan, corticosteroids, and combinations of vincristine, dexamethasone, and doxorubicin. However, the mid-1990s witnessed a pivotal shift in treatment paradigms, with the advent of Autologous Stem Cell Transplantation (ASCT) and high-dose chemotherapy demonstrating improved event-free survival when juxtaposed with standard chemotherapy regimens [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe past two decades have ushered in a new era in MM management, marked by the introduction and FDA approval of several novel therapeutic agents that can be sequenced for enhanced patient outcomes. Among these, proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (MAbs), selective inhibitors of nuclear export (SINEs), and chimeric antigen receptor (CAR) T-cell therapies, bispecific monoclonal antibodies (BsAbs) have emerged as critical components of contemporary treatment strategies.\u003c/p\u003e \u003cp\u003eThe mechanistic actions of these agents vary significantly; for instance, compounds such as Bortezomib and carfilzomib function by inducing endoplasmic reticulum (ER) stress, thereby activating antiproliferative signals and apoptotic pathways responsible for promoting cellular apoptosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In contrast, IMiDs such as thalidomide and lenalidomide exert their cytotoxic effects through diverse mechanisms, including the activation of pro-apoptotic factors, caspase activation, inhibition of transcription factors, and diminished cytokine production [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Similarly, MAbs such as daratumumab and elotuzumab, categorized as naked monoclonal antibodies, achieve their therapeutic effects by activating natural killer (NK) cells and enhancing antibody-dependent cellular cytotoxicity through the classical complement pathway [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Furthermore, BsAbs like teclistamab, which possess dual antigen-binding sites, have also been integrated into treatment protocols.\u003c/p\u003e \u003cp\u003eIn addition to the development of novel agents, the intensification of frontline therapy has been evident over the past three decades. Specifically, the routine adoption of ASCT since the mid-1990s and the preference for triplet therapy\u0026mdash;combining an immunomodulatory agent, a proteasome inhibitor, and dexamethasone\u0026mdash;over traditional doublet therapy have been pivotal since the mid-2010s in the United States [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Although MM remains an incurable malignancy, were reviewed. These trends are reported as Annual Percent Change (APC) with a 95% confidence interval (CI), using a two-sided p-value below 0.05 to determine significance. A Joinpoint regression model was used to determine the Annual Percent Change (APC) utilizing the Joinpoint Trend Analysis Software, Version 5.1, April 2024, National Cancer Institute [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The timeline and clinical benefit reported in clinical trials for FDA approvals of MM treatments during this period, to explore any temporal associations with MM mortality trends, was also reviewed.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData Source\u003c/h2\u003e \u003cp\u003eThis retrospective analysis is based on publicly available and de-identified SEER data. According to the Common Rule, institutional review board approval and patient consent were not required for the anonymized and publicly available data. This study analyzed long-term mortality rate trends of Multiple Myeloma from 1975 to 2022 using the Surveillance, Epidemiology, and End Results Program (SEER) database in the context of changing MM treatment paradigms. The SEER database, by the National Cancer Institute, is an open-access database that provides cancer statistics of the U.S. population. The SEER database contains patient information since 1973 and encompasses 48% of the United States population across 22 U.S. geographic areas. The SEER program is publicly available and uses de-identified patient data from the National Center for Health Statistics, Centers for Disease Control and Prevention, and US Mortality Files. Adult patients (18 years or older) diagnosed with MM from 1975 to 2022 were included [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe SEER database has mortality rates reported per 100,000 individuals age-adjusted to the 2000 US Standard Population. The data regarding MM mortality for the period from 1975 to 2022 were reviewed. These trends are reported as Annual Percent Change (APC) with a 95% confidence interval (CI), using a two-sided p-value below 0.05 to determine significance. A Joinpoint regression model was used to determine the Annual Percent Change (APC) utilizing the Joinpoint Trend Analysis Software, Version 5.1, April 2024, National Cancer Institute [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The timeline for FDA approvals of MM treatments during this period to explore any temporal associations with MM mortality trends was also reviewed.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe age-adjusted U.S. myeloma mortality rate showed an increasing trend from 1975 to 1994 (APC, 1.43% [95% CI, 1.33\u0026ndash;1.55]; P\u0026thinsp;\u0026lt;\u0026thinsp;.01. During this period, the available treatments, such as melphalan, provided no clinically meaningful benefit or improvement in overall survival outcomes. Melphalan was introduced in the 1950s, which was subsequently combined with corticosteroids. However, the clinical benefit of this regimen remained marginal over a three-decade span [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe pivotal shift in management emerged in the 1990s with the advent of high-dose melphalan (HDM) with autologous stem cell transplantation (ASCT). ASCT was introduced in upfront therapy to rescue the myelosuppression caused by high doses. This approach marked a significant improvement in patient outcomes, evidenced by a survival rate of 52% in the HDM plus ASCT group versus 12% in the conventional dose arm (P\u0026thinsp;=\u0026thinsp;0.03) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Following this innovation, a decrease in the MM-specific population mortality rate was observed between 1994 and 2002, with an APC of -0.70% (95% CI, -1.03 to -0.21; P\u0026thinsp;=\u0026thinsp;.02).\u003c/p\u003e \u003cp\u003eA more significant decline in mortality rates was seen during 2002 to 2009, where an APC of -1.85% (95% CI, -2.78 to -1.50; P\u0026thinsp;\u0026lt;\u0026thinsp;.01) coincided with the introduction of two classes of novel agents i.e. PIs and IMiDs. Thalidomide was the first new effective drug to treat MM in decades. Even though thalidomide had been used off-label in the treatment of multiple myeloma since the late 1990s [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], its use became more widespread after the FDA officially approved it in 2006 for combination therapy with dexamethasone based on E1A00. The E1A00 study reported that the median PFS was 22.6 months in the thalidomide group versus 6.5 months in the dexamethasone-only group, demonstrating the significant and impressive efficacy of the combination therapy in newly diagnosed multiple myeloma patients. Despite these advancements, an overall survival benefit remained elusive at that time [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The emergence of proteasome inhibitors, particularly bortezomib, marked another milestone in MM therapy. The combination of doxorubicin and bortezomib demonstrated a modest improvement in time to progression in relapsed/refractory multiple myeloma in 2006. However, due to the small benefits and associated toxicities, doxorubicin is no longer used in clinical practice [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Bortezomib was the first FDA-approved as an induction treatment in 2007. Induction with bortezomib in combination with melphalan and prednisone was approved based on the results of the VISTA study. The study found that the median duration of response was significantly longer in the bortezomib group at 19.9 months, compared to 13.1 months in the control group. Additionally, the hazard ratio for overall survival was 0.61 for the bortezomib group (P\u0026thinsp;=\u0026thinsp;0.008), indicating a notable survival benefit for patients treated with bortezomib [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].This marked a pivotal moment when treatments began showing overall survival benefits in clinical trials.\u003c/p\u003e \u003cp\u003eDuring the period from 2009 to 2014, no new drug classes were introduced. This coincided with the stagnant MM-specific mortality rates (APC 0.52% [95% CI, -0.10 to 1.69]; p-value 0.10 during the period between 2009 and 2014, while no significant improvement in multiple myeloma (MM) mortality was noted, existing drug classes were further developed. This is exemplified by the FDA approval of carfilzomib, a selective PI in 2012 and pomalidomide, an IMiD in 2013 for relapsed/refractory cases based on their clinical efficacy [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFrom 2014 to 2022, a significant decline in MM-specific mortality was observed (APC \u0026minus;\u0026thinsp;2.08% [95% CI, -2.40 to -1.81]; P\u0026thinsp;\u0026lt;\u0026thinsp;.01), marking a substantial improvement compared to the preceding four decades. paralleling the introduction of numerous novel agents and combination therapies as well as the introduction of the concept of maintenance treatments. In 2015, the FDA approved three different drug combinations for relapsed/refractory multiple myeloma (MM). The first combination is panobinostat (a histone deacetylase inhibitor) with bortezomib and dexamethasone. Panobinostat received accelerated approval by the FDA based on phase 3 PANORAMA1 study. However, as the post-approval clinical research was not completed, the approval was later withdrawn in 2022 by the FDA [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The second combination is ixazomib (a proteasome inhibitor) with lenalidomide and dexamethasone. In the TOURMALINE-MM1 trial, patients were assigned to lenalidomide and dexamethasone with or without ixazomib. Patients from the ixazomib group showed improved median PFS of 20.6 months vs 14.7 months in the lenalidomide and dexamethasone alone group (HR, 0.74; P\u0026thinsp;=\u0026thinsp;.012) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The third combination is elotuzumab (a monoclonal antibody) with lenalidomide and dexamethasone. Elotuzumab is the first monoclonal antibody used in the treatment of MM. It was approved in combination with lenalidomide plus dexamethasone in 2015 and also approved in combination with pomalidomide plus dexamethasone in 2018 based on the results from the ELOQUENT-2 and 3 studies, respectively. ELOQUENT-2 showed the median PFS was 19.4 months in the ERd group compared to 14.9 months in the Rd group, representing a 30% reduction in the risk of disease progression or death (HR, 0.70; P\u0026thinsp;=\u0026thinsp;0.0004) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].In addition, daratumumab, an anti-CD38 monoclonal antibody, was first granted accelerated approval in November 2015 as a monotherapy for relapsed/refractory MM in patients who had received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who were double refractory.\u003c/p\u003e \u003cp\u003eIn November 2016, the FDA expanded the approval of daratumumab for relapsed/refractory multiple myeloma to include its use in combination with standard regimens such as lenalidomide and dexamethasone (POLLUX trial) and bortezomib and dexamethasone (CASTOR trial). [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In the POLLUX (MMY3003) study, the median PFS was not reached in the trial group (Daratumumab plus lenalidomide and dexamethasone) and was 18.4 months in the control group (lenalidomide and dexamethasone only) with a median follow-up of 13.5 months. In the CASTOR (MMY3004) study, the median PFS in the trial arm (Daratumumab plus bortezomib and dexamethasone) was not reached, compared with a median PFS of 7.2 months in the control arm (bortezomib and dexamethasone alone at a median follow-up of 7.4 months. Later in 2019, daratumumab was approved for newly diagnosed MM based on the MAIA trial, which showed improved PFS. According to the results from this trial, a median PFS was not reached in the trial arm (Daratumumab in combination with lenalidomide and dexamethasone) compared to the median PFS of 31.9 months in the control arm (lenalidomide and dexamethasone) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2017, Lenalidomide was approved by the FDA as maintenance therapy in patients with newly diagnosed multiple myeloma who had undergone autologous stem cell transplantation (ASCT). This approval was based on the CALGB 100104 trial in which TTP was 57.3 months in the lenalidomide arm compared to 28.9 months in the placebo arm (HR, 0.57; 95% CI 0.46\u0026ndash;0.71; P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). OS was also improved [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSelinexor, an NF-κB inhibitor, was approved by the FDA in 2019 for treating triple-class refractory multiple myeloma (MM). In a study involving its combination with dexamethasone, 26% achieved a partial response or better. The median response time was 4.1 weeks, with 39% of patients showing at least a minimal response. Additionally, the median overall survival was 8.6 months, and the median progression-free survival was 3.7 months. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2020, the FDA granted accelerated approval to belantamab mafodotin-blmf as a monotherapy for the treatment of relapsed/refractory multiple myeloma (MM). This marked the first approval of an antibody-drug conjugate (ADC) for MM. The approval was based on the results from the pivotal phase 2 single-arm DREAMM-2 study, which demonstrated clinically meaningful and durable overall response rates [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In 2020, the FDA also approved a novel anti-CD38 monoclonal antibody named isatuximab, in combination with pomalidomide and dexamethasone, for the treatment of relapsed/refractory multiple myeloma (MM). This approval was based on the results from the phase 3 ICARIA-MM study. The combination therapy demonstrated an improved progression-free survival (PFS) of 11.53 months (95% CI: 8.94\u0026ndash;13.9) compared to 6.47 months (95% CI: 4.47\u0026ndash;8.28) in the pomalidomide and dexamethasone alone arm (HR: 0.596; 95% CI: 0.44\u0026ndash;0.81; P\u0026thinsp;=\u0026thinsp;0.0010) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Additionally, in 2021, the FDA approved isatuximab in combination with carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. This approval was based on the results from the Phase 3 IKEMA trial, which showed an improved median progression-free survival (PFS) that was not reached in the trial arm (isatuximab with carfilzomib and dexamethasone) compared to a PFS of 20.27 months in the control arm (carfilzomib and dexamethasone alone) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2021, the FDA approved idecabtagene vicleucel (ide-cel) as the first anti-BCMA CAR T cell therapy for relapsed or refractory multiple myeloma. This personalized immune cell therapy is manufactured using the patient\u0026rsquo;s white blood cells. The FDA approval was based on data from the pivotal Phase II KarMMa trial, which demonstrated unprecedented response rates in relapsed/refractory multiple myeloma [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn February 2022, the FDA approved ciltacabtagene autoleucel (CARVYKTI), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell immunotherapy, for the treatment of relapsed or refractory multiple myeloma. This approval was based on the results from the Phase 1b/2 CARTITUDE-1 study. The study demonstrated an overall response rate of 98% (95% CI, 92.7%-99.7%) with a stringent complete response rate of 78% (95% CI, 68.8%-86.1%) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Teclistamab-cqyv, a bispecific BCMA-directed CD3 T-cell engager was approved for adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy in October 2022. The approval was based on the MajesTEC-1 study, which showed an overall response rate of 61.8% [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. While clinical trials demonstrated PFS benefits over short durations, these effects translated into population-level mortality reductions. The cumulative real-world survival benefit observed was likely due to optimized sequencing of therapies, with clear temporal associations to the introduction and widespread use of new drug classes.real-world survival benefit observed was likely due to optimized sequencing of therapies.\u003c/p\u003e \u003cp\u003eThese results are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;2.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLong-Term Trends in U.S. Age-Adjusted Mortality Rates, 1975\u0026ndash;2022 and key developments\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYear Range\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge Adjusted U.S. Myeloma Mortality Rate ; APC (%), 95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP-Value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInterpretation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKey Developments\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1975\u0026ndash;1994\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.43 (1.33, 1.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIncreasing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo effective treatments available. Melphalan and corticosteroids used with marginal benefit.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1994\u0026ndash;2002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.70 (-1.03, -0.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDecreasing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUse of high dose melphalan with autologous stem cell transplantation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2002\u0026ndash;2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-1.85 (-2.78, -1.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDecreasing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIntroduction of immunomodulatory drugs and proteasome inhibitors.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2009\u0026ndash;2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.52 (-0.10, 1.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo Statistically significant change\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo novel drug classes approved.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2014\u0026ndash;2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-2.08 (-2.40, -1.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDecreasing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIntroduction of more novel drug classes like monoclonal antibodies, selective inhibitors of nuclear export (SINEs), CAR-T cell therapies, and bispecific antibodies\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003cp\u003eAbbreviations: APC, annual percent change; %, percent; CI, Confidence interval\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides a comprehensive analysis of multiple myeloma (MM)-specific mortality trends over the past five decades, demonstrating a strong correlation between the advent of modern therapeutic approaches, including novel pharmacological agents and the intensification of frontline treatments and population-level survival improvements. The novel therapies are reshaping the epidemiology of the disease\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Over the past five decades, MM treatment has undergone transformative shifts, beginning with alkylating agents and corticosteroids and progressing toward autologous stem cell transplantation (ASCT), immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (MAbs), selective inhibitors of nuclear export (SINEs), chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies (BsAbs).\u003c/p\u003e\n\u003cp\u003eDuring 1975–1994, MM-specific mortality increased (APC 1.43%; p \u0026lt; 0.01) due to the limited efficacy of available treatments. However, between 1994–2002, the introduction of high-dose melphalan with ASCT contributed to a modest decline (APC -0.70%; p = 0.02). A more pronounced decline was observed during 2002–2009 (APC -1.85%; p \u0026lt; 0.01) with the integration of IMiDs and PIs, followed by 2014–2022, which demonstrated the most substantial decrease in mortality rates (APC -2.08%; p \u0026lt; 0.01) with the arrival of multiple new drug classes.\u003c/p\u003e\n\u003cp\u003eWhile clinical trials primarily report progression-free survival (PFS) benefits, this study highlights that these short-term trial outcomes translated into long-term, real-world population-level mortality reductions. The sequencing and optimization of available treatments played a critical role in enhancing survival rates, even before overall survival (OS) improvements were fully established in clinical settings.\u003c/p\u003e\n\u003cp\u003eRecent studies highlight significant global and regional disparities in MM trends. Globally, age-standardized incidence rates (ASIR) and mortality rates (ASMR) have risen over recent decades, with middle Socio-Demographic Index regions being particularly impacted [33, 34]. Europe demonstrates the highest ASIR and prevalence rates, reflecting advanced diagnostic capabilities [33]. However, mortality trends across European countries vary—some, like Sweden, report declines, whereas others, such as Bulgaria, show increases [34]. In North America, contrasting trends are evident; while overall mortality rates are reported to have increased in the region [33], data specific to the United States indicate declining mortality due to advancements in early detection, innovative treatments, and improved healthcare access [35, 36]. These findings underscore the need for region-specific strategies and the global dissemination of advanced therapies to address MM’s growing burden.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Similar to MM trends of decreasing cancer-specific population mortality have been observed in other cancers, such as lung cancer and melanoma [36,37]. This is an exciting development, but it also highlights the rising cost of healthcare [38]. As survival rates improve, an increasing number of MM patients are expected to live longer, necessitating a shift in focus toward managing long-term treatment-related toxicities . The side effects associated with contemporary MM therapies—including neuropathy, cytopenias, cardiovascular risks, and immune dysfunction—pose significant challenges, particularly for those undergoing maintenance therapy or repeated lines of treatment. Ensuring multidisciplinary support and equitable access to survivorship care will be crucial for enhancing long-term quality of life for MM survivors.\u003c/p\u003e\n\u003cp\u003eThe strength of our study lies in its large, population-based sample derived from the publicly available SEER database, which is representative of the U.S. population. This dataset includes older and socioeconomically disadvantaged patients who are often underrepresented in randomized clinical trials, thereby enhancing the generalizability of our findings. However, several limitations must be considered. As a retrospective analysis, the study is susceptible to unaddressed confounders and selection bias inherent to the SEER database. Additionally, the SEER database lacks detailed clinical and chemotherapeutic data for individual patients, limiting our ability to assess specific treatment regimens. Variations in treatment protocols, adherence, and reporting inconsistencies may also introduce biases. Finally, the observational nature of this study precludes the definitive establishment of temporal relationships between therapeutic interventions and patient outcomes. Despite these limitations, our findings provide critical insights into MM-specific mortality trends and emphasize the impact of evolving treatment strategies on real-world population-level survival outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe declining MM-specific mortality rates over the past five decades highlight the profound impact of therapeutic innovations on patient survival. The introduction of novel drug classes, optimized treatment sequencing, and intensified frontline therapies has contributed to substantial improvements, reinforcing MM’s transition into a more manageable chronic condition.\u003c/p\u003e\n\u003cp\u003eWhile these advancements have significantly reshaped MM treatment, they also bring new challenges, including long-term toxicities, healthcare accessibility, and financial burdens. Addressing disparities in treatment access and rising costs remains critical to ensuring equitable benefits for all patients as MM therapies continue to evolve.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVan de Donk NW, Pawlyn C, Yong KL (2021) Multiple myeloma. 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JAMA Oncol 9(4):465\u0026ndash;472. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamaoncol.2022.7826\u003c/span\u003e\u003cspan address=\"10.1001/jamaoncol.2022.7826\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Multiple myeloma, epidemiologic trends, mortality reduction, therapeutic advancements, FDA-approved treatments, SEER database","lastPublishedDoi":"10.21203/rs.3.rs-6624519/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6624519/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultiple myeloma (MM) is the second most common hematologic malignancy, accounting for approximately 2% of cancer-related deaths in the United States. Over the past five decades, therapeutic advancements, including novel drug approvals and intensified treatment strategies, have significantly transformed MM management. This study examines temporal trends in MM-specific mortality and their association with evolving therapeutic approaches.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective cross-sectional study utilized the Surveillance, Epidemiology, and End Results (SEER) database to evaluate age-adjusted MM mortality rates from 1975 to 2022. Annual Percent Change (APC) was calculated using Joinpoint regression analysis to identify significant shifts in mortality trends. The timeline of FDA-approved MM treatments was reviewed to explore potential temporal associations with mortality reductions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMM mortality increased from 1975 to 1994 due to limited treatment options. The introduction of autologous stem cell transplantation in 1994 correlated with a modest decline. A marked decrease in mortality was observed from 2002 to 2009 with the emergence of immunomodulatory drugs and proteasome inhibitors, followed by significant reductions between 2014 and 2022 with the approval of multiple novel therapeutic agents. Stagnant mortality trends between 2009 and 2014 coincided with a period of no new drug class approvals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMM-specific mortality in the U.S. has declined substantially over the past two decades, reflecting the impact of novel therapies and frontline treatment intensification. The findings highlight MM’s epidemiologic transformation into a more manageable chronic condition. Addressing disparities in healthcare accessibility and costs is crucial to ensuring equitable treatment benefits for all patients.\u003c/p\u003e","manuscriptTitle":"Temporal Trends in Multiple Myeloma Mortality and Their Relationship to Evolving Treatment Strategies: A Retrospective Analysis Using SEER Data","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-16 03:07:15","doi":"10.21203/rs.3.rs-6624519/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5878d5e8-9e0f-44f2-b5f8-2f13ff98a6f2","owner":[],"postedDate":"May 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-16T03:07:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-16 03:07:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6624519","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6624519","identity":"rs-6624519","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}