Abstract
Multiple myeloma (MM), a malignancy of clonal bone marrow plasma cells, represents an escalating global health challenge. Over the past two decades, global incidence has more than doubled, driven primarily by population aging and improved diagnostic capacity. Simultaneously, the therapeutic landscape has undergone a paradigm shift—from conventional chemotherapy to proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), anti-CD38 monoclonal antibodies, chimeric antigen receptor T-cell (CAR-T) therapies, and bispecific antibodies—yielding dramatic survival improvements in high-income settings. Despite these advances, profound disparities persist across geographic regions, racial and ethnic groups, and socioeconomic strata, underscoring the urgent need for equitable access to diagnostics and novel therapies. This review synthesizes contemporary evidence from the Global Burden of Disease (GBD) 2021 study, GLOBOCAN 2024, SEER data, population-based registries, and major clinical trials to characterize MM's evolving global burden, survival determinants, and treatment landscape as of mid-2026.
Global Disease Burden and Epidemiologic Trends
MM is estimated to account for approximately 1.7% of all new cancer cases and cancer deaths globally. According to GBD 2021 data, approximately 148,755 new MM cases were diagnosed worldwide in 2021 (age-standardized incidence rate [ASIR]: 1.7 per 100,000; 95% uncertainty interval [UI]: 1.5–1.9), representing a 167% increase in absolute case counts since 1990 6. Global prevalence reached 394,480 cases (age-standardized prevalence rate [ASPR]: 4.55 per 100,000), a 218% increase over the same period. Mortality totaled 116,360 deaths (age-standardized mortality rate [ASMR]: 1.37 per 100,000; 95% UI: 1.22–1.52), with disability-adjusted life years (DALYs)—a composite metric of disease burden capturing both premature mortality and years lived with disability—rising from 1.12 million in 1990 to 2.60 million in 2021 6.
Population growth accounted for 63–86% of this increased DALY burden globally, with aging contributing 9–30% and true epidemiologic change playing a smaller but variable role depending on sociodemographic index (SDI) quintile 16. Critically, in high-SDI countries, epidemiologic change contributed negatively to the DALY burden (−29.75%), reflecting survival improvements from therapeutic advances; in contrast, low- and low-middle SDI regions showed positive epidemiologic contributions of 24–38%, indicating persistent unmitigated disease severity 1.
Geographic and Demographic Variation
Regional disparities in MM burden are pronounced. Australasia reported the highest ASIR (5.5 per 100,000; 95% UI: 4.8–6.2), followed by Western Europe (4.3 per 100,000) and high-income North America (3.22 per 100,000). The lowest rates were recorded in Oceania and Central Africa (approximately 0.4–0.5 per 100,000) 23. Notably, East Asia demonstrated the most rapid escalation globally, with an estimated annual percentage change (EAPC) in ASIR of 3.88% (95% CI: 3.25–4.51%), driven by rapid aging, improved diagnostic infrastructure, and economic development across China and neighboring regions 26. Conversely, high-income North America showed a declining ASIR (EAPC: −0.39%), likely reflecting therapeutic optimization reducing MM-attributable mortality and improved registry capture.
Male sex consistently confers higher MM incidence and mortality across all regions, with a male-to-female ratio of approximately 1.5:1—potentially reflecting gender-specific health behaviors, occupational exposures, and immunologic differences 6. Peak incidence occurs in the 70–74 age group (median age at diagnosis: 65–70 years globally; 69 years in SEER data), and approximately 65% of new cases in the United States arise in individuals aged 65 or older 3. Racial disparities are particularly striking in the United States: non-Hispanic Black individuals exhibit incidence rates approximately 2.2 times higher than non-Hispanic Asian/Pacific Islander populations (9.1 vs. 5.2 per 100,000 for males) 3.
Risk Factors and Disease Biology
Established risk factors for MM include older age, male sex, African ancestry, positive family history of lymphohematopoietic cancers, and obesity 10. The precursor state monoclonal gammopathy of undetermined significance (MGUS) is near-universally present before MM development; hyperdiploid MM (characterized by trisomies of chromosomes 3, 7, 9, 11, 15, and 19) appears to originate early, with 40% of MGUS cases already demonstrating hyperdiploid features by fluorescence in situ hybridization (FISH) 8. Disease progression from MGUS to smoldering MM (SMM) to overt MM is driven by progressive clonal dominance: proportions of plasma cells carrying driver mutations (including t(4;14), del13, and 1q gain) increase significantly from MGUS through SMM to MM, suggesting that cytogenetic evolution characterizes disease advancement 13. High-risk cytogenetic features—del(17p), t(4;14), t(14;16)—define a subgroup with markedly inferior outcomes and represent critical determinants of prognosis and treatment selection 14.
Survival Trends and Outcome Disparities
The improvement in MM survival over the past two decades ranks among oncology's most notable achievements. In the United States, the 5-year relative survival rate rose from approximately 26% in 1975–1977 to 63.7% in 2016–2022 (SEER data), with age-adjusted mortality declining approximately 3.0% annually from 2015 to 2024 3. In the Connect MM Registry—a prospective US cohort of 3,011 newly diagnosed MM (NDMM) patients enrolled 2009–2016—the estimated 8-year overall survival (OS) rate was 40%, consistent with SEER-based estimates; 65% of long-term survivors (LTS) had received autologous stem cell transplantation (ASCT), and only 2% experienced early disease progression within 6 months of first-line therapy 2.
However, survival gains are strikingly unequal. In China, the 5-year survival rate remains approximately 24.8%, substantially below European and North American benchmarks (~46–63%), reflecting delayed diagnosis, limited access to novel agents outside urban centers, and healthcare affordability constraints 2. Similarly, in Sweden—despite universal tax-funded healthcare—income and education disparities profoundly affect outcomes: patients in the highest income quartile achieved median OS of 7.5 years versus 2.8 years in the lowest quartile, with low-income patients carrying a 40% higher mortality risk (hazard ratio [HR]: 1.4; 95% CI: 1.3–1.5) and receiving less lenalidomide, pomalidomide, and ASCT 4. Among US racial and ethnic groups, non-Hispanic Black and Hispanic patients had significantly higher odds of early mortality (death within 2 years) compared with non-Hispanic White patients (odds ratio [OR]: 1.10 and 1.21, respectively), with this disparity concentrated in the early post-diagnosis period and persisting after income adjustment 3.
Minimal residual disease (MRD) negativity—assessed by next-generation sequencing (NGS) or next-generation flow cytometry at sensitivity thresholds of 10⁻⁵—has emerged as a powerful prognostic surrogate: the FDA Oncologic Drugs Advisory Committee recognized MRD negativity as correlating with a global OR of 4.72 for longer progression-free survival (PFS) and 4.02 for superior OS 2.
Therapeutic Advances and Clinical Impact
The treatment paradigm for MM has undergone successive revolutions. In the conventional chemotherapy era, median OS was approximately 33 months. ASCT, introduced in the 1990s, extended median OS to 50–70 months. Sequential introduction of PIs (bortezomib, 2003; carfilzomib; ixazomib) and IMiDs (thalidomide; lenalidomide, 2006; pomalidomide, 2013) further improved outcomes to 80–120 months in favorable cohorts 12.
The addition of anti-CD38 monoclonal antibodies (daratumumab, 2015; isatuximab, 2020) enabled quadruplet induction regimens that represent current state-of-the-art therapy. The PERSEUS trial demonstrated superior 4-year PFS with daratumumab–bortezomib–lenalidomide–dexamethasone (Dara-VRd) versus VRd (84.3% vs. 67.7%) in transplant-eligible NDMM. The IMROZ trial (ASCO 2024), evaluating isatuximab-VRd (Isa-VRd) in transplant-ineligible patients, showed 63% of patients in remission at 4 years versus 45% with VRd—a 40.4% reduction in the risk of progression or death 3. The GMMG-HD7 trial further demonstrated superior MRD negativity rates with Isa-VRd (50.1% vs. 35.6%; p < 0.001) 2.
For relapsed/refractory MM (RRMM), the ICARIA-MM trial showed that isatuximab–pomalidomide–dexamethasone (Isa-Pd) achieved a clinically meaningful OS benefit (24.6 vs. 17.7 months; HR = 0.78; p = 0.0319) versus pomalidomide–dexamethasone 2. The DREAMM-7 trial demonstrated that belantamab mafodotin (an anti-BCMA antibody-drug conjugate [ADC])–bortezomib–dexamethasone yielded a median PFS of 36.6 versus 13.4 months compared to daratumumab-bortezomib-dexamethasone 3.Belantamab mafodotin was voluntarily withdrawn from the US market in November 2022 after its confirmatory DREAMM-3 trial did not meet the primary endpoint, but was subsequently re-submitted for FDA approval based on the positive DREAMM-7 and DREAMM-8 results.
CAR-T cell therapies targeting B-cell maturation antigen (BCMA)—idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti)—received expanded FDA approvals in April 2024, with the CARTITUDE-4 trial demonstrating substantial benefit particularly in patients relapsing within 18 months of initial response 3. Bispecific antibodies (teclistamab targeting BCMA/CD3; talquetamab targeting GPRC5D/CD3; elranatamab) offer off-the-shelf availability; the MajesTEC-3 combination demonstrated an OS HR of 0.46 (95% CI: 0.32–0.65) and PFS HR of 0.17 3. Prophylactic tocilizumab has reduced cytokine release syndrome (CRS) incidence from 72% to 25%, substantially improving tolerability 3.
Tables
Table 1. Global MM Epidemiology and Disease Burden by Region (GBD 2021) 236
| Region | ASIR (per 100,000) | ASDR (per 100,000) | Age-Standardized DALY Rate (per 100,000) | EAPC ASIR (1990–2021) |
|---|---|---|---|---|
| Global | 1.7 (1.5–1.9) | 1.4 (1.2–1.5) | 30.0 (26.2–33.4) | +0.48 |
| Australasia | 5.5 (4.8–6.2) | 2.9 (2.5–3.2) | 60.6 (54.1–67.4) | +1.03 |
| Western Europe | 4.3 (3.9–4.6) | 2.6 (2.3–2.8) | 53.6 (49.6–56.6) | +0.64 |
| High-income North America | 3.2 (2.9–3.3) | 2.8 (2.5–3.0) | 57.3 (44–49.8) | −0.39 |
| East Asia | ~0.8 (0.5–1.1) | ~0.6 (0.4–0.8) | 16.3 (10.4–21.4) | +3.88 |
| High SDI (overall) | 3.2 (2.9–3.3) | 2.3 (2.1–2.4) | 47.3 (44–49.8) | +0.15 |
| Middle SDI | 1.0 (0.8–1.2) | 0.9 (0.7–1.0) | 21.8 (17.5–25.6) | +2.15 |
| Low SDI | 0.8 (0.5–1.0) | 0.8 (0.5–1.0) | 18.4 (12.3–24.9) | +0.95 |
| Central Africa | ~0.35 | — | 8.65 | — |
ASIR, age-standardized incidence rate; ASDR, age-standardized death rate; DALY, disability-adjusted life year; SDI, Sociodemographic Index; EAPC, estimated annual percentage change. Data from GBD 2021 and regional registries.
Table 2. Survival Trends and Key Determinants of Outcomes 12345
| Population / Cohort | Survival Metric | Value | Key Determinant |
|---|---|---|---|
| USA (SEER, 1975–1977) | 5-year relative survival | ~26% | Conventional chemotherapy era |
| USA (SEER, 2016–2022) | 5-year relative survival | 63.7% | Novel agents (PIs, IMiDs, anti-CD38 Ab) |
| USA (SEER, 2015–2024) | Annual mortality decline | ~3.0%/year | Improved treatment efficacy |
| Connect MM Registry (USA, 2009–2016) | 8-year OS | 40% | 65% ASCT rate; sequential therapy |
| Sweden (2008–2021), highest income quartile | Median OS | 7.5 years | Universal healthcare + income advantage |
| Sweden (2008–2021), lowest income quartile | Median OS | 2.8 years | Reduced ASCT, lenalidomide access (HR 1.4) |
| China (contemporary) | 5-year survival | ~24.8% | Limited novel agent access; delayed diagnosis |
| USA Non-Hispanic Black vs. NHW | Early mortality (≤2 years) | OR 1.10 (1.04–1.15) | Structural barriers; concentrated in early post-diagnosis |
| USA Hispanic vs. NHW | Early mortality (≤2 years) | OR 1.21 (1.14–1.28) | Socioeconomic and access factors |
| Puerto Rico, males <65 years (2001–2019) | 5-year OS | 54.6% (47.2–61.5%) | Stable mortality rates; no improvement trend |
| MRD-negative (contemporary trials) | Relative PFS/OS | OR 4.72 (PFS); OR 4.02 (OS) | NGS/NGF MRD assessment at 10⁻⁵ |
| ASCT-eligible (trial settings) | 10-year OS | ~60% | Quadruplet induction + transplant + maintenance |
OS, overall survival; PFS, progression-free survival; ASCT, autologous stem cell transplantation; MRD, minimal residual disease; NHW, non-Hispanic White; HR, hazard ratio; OR, odds ratio; NGS, next-generation sequencing; NGF, next-generation flow cytometry.
Table 3. Major Therapeutic Advances and Clinical Impact 23
| Therapeutic Class / Agent | Timeline | Key Trial(s) | Primary Outcome | Key Result | Setting |
|---|---|---|---|---|---|
| Conventional chemotherapy | Pre-2000 | — | Median OS | ~33 months | NDMM |
| ASCT + novel agent induction | 1990s–2000s | Multiple | Median OS | ~50–70 months | NDMM, eligible |
| Proteasome inhibitors (bortezomib, carfilzomib) | 2003–2015 | ENDEAVOR | PFS | Kd vs. Vd: 18.7 vs. 9.4 mo (HR 0.53) | RRMM |
| IMiDs (lenalidomide, pomalidomide) | 2006–2013 | ASPIRE | PFS/OS | KRd vs. Rd: 26.3 vs. 17.6 mo | RRMM |
| Anti-CD38 antibody (daratumumab) | 2015+ | PERSEUS | 4-yr PFS | Dara-VRd: 84.3% vs. 67.7% (VRd) | NDMM, transplant-eligible |
| Anti-CD38 antibody (isatuximab) | 2020+ | IMROZ (2024) | 4-yr remission rate | Isa-VRd: 63% vs. 45% (VRd); 40.4% risk reduction | NDMM, transplant-ineligible |
| Anti-CD38 antibody (isatuximab) | 2020+ | ICARIA-MM | Median OS | Isa-Pd: 24.6 vs. 17.7 mo (HR 0.78; p = 0.032) | RRMM, lenalidomide-refractory |
| ADC (belantamab mafodotin) | 2020+ | DREAMM-7 (2024) | Median PFS | BVd: 36.6 vs. 13.4 mo (vs. DVd) | RRMM, early relapse |
| ADC (belantamab mafodotin) | 2020+ | DREAMM-8 (2024) | Median PFS | Not reached vs. 13 mo (vs. VPd) | RRMM, early relapse |
| CAR-T (cilta-cel, ide-cel) | 2021+ | CARTITUDE-4, KarMMa-3 | Deep response/PFS | FDA expanded approval April 2024; benefit in high-risk relapse | RRMM, ≥2 prior lines |
| Bispecific Ab (teclistamab + daratumumab) | 2023+ | MajesTEC-3 | OS/PFS | OS HR 0.46; PFS HR 0.17 | RRMM, early relapse |
| Quadruplet regimens (Isa-VRd) | 2020+ | GMMG-HD7 | MRD negativity | 50.1% vs. 35.6% (VRd; p < 0.001) | NDMM, transplant-eligible |
NDMM, newly diagnosed MM; RRMM, relapsed/refractory MM; ASCT, autologous stem cell transplantation; Dara-VRd, daratumumab–bortezomib–lenalidomide–dexamethasone; Isa-VRd, isatuximab–VRd; KRd, carfilzomib–lenalidomide–dexamethasone; Kd, carfilzomib–dexamethasone; Vd, bortezomib–dexamethasone; BVd, belantamab mafodotin–bortezomib–dexamethasone; DVd, daratumumab–bortezomib–dexamethasone; VPd, bortezomib–pomalidomide–dexamethasone; CAR-T, chimeric antigen receptor T-cell; ADC, antibody-drug conjugate; MRD, minimal residual disease; HR, hazard ratio; PFS, progression-free survival; OS, overall survival.
Public Health and Clinical Implications
The global epidemiology of MM reveals a disease of accelerating burden, particularly in aging and middle-income populations experiencing the steepest incidence growth. While therapeutic innovation has transformed survival for patients with access to modern quadruplet regimens—achieving median OS approaching 10 years or longer in well-resourced trial settings—these gains have not been equitably distributed 23. In low- and middle-income countries (LMICs), treatment typically relies on older agents such as bortezomib–cyclophosphamide–dexamethasone (VCD) or thalidomide-based regimens; lenalidomide remains prohibitively expensive or unavailable, ASCT is rarely performed, and limited diagnostic infrastructure (serum protein electrophoresis, advanced imaging, FISH-based cytogenetics) results in late-stage presentation and inadequate risk stratification 3. The estimated cost of a standard 23-course daratumumab treatment exceeds USD 162,000, representing a fundamental barrier to equitable care globally 2.
Critically, even within universal healthcare systems, socioeconomic status independently predicts treatment access and survival 4. Addressing these disparities requires targeted policy interventions: expanding generic drug availability, implementing tiered pricing models, strengthening health system capacity for ASCT and molecular diagnostics, and integrating MRD-guided strategies into resource-appropriate clinical pathways.
Substantial unmet needs remain even in high-resource settings: management of del(17p), t(4;14), and complex cytogenetic high-risk MM; treatment of frail elderly patients with significant comorbidity burden; optimal sequencing of bispecific antibodies, CAR-T therapies, and ADCs; managing toxicities including CRS and ocular adverse effects from belantamab mafodotin; and strategies for daratumumab-refractory disease 314. The emerging evidence base for anti-BCMA bispecific antibodies and GPRC5D-directed therapy (talquetamab) offers promising alternatives, with target switching between BCMA-directed and GPRC5D-directed agents representing an evolving sequencing strategy 3.
Concluding Perspective
Multiple myeloma has been transformed from an incurable disease with a median survival of less than 3 years to a chronic, manageable condition in many patients, with a subset achieving durable long-term remission. The convergence of quadruplet induction regimens, MRD-guided maintenance strategies, and a rapidly expanding toolkit of immunotherapies—including CAR-T cells, bispecific antibodies, and ADCs—promises to further extend and deepen these survival gains through the remainder of this decade 23. However, the full realization of these advances requires simultaneous progress on global equity: bridging the profound survival gap between high-income nations and LMICs, eliminating within-country socioeconomic and racial disparities, and generating robust real-world evidence across diverse populations. As epidemiologic projections indicate continued increases in MM burden through 2050—driven predominantly by population aging—coordinated investment in surveillance, early detection of MGUS/SMM precursor states, and equitable health system strengthening will be essential to ensure that future therapeutic progress benefits all MM patients worldwide 6.