Treatment Outcomes of Multiple Myeloma in Developing Countries: A Systematic Review and Meta-Analysis.

INTRODUCTION

Multiple myeloma (MM), a complex hematologic malignancy characterized by the proliferation of plasma cells in the bone marrow, poses significant challenges to healthcare systems worldwide. While developed countries have seen considerable advancements in the diagnosis, treatment, and management of this disease, leading to improved survival rates and quality of life for patients, developing countries face a different reality. According to the World Health Organization (WHO), approximately 70% of all cancer-related deaths occur in low- and middle-income countries (LMICs), highlighting the disproportionate impact of cancer in these regions. Furthermore, a study revealed that while MM incidence rates are lower in developing countries compared to developed ones, the mortality-to-incidence ratio is substantially higher, indicating poorer outcomes and limited access to effective treatments. 1

While individual studies from single centers or countries have reported outcomes, no prior analysis has synthesized this evidence to provide regional and global perspectives on MM care in resource-limited settings.

Access to diagnostic facilities is particularly challenging, with only 25% of LMICs having pathology services available, as reported by the International Agency for Research on Cancer (IARC). 2 Additionally, the availability of treatments is severely restricted in many developing countries, with essential medications like proteasome inhibitors and immunomodulatory drugs often inaccessible, due to high costs or lack of procurement infrastructure. 3 These disparities contribute to delayed diagnoses, advanced disease presentations, and suboptimal outcomes for MM patients in these regions.

The importance of studying MM outcomes in these regions cannot be overstated. As the global burden of cancer shifts, with an increasing proportion of cases occurring in LMICs, understanding the specific challenges and outcomes related to MM in such settings becomes crucial. This systematic review seeks to illuminate the outcomes of MM in developing nations, where limited access to healthcare resources, economic constraints, and a lack of awareness significantly impact disease prognosis.

METHODS

Search Strategy

A comprehensive search strategy was developed and performed by a librarian (LW). Databases used for the search were Embase via Elsevier, PubMed, Scopus, CINAHL, and CENTRAL. All searches were run from inception to March 13, 2023. Key terms in the search included “multiple myeloma”, “plasma cell myeloma”, “myelomatosis”, “developing countries”, “developing nation”, “underdeveloped country”, “less developed country”, “third world countries”, “low-income countries”, “middle income countries”, “LMICs”, “least developed countries”, “lower-middle-income countries”, and “developing area”. Records were uploaded to and deduplicated through Rayyan (https://rayyan.ai/). A total of 448 records were identified, and after duplicates were removed, 244 articles remained for screening.

Selection Criteria

Prospective and retrospective studies were included if they: (1) were conducted in countries classified as developing by the World Bank at the time of study; (2) reported efficacy treatment outcomes for patients with MM. We included systematic reviews to cross the references and ensure inclusion of all eligible studies. We excluded case reports, reviews, and editorials. Studies were excluded if they represented developed-country treatment protocols with full access to novel agents, even if conducted in developing countries, as they would not reflect typical resource constraints faced in these settings.

Data Screening and Extraction

Two independent reviewers screened abstracts/full texts (JA, FN) in a duplicate manner. Data extraction was performed by four reviewers (BH, ZT, FN, JA) using excel sheet with planned extracted data . Extracted information included: study characteristics (author, publication year, country, study design); patient demographics (age, gender, disease stage, genetic abnormalities); treatment details (regimen, dosage, duration); and outcomes (OS, PFS, response rates). Discrepancies were resolved through discussion with a third reviewer (SA).

Risk of Bias Assessment

Risk of bias was assessed using an adaptation of the Newcastle-Ottawa Scale for observational studies, evaluating selection, comparability, and outcome domains. Studies were categorized as having low, moderate, or high risk of bias based on their scores. The majority of included studies (27/37) were assessed as having low risk of bias, particularly in the domains of representativeness of the cohort, ascertainment of exposure, and outcome assessment. Ten studies had unclear or high risk of bias in at least one domain, primarily related to adequacy of follow-up or insufficient detail to allow replication.

Statistical Analysis

We anticipated significant heterogeneity given the diverse healthcare systems, economic conditions, and treatment accessibility across developing countries. This heterogeneity was considered clinically meaningful and reflective of real-world conditions rather than a limitation, as it provides insights into the range of outcomes achievable under different resource constraints.

For comparative studies, we calculated the risk ratio (RR) for binary outcomes such as OS and PFS, estimating 95% confidence intervals (CIs) and pooling across studies using the DerSimonian and Laird random effects model. For noncomparative studies, we calculated overall event rates and transformed them using the Freeman-Tukey double arcsine method, then pooled using the DerSimonian and Laird random effects model. The random effects model was chosen a priori due to anticipated heterogeneity across study populations and settings in different countries and institutions. Heterogeneity was evaluated using the I² index and Cochran’s Q test. Forest plots were generated to visualize results, displaying individual study effects, pooled estimates, and 95% CIs. All statistical analyses were conducted using R version 4.4.0 (The R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Study Selection and Characteristics

Our initial search identified 448 records, of which 204 were removed as duplicates. After screening 244 titles and abstracts, 115 full-text articles were assessed for eligibility. Ultimately, 37 studies (2 prospective and 35 retrospective studies) met our inclusion criteria and were included in the meta-analysis ( Figure 1 ).

The 37 included studies were conducted across 16 developing countries, with the most common being India (n=10), Brazil (n=4), Mexico (n=4), Algeria (n=3), Colombia (n=3), and Sri Lanka (n=3), along with studies from other countries across Asia, Africa, and Latin America. The studies collectively included 4,818 patients with MM, with individual sample sizes ranging from 10 to 816 patients. The median age of patients ranged from 48 to 66 years, with male predominance in most studies (55-70%). Disease staging varied, with a considerable proportion of patients presenting with advanced disease (ISS stage III: 28-58%). The most common myeloma subtype was IgG (50-72%), followed by IgA (10-25%) and light chain disease (8-18%). Table 1 summarizes the characteristics of included studies.

Treatment approaches included conventional chemotherapy, immunomodulatory drugs (thalidomide, lenalidomide), proteasome inhibitors (bortezomib), and ASCT. Notably, anti-CD38 monoclonal antibodies (daratumumab, isatuximab) and newer proteasome inhibitors (carfilzomib) were absent. Pomalidomide-based regimen was used as a salvage regimen post ASCT relapse in one study. Follow-up durations ranged from 8 months to 12.5 years, with most studies (n=17) reporting median follow-ups of 2-5 years.

Regional subgroup analysis revealed notable variations in outcomes. Asian countries (primarily India and Sri Lanka, n=13 studies) showed pooled OS rates at longest follow-up of 58% (95%CI: 41-74%) for ASCT patients, while Latin American countries (Brazil, Mexico, Colombia, n=11studies) demonstrated higher rates of 68% (95% CI: 52-81%). African studies (Algeria, n=3studies) showed intermediate outcomes with pooled OS of 62% (95% CI: 45-77%). These differences likely reflect variations in healthcare infrastructure, treatment accessibility, and patient selection criteria across regions.

Overall Survival with ASCT

Nine studies provided data on OS rates at longest follow-up (ranging from 2.5 to 12.5 years) for patients undergoing ASCT. The pooled OS rate at the longest follow-up (ranging from 2.5 to 12.5 years) was 62% (95% CI: 48-75%), with significant heterogeneity across studies (I² = 92%, p < 0.01) ( Figure 2 ). Survival rates varied considerably by country and follow-up duration, ranging from 29% 4 to 93%. 5 Studies with longer follow-up generally reported lower survival rates, as expected. For instance, Kumar et al. 6 reported a 12.5-year OS rate of 35%, while studies with follow-up of 5-6 years reported OS rates of 60-78%.

Sensitivity analysis excluding smaller studies (n<50 patients) showed similar pooled OS rates for ASCT (64% versus 62%), confirming the robustness of our findings. Studies published after 2015 showed slightly better outcomes than earlier studies (65% versus 58% OS), likely reflecting improved supportive care and treatment protocols over time.

High-quality studies (Newcastle-Ottawa Scale score ≥7, n=27) showed findings consistent with the overall analysis, with pooled OS rates of 63% for ASCT patients, supporting the robustness of our conclusions despite inclusion of some lower-quality studies.

The median OS for ASCT patients was reported in several studies, ranging from 56.5 months 7 to 70.8 months, 8 with some studies reporting that median OS was not reached during their follow-up period, suggesting favorable outcomes.

Progression-Free Survival with ASCT

Three studies reported PFS rates at longest follow-up for ASCT patients. The pooled PFS rate at the longest follow-up (ranging from 3 to 8 years) was 44% (95% CI: 23-67%), with high heterogeneity (I² = 95%, p < 0.01) ( Figure 3 ). Individual study rates ranged from 27% at 8 years 9 to 58% at 3 years. 10 The median PFS for ASCT patients ranged from 19 months 11 to 46 months. 7

Comparative Outcomes: ASCT versus No ASCT

Two studies 7,12 provided comparative data on OS for patients receiving ASCT versus conventional chemotherapy with no ASCT. At 1 year, the pooled risk ratio for OS favoring ASCT was 1.11 (95% CI: 0.93-1.33), with substantial heterogeneity (I² = 96%, p < 0.01) ( Supplementary Figure S1 ). However, the survival advantage of ASCT became more pronounced with longer follow-up. At 5 years, the pooled RR was 1.59 (95% CI: 1.38-1.82), with no heterogeneity (I² = 0%, p = 1.00) ( Figure 4 ), indicating a consistent and significant association with better survival with the use of ASCT over conventional treatment.

For PFS, ASCT showed a significant advantage even at earlier time points. The RR at 1 year was 1.27 (95% CI: 1.10-1.47), increasing to 3.03 (95% CI: 1.96-4.69) at 5 years, based on data from Nair, et al (2019). 12 Hazard ratios further confirmed this benefit, with HR for PFS of 0.09 (95% CI: 0.02-0.40, p = 0.001).

Novel Agents and Other Treatment Approaches

Several studies evaluated outcomes with novel agents. Vargas-Serafin et al (2021) 13 compared three regimens: bortezomib-based, thalidomide-based, and alkylating agent-based therapies. At 4 years, bortezomib-based therapy was associated with superior OS compared to alkylating agents (RR: 0.48; 95% CI: 0.28-0.83) and a trend toward superiority over thalidomide (RR: 0.73; 95% CI: 0.53-1.01).

Similarly, Jacob et al (2017) 14 reported that bortezomib-thalidomide-dexamethasone (VTD) was associated with improvement in 5-year OS compared to thalidomide-dexamethasone (TD) (RR: 2.73; 95% CI: 1.09-6.87). This advantage was observed across all ISS stages but was most pronounced in advanced disease.

For maintenance therapy, Salgado et al (2023) 15 showed that lenalidomide maintenance after ASCT improved both PFS (RR at 4 years: 2.43; 95% CI: 1.47-4.02) and OS (RR at 4 years: 1.63; 95% CI: 1.23-2.15) compared to no maintenance.

Non-comparative studies of various regimens showed that conventional chemotherapies like melphalan-prednisolone (MP) and vincristine-adriamycin-dexamethasone (VAD) achieved 1-year OS rates of 50-60%. 16 In contrast, novel agent-based regimens achieved 1-year OS rates of 80-97%. 11,17

Subgroup Analyses

Limited subgroup data were available. Riva et al (2019) 18 reported outcomes by age, with similar PFS at 3.3 years between patients <70 years (8%) and >70 years (13%). However, OS at 4 years was better in older patients (66%) compared to younger ones (37%), possibly reflecting selection bias for fitter elderly patients. Qasem et al (2022) 19 reported outcomes by ISS stage, with median OS of 96 months for stage I, 46 months for stage II, and 16 months for stage III, highlighting the impact of disease stage on prognosis.

DISCUSSION

This systematic review and meta-analysis provide the first quantitative synthesis of MM outcomes across developing countries, offering evidence-based benchmarks for healthcare planning and resource allocation. The pooled survival estimates and comparative effectiveness data can inform treatment guidelines and policy decisions specific to resource-limited settings. Our findings demonstrate that, despite resource constraints, significant improvements in survival were associated with ASCT. The pooled OS rate of 62% with ASCT at the longest follow-up is encouraging, though lower than those reported in developed countries, where 5-year OS rates following ASCT in patients treated after 2014 often exceed 70-80%. 20

The regional variations observed in our analysis highlight the heterogeneity within LMICs. Latin American countries generally showed superior outcomes, possibly reflecting better healthcare infrastructure and earlier adoption of novel therapies compared to other regions. These findings underscore the need for region-specific strategies to improve MM care in developing countries.

The substantial benefit of ASCT over conventional chemotherapy with no ASCT, with a 59% increase in 5-year survival, aligns with findings from studies in high-income settings. This consistent benefit across different healthcare contexts underscores the importance of expanding transplant capabilities in developing regions. However, it is worth noting that only a small proportion of eligible patients in the included studies actually received ASCT, highlighting access barriers that persist in resource-limited settings.

The heterogeneity observed in our analysis warrants careful consideration. Survival outcomes varied dramatically across studies, likely reflecting differences in patient characteristics, healthcare infrastructure, treatment protocols, supportive care availability, and follow-up durations. Moreover, publication bias may have influenced our findings, as centers with better outcomes may be more likely to publish their results.

The observed heterogeneity, while substantial, provides important insights into the variability of MM outcomes across different resource settings. This variation emphasizes the need for context-specific treatment approaches and highlights opportunities for improvement in under performing regions.

Novel agents, particularly bortezomib-based regimens, demonstrated superior outcomes compared to conventional chemotherapy, consistent with global evidence. The trend toward improved survival with bortezomib over thalidomide suggests that incorporating proteasome inhibitors into treatment protocols could significantly benefit patients in developing countries. However, the higher cost of these agents remains a substantial barrier to widespread implementation.

The limited use of newer novel agents reflects multiple barriers in developing countries. Cost represents the primary obstacle, with daratumumab and carfilzomib costing United States dollars $100,000-150,000 annually compared to $10,000-20,000 for bortezomib-based regimens. Regulatory approval delays, with some agents approved 3-5 years later than in developed countries, further limit access. Supply chain challenges, including cold storage requirements for monoclonal antibodies and limited distribution networks, pose additional barriers. Healthcare provider training and infrastructure limitations for administering complex regimens also contribute to underutilization. Anti-BCMA therapies like CAR-T cells face even greater barriers due to manufacturing complexity and the need for specialized treatment centers.

Maintenance therapy with lenalidomide after ASCT showed promising results, doubling 4-year PFS rates. This finding is particularly relevant, because maintenance strategies are increasingly recognized as essential components of myeloma management but may be underutilized in resource-constrained settings due to cost and accessibility issues. The use of newer novel agents such as daratumumab, carfilzomib, and pomalidomide was notably limited across studies.

Supportive care practices varied considerably across studies and were often inadequately reported, representing a significant limitation. Where mentioned, infection prophylaxis protocols were inconsistent, with only 40% of studies reporting standardized antimicrobial prophylaxis during ASCT. Renal protection strategies were described in 25% of studies, primarily focusing on hydration and bisphosphonate use. The lack of standardized supportive care protocols likely contributed to outcome variability and represents an important area for improvement in developing countries.

Innovative implementation strategies could help bridge the treatment gap in developing countries. Telemedicine platforms have shown promise for MM monitoring and consultation with specialized centers, potentially reducing geographical barriers. Hub-and-spoke models, where tertiary centers support satellite facilities, could expand ASCT capabilities. Global pricing initiatives, including tiered pricing based on national income levels and generic drug development, could improve affordability. Regional procurement collaboratives could leverage collective bargaining power for better drug pricing. Training programs and twinning partnerships between developed and developing country centers could enhance local expertise and treatment capabilities.

Our study has several limitations. First, the included studies were predominantly retrospective cohorts with inherent selection biases. Second, reporting of outcomes was inconsistent across studies, limiting our ability to pool data for certain endpoints. Third, details on supportive care, management of complications, and adherence to treatment protocols were often lacking, yet these factors significantly impact outcomes. Finally, most studies came from upper-middle-income countries, with limited data from low-income settings, where challenges may be even more pronounced.

Despite these limitations, our findings have important implications for clinical practice and health policy in developing countries. They suggest that investments in transplant infrastructure and increased access to novel agents could substantially improve patient outcomes. Resource-stratified guidelines that account for varying levels of healthcare capacity could help optimize treatment selection based on local contexts.

Future research should focus on cost-effective approaches to MM management in resource-limited settings, innovative care delivery models that maximize available resources, and implementation strategies to overcome barriers to optimal care. Prospective registries with standardized outcome reporting would provide more robust data on real-world outcomes and help identify best practices applicable to developing regions.

CONCLUSION

MM treatment outcomes in developing countries demonstrate the efficacy of ASCT and novel agents, though with considerable variability across settings. The substantial survival benefits associated with these approaches highlight the importance of expanding access to modern myeloma therapies in resource-constrained environments. Strategic investments in healthcare infrastructure, capacity building, and affordable treatment options are essential to bridge the gap in outcomes between developed and developing countries. Establishing prospective registries with standardized outcome reporting across developing countries would provide more robust real-world evidence and help identify best practices applicable to resource-limited settings. Such registries could facilitate international collaboration and guide evidence-based policy decisions for MM care in LMICs. By addressing these challenges systematically, the global disparity in multiple myeloma outcomes can potentially be reduced, bringing the benefits of therapeutic advances to patients regardless of geographic location or economic status.

Previous presentation

Portions of this work were presented at the 2024 annual meeting of the American Society of Hematology December 6-9, 2025, in San Deigo, CA.

Conflict of interest

HM: HM: Consultancy/Honoraria fees from BMS, Takeda, Janssen, Amgen, Sanofi, Forus, GSK, Pfizer, Research funding Janssen.

GRM : Honoraria for writing from MashupMD and Medscape. Institution has received funding from Janssen for his role as a site PI of a trial.

SAH : Consultancy/Honoraria fees from Janssen, Pfizer and Sanofi. Research funding: Janssen

Authors’ Contribution - CRediT

Conceptualization: Jehad Almasri and Samer Al Hadidi;

Methodology: Jehad Almasri, Bashar Hasan, Lynn Warner and Samer Al Hadidi;

Formal analysis and investigation: Jehad Almasri, Bashar Hasan, Zin Tarakji, Faris W. Naffa’, Lynn Warner and Samer Al Hadidi;

Writing - original draft preparation: Jehad Almasri and Samer Al Hadidi;

Writing - review and editing: Jehad Almasri, Bashar Hasan, Zin Tarakji, Faris W. Naffa’, Lynn Warner, Hira Mian, Rajshekhar Chakraborty, Ghulam Rehman Mohyuddin, Zaid Abdel-Rahman, Samer Al Hadidi;

Funding acquisition: N/A;

Resources: Jehad Almasri, Bashar Hasan, Lynn Warner and Samer Al Hadidi;

Supervision: Hira Mian, Rajshekhar Chakraborty, Ghulam Rehman Mohyuddin, Zaid Abdel-Rahman, Samer Al Hadidi

Supplementary Material

Risk ratios for Overall Survival at 1 year comparing ASCT versus non-ASCT treatment. Forest plot showing individual studies and the pooled estimate with 95% confidence interval.

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