Bone Marrow Microenvironment–Driven Resistance in Multiple Myeloma: A Prospective Clinical and Molecular Correlation Study

RESEARCH ARTICLE
Open Access

Bone Marrow Microenvironment–Driven Resistance in Multiple Myeloma: A Prospective Clinical and Molecular Correlation Study

Thabo M. Nkosi 1, Ayesha K. Naidoo 2*  

1University of the Witwatersrand, Johannesburg, South Africa
2University of Cape Town, Cape Town, South Africa
Copyright: © 2026 Naidoo, et al. This is an open-access article under a Creative Commons license (CC BY 4.0).

ABSTRACT

Background

Multiple myeloma (MM) remains an incurable plasma cell malignancy characterized by progressive disease and the development of therapeutic resistance. Increasing evidence suggests that the bone marrow microenvironment (BMM) plays a critical role in promoting tumor survival, immune evasion, and resistance to therapy. However, data from sub-Saharan Africa remain limited, particularly in populations with a high burden of comorbidities such as HIV infection.

Objectives

To evaluate the role of bone marrow microenvironment–driven mechanisms in mediating treatment resistance in patients with multiple myeloma in South Africa, through integrated clinical, immunological, and molecular analyses.

Methods

This prospective observational cohort study included 150 patients with newly diagnosed or relapsed/refractory multiple myeloma recruited from tertiary centers in South Africa. Clinical data, treatment response, and survival outcomes were collected over a median follow-up of 18 months. Bone marrow samples were analyzed using flow cytometry, cytokine profiling, gene expression analysis, and immunohistochemistry to assess microenvironmental factors including cytokine levels, immune checkpoint expression, angiogenesis, and resistance-associated pathways. Statistical analyses included Kaplan–Meier survival estimates and multivariate Cox regression modeling.

Results

A total of 138 patients were included in the final analysis. The median age was 59 years, and 28% were HIV-positive. Overall response rate was 74%, with 26% of patients exhibiting refractory disease.
Refractory patients demonstrated significantly elevated levels of:
IL-6 (34.7 vs 18.5 pg/mL, p < 0.001)
VEGF (262 vs 145 pg/mL, p < 0.001)
TNF-α (p < 0.001)
Increased PD-L1 expression (48% vs 27%, p = 0.003) and reduced NK cell proportions (p = 0.01) were observed in resistant cases.
Microvessel density was significantly higher in refractory patients (38 ± 9 vs 21 ± 7 vessels/HPF, p < 0.001). Gene expression analysis revealed upregulation of BCL2, MDR1, HIF-1α, STAT3, and AKT in resistant disease.
Elevated IL-6 (HR 2.6, p < 0.001), PD-L1 expression (HR 1.9, p = 0.006), and R-ISS stage III (HR 2.3, p < 0.001) were independent predictors of treatment resistance. Median progression-free survival was significantly shorter in refractory patients (8.2 vs 16.8 months, p < 0.001).

Conclusion

The bone marrow microenvironment is a key determinant of therapeutic resistance in multiple myeloma, driven by cytokine signaling, immune evasion, angiogenesis, and hypoxia-related pathways. These findings highlight the importance of incorporating microenvironment-targeted strategies into treatment paradigms, particularly in resource-limited settings. Understanding these mechanisms in African populations is essential for improving outcomes and developing context-specific therapeutic approaches.

Keywords: Multiple myeloma; Bone marrow microenvironment; Drug resistance; Cytokines; Angiogenesis; PD-L1; HIV.

Recommended Citation

Nkosi TM, Naidoo AK. Bone Marrow Microenvironment–Driven Resistance in Multiple Myeloma: A Prospective Clinical and Molecular Correlation Study. Journal of Global Hematology. 2026;4(1):1-15.

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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Journal of Global Hematology cover
Volume 4, Issue 1, 2026
Pages: 37–53
Received: 11 January 2026
Revised: 13 February 2026
Accepted: 11 March 2026
Published: 21 April 2026
DOI: 10.18081/2378-5225/15.37

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globalhematology. <span class="hpt_headertitle">Bone Marrow Microenvironment–Driven Resistance in Multiple Myeloma: A Prospective Clinical and Molecular Correlation Study</span>. Journal of Global Hematology. 2026.
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