Multiple myeloma (MM) is a complex hematologic malignancy characterized by clonal proliferation of plasma cells in the bone marrow.

Despite advances in frontline therapies, relapse remains a significant challenge, impacting survival and quality of life. Effective management of multiple myeloma relapse requires an understanding of disease biology, previous treatments, and patient-specific factors to tailor therapeutic strategies that optimize outcomes.

Understanding Multiple Myeloma Relapse

Relapse in multiple myeloma is defined as the return of disease activity after a period of remission. The biology of relapsed MM often includes resistance to prior therapies, genetic evolution, and tumor microenvironment changes that complicate treatment. Relapse can be classified as biochemical, characterized by laboratory abnormalities without symptoms, or clinical, where symptoms or organ damage occur. Early detection and timely intervention are crucial to prevent complications.

Current Treatment Options for Relapse

Management of relapsed MM is complex and must be individualized. Commonly used treatment modalities include proteasome inhibitors, immunomodulatory drugs (IMiDs), corticosteroids, monoclonal antibodies, and chemotherapy.

Proteasome Inhibitors

Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib disrupt protein degradation pathways, inducing apoptosis in myeloma cells. These agents are effective in relapsed MM and often used in combination regimens. Bortezomib remains a backbone drug with demonstrated efficacy in both early and late relapse settings.

Immunomodulatory Drugs (IMiDs)

Lenalidomide and pomalidomide modulate the immune system and have direct anti-myeloma activity. They are often combined with corticosteroids and other agents in relapsed MM. Pomalidomide is particularly useful in patients refractory to lenalidomide and proteasome inhibitors.

Monoclonal Antibodies

Monoclonal antibodies have transformed relapse treatment. Daratumumab targets CD38 on myeloma cells, offering significant efficacy in combination regimens. Elotuzumab targets SLAMF7 and is approved

in combination with IMiDs. These agents improve progression-free survival (PFS) and overall survival (OS).

Emerging Therapies in Relapse Management

Advancements in understanding MM pathogenesis have led to innovative treatments showing promise in relapsed disease.

Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

CAR-T therapy is a personalized immunotherapy involving genetic modification of patient T-cells to recognize and kill myeloma cells, specifically targeting B-cell maturation antigen (BCMA). Clinical trials have reported high response rates in heavily pretreated relapsed MM, with durable remissions, though toxicity management remains essential.

Bispecific T-Cell Engagers (BiTEs)

Bispecific antibodies engage both T-cells and myeloma cells to enhance cytotoxicity. Agents such as teclistamab are in advanced clinical development and have demonstrated efficacy in relapsed and refractory MM, offering an off-the-shelf immunotherapy option.

Antibody-Drug Conjugates (ADCs)

Belantamab mafodotin is an ADC targeting BCMA, delivering cytotoxic agents directly to myeloma cells. It provides another mechanism to overcome drug resistance and is approved for heavily pretreated relapsed MM.

Personalized Treatment Considerations

Relapse management is influenced by several factors including prior therapy exposure, duration of response, cytogenetic risk, patient comorbidities, and preferences. Rechallenge with previously effective drugs may be considered if a long remission occurred. Conversely, changing classes of agents is recommended for patients with refractory disease.

Additionally, supportive care addressing bone health, infection prevention, and symptom management remains critical throughout relapse treatment.

Conclusion

Relapse management in multiple myeloma is a dynamic and evolving field. Combining established therapies with emerging novel agents provides hope for prolonged disease control and improved patient quality of life. Future directions include optimizing sequencing of therapies, minimizing toxicity, and integrating precision medicine approaches to tailor treatments effectively. Collaborative care and clinical trial participation are essential to advance outcomes in relapsed MM.