Refractory multiple myeloma (MM) is a challenging condition characterized by the disease's resistance to standard therapies.

Despite advances in treatment, a subset of patients develop resistance to conventional therapies, necessitating the exploration of novel treatment approaches. This article reviews current strategies and emerging therapies in the management of refractory MM.

Current Treatment Strategies

Standard treatment for refractory MM often involves the use of combination therapies. Regimens such as bortezomib, lenalidomide, and dexamethasone (VRd) have shown efficacy in patients who have relapsed after initial therapy. Additionally, the combination of carfilzomib, lenalidomide, and dexamethasone has demonstrated improved progression-free survival (PFS) compared to lenalidomide and dexamethasone alone.

Stem Cell Transplantation

Autologous stem cell transplantation (ASCT) remains a cornerstone in the treatment of refractory MM, particularly for patients who have achieved a good response to prior therapies. Studies indicate that salvage ASCT can significantly extend median PFS and overall survival (OS) in these patients. However, the decision to proceed with ASCT should be individualized, considering factors such as the patient's age, performance status, and response to prior treatments.

Monoclonal Antibodies

Monoclonal antibodies have revolutionized the treatment landscape for refractory MM. Daratumumab, an anti-CD38 monoclonal antibody, has shown significant efficacy in combination with other agents. For instance, the combination of daratumumab with bortezomib and dexamethasone has demonstrated improved OS compared to bortezomib and dexamethasone alone. Similarly, the combination of daratumumab with lenalidomide and dexamethasone has shown improved PFS compared to lenalidomide and dexamethasone alone.

Emerging Therapies

Recent advancements have introduced several novel therapies into the treatment arsenal for refractory MM.

Belantamab Mafodotin

Belantamab mafodotin is an antibody-drug conjugate targeting B-cell maturation antigen (BCMA). It has shown promising activity in patients with refractory MM. Recent studies have demonstrated that combinations of belantamab mafodotin with other agents, such as bortezomib and dexamethasone, can significantly improve PFS compared to standard treatments.

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

CAR-T therapy involves modifying a patient's T-cells to express receptors specific to cancer cells. In MM, CAR-T therapies targeting BCMA have shown encouraging results. Clinical trials have reported high response rates and durable remissions in patients with refractory MM treated with BCMA-targeted CAR-T cells.

Bispecific Antibodies

Bispecific antibodies, such as teclistamab, are designed to engage two different antigens simultaneously. These agents have demonstrated efficacy in refractory MM by redirecting T-cells to target and eliminate myeloma cells. Early-phase clinical trials have shown promising response rates with manageable safety profiles.

Management of Refractory Disease

The management of refractory MM should be individualized based on factors such as the duration of the initial response, cytogenetic abnormalities, and patient comorbidities. For patients with slowly progressive and asymptomatic relapse, close observation may be appropriate. In contrast, patients with symptomatic relapse or high-risk features should receive immediate treatment.

Clinical practice guidelines recommend the use of triplet regimens as first-line treatment for refractory MM. These combinations typically include a proteasome inhibitor, an immunomodulatory drug, and a corticosteroid. The choice of specific agents should be guided by prior treatment history, patient tolerance, and the presence of adverse prognostic factors.

Conclusion

The treatment landscape for refractory MM has evolved significantly with the introduction of novel therapies, including monoclonal antibodies, CAR-T therapy, and bispecific antibodies. While these advancements offer hope for improved patient outcomes, ongoing research and clinical trials are essential to further refine treatment strategies and identify optimal therapeutic combinations. Personalized treatment approaches, considering individual patient characteristics and disease biology, remain crucial in the management of refractory MM.