What are the next steps for a patient with lenalidomide (Revlimid) refractoriness?

From the Guidelines

Lenalidomide refractory patients should be treated with daratumumab, pomalidomide, and dexamethasone (DPd) as a first-line option, considering its efficacy and tolerability, as shown in the study by Chari et al 1. This recommendation is based on the most recent and highest quality study available, which demonstrated a response rate of 58% in heavily pretreated patients, including those refractory to lenalidomide and bortezomib. The treatment selection for lenalidomide refractory patients depends on various factors, including prior therapies, side effect profiles, and patient characteristics. Some key considerations include:

• Prior exposure to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs)
• Presence of high-risk cytogenetic abnormalities
• Patient's performance status and comorbidities
• Availability of novel agents and clinical trial options Other treatment options for lenalidomide refractory patients may include:
• Carfilzomib-based regimens, such as carfilzomib, dexamethasone, and an additional agent
• Pomalidomide-based therapies, such as pomalidomide and dexamethasone
• Selinexor (100mg weekly) or belantamab mafodotin (2.5mg/kg every 3 weeks) for heavily pretreated patients
• CAR-T cell therapies, such as idecabtagene vicleucel or ciltacabtagene autoleucel, for eligible patients Regular monitoring with serum protein electrophoresis, free light chain assays, and bone marrow examinations is essential to detect resistance early and adjust treatment promptly to maintain disease control, as recommended by the NCCN guidelines 1. Additionally, the study by Chari et al 1 highlights the importance of considering the patient's previous treatment history and response to therapy when selecting a new treatment regimen. In contrast, the study by Dingli et al 1 suggests that patients who experience an indolent relapse of their disease while receiving lenalidomide maintenance or soon after discontinuing lenalidomide maintenance or are considered frail can be treated with IRd or ERd. However, the most recent study by the NCCN guidelines 1 recommends ixazomib/pomalidomide/dexamethasone as a treatment option for patients with relapsed/refractory MM who have received at least 2 prior therapies including an IMiD and a PI and have shown disease progression on or within 60 days of completion of the last therapy. Overall, the treatment of lenalidomide refractory patients requires a personalized approach, taking into account the patient's individual characteristics, prior therapies, and response to treatment, as well as the latest clinical trial data and guidelines, including those from the Mayo Clinic Proceedings 1 and the Journal of the National Comprehensive Cancer Network 1.

From the Research

Lenalidomide Refractory Multiple Myeloma

• Lenalidomide refractory multiple myeloma is a condition where patients no longer respond to lenalidomide-based treatments 2.
• The development of refractoriness to lenalidomide often occurs early in the disease course, typically after the first treatment 2.
• Lenalidomide-free regimens have shown limited efficacy in lenalidomide-refractory patients, highlighting the need for alternative treatment options 2.

Treatment Options for Lenalidomide Refractory Multiple Myeloma

• Carfilzomib, pomalidomide, and dexamethasone (CPD) is a novel therapeutic regimen that has shown promise in treating lenalidomide-refractory patients 3.
• The combination of carfilzomib, daratumumab, and dexamethasone (KdD) has been evaluated as a lenalidomide-sparing option and has demonstrated significant improvements in progression-free survival compared to pomalidomide-containing triplets 4.
• Carfilzomib-lenalidomide-dexamethasone (KRd) has been shown to improve progression-free survival compared to lenalidomide-dexamethasone (Rd) in relapsed multiple myeloma patients, including those with previous lenalidomide exposure 5.

Challenges and Future Directions

• The management of lenalidomide-refractory multiple myeloma remains a challenge, and there is a need for further research to identify effective treatment options 2.
• Immunotherapy has been debated as a potential treatment option for relapsed/refractory multiple myeloma patients, including those with lenalidomide refractoriness 2.
• The optimization of lenalidomide-based treatment regimens and the development of new therapies are crucial to improving outcomes for patients with lenalidomide-refractory multiple myeloma 6.