Defining refractoriness in multiple myeloma

Refractoriness to different drugs and drug classes is an important consideration in determining the best treatment strategy and eligibility for clinical trials for relapsed multiple myeloma.
Defining refractoriness in multiple myeloma
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Lenalidomide containing regimens are extensively used as first line therapy for the treatment of multiple myeloma. Current consensus definition of refractoriness in multiple myeloma is: disease that progresses while on therapy or within 60 days of last therapy with the drug in consideration. Since current treatment approaches often involve lenalidomide maintenance until progression, a majority of patients end up having disease that is refractory to lenalidomide at the time of first relapse. 

Defining refractoriness to lenalidomide is important, as disease that is considered refractory to lenalidomide would likely not benefit much from a lenalidomide containing regimen at first relapse. On the other hand,  lenalidomide sensitive disease is more likely to respond to another lenalidomide containing regimen as second line therapy.

While current management approaches recognize lenalidomide refractoriness as an important consideration in selecting second line multiple myeloma therapy , it remains a point of debate whether resistance to lenalidomide varies among patients who have disease progression on standard/ full doses of lenalidomide (25 mg once daily) as compared to those who experience progression on single agent maintenance doses (e.g., 5-15 mg once daily). To this extent, often disease progressing on standard dose of lenalidomide is considered refractory to lenalidomide, while that progressing on maintenance doses is considered lenalidomide sensitive. More generally, this applies to all myeloma drugs where there are limited data assessing and defining refractoriness to different doses/administration schedules of systemic myeloma therapies. 

In this retrospective study, we assessed the impact of refractoriness to standard dose vs low doses of lenalidomide on outcomes with subsequent therapies in patients with multiple myeloma. We found that the progression free survival for second line therapy and the progression free survival with the next lenalidomide containing line of therapy after the first line therapy (lenalidomide retreatment) did not differ between disease that was refractory to standard dose lenalidomide vs low dose lenalidomide. Additionally, the outcomes of both these groups were significantly inferior to patients that were not refractory to lenalidomide. 

These findings are important for determining the choice of regimen at first relapse, and in determining clinical trial eligibility for relapsed multiple myeloma trials. This study suggests that the definition of refractoriness to lenalidomide should not be dependent on the dose of lenalidomide to which the disease was considered refractory. Patients progressing on lower maintenance doses (5–15 mg) should be considered as refractory to lenalidomide as patients progressing on the 25 mg dose.

Future studies should assess the impact of refractoriness to different doses and schedules of other myeloma drugs like proteasome inhibitors and daratumumab, and work on a uniform definition of drug refractoriness based on administration schedules of drugs.

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