Lenalidomide Related Diarrhea Correlates With Survival In Multiple Myeloma

We hypothesized lenalidomide (len) related diarrhea (LRD) may correlate with activation of an immune response against multiple myeloma (MM) based on colon biopsies that showed crypt apoptosis reminiscent of GVHD in 3 MM patients with severe LRD but without prior allogeneic stem cell transplantation or gastrointestinal disorder. To investigate whether survival may be influenced by the presence of LRD we performed a retrospective chart review.

Patients who developed symptomatic MM on or after 1/1/2005 as defined by the start of anti-MM therapy and had been on len for at least 6 consecutive months by 12/31/2010 were included in the analysis. Significant LRD was considered present if the treating physician attributed the diarrhea to len and recommended supportive therapy in at least two clinic notes.  The first time treatment for LRD was recommended was used as the date of onset of LRD. As possible confounding factors age at the start of len therapy, number of prior regimens, prior high dose chemotherapy with autologous stem cell transplant (ASCT), and use of antineoplastic agents other than corticosteroids at any time during the continuous len therapy were collected. The primary outcome was overall survival (OS), which was calculated from the start of len. Fisher’s exact test, Mann-Whitney test, and the logrank test were used to compare characteristics and duration of len between patients with and without LRD. Proportional hazards models were used to assess the impact of LRD on OS. The lag between the start of len and development of LRD was accounted for by treating LRD as a time-varying covariate in these models.

161 patients were identified, 47 (29%) had LRD, and 59 (37%) died during follow up. LRD and no LRD groups were balanced for gender, age, number of prior regimens, prior transplant, and use of antineoplastic agents other than corticosteroids with len, but len treatment duration differed; LRD patients had received a median of  43.4 consecutive months of len (range 5.8-82.9) compared to 14.6 (range 5.9-89) for patients without LRD (p=0.001). Onset of LRD occurred after a median of 17.7 months (range 0.3-75.4) of len therapy. In multivariable analyses, development of LRD (HR 0.46, 95% C.I. 0.21-1.00, p=0.05) was associated with improved OS as were the number of prior therapies (0-2, vs >2, HR 0.16, 95% C.I. 0.08-0.32, p<0.0001) and no use of antineoplastic therapy other than corticosteroids during len therapy (HR 0.52, 95% C.I. 0.29-0.93, p=0.03), while age and prior ASCT (p=0.52 and 0.49, respectively) were not.

Late onset of lenalidomide related diarrhea (LRD) is compatible with an immune mediated effect that may signal anti-MM immune activity since LRD requiring supportive measures correlated with survival in MM in analyses that adjusted for lag time. While more study is needed to prove this hypothesis, our findings suggest that diarrhea on len may argue for continued therapy rather than discontinuation.

Faiman:Celgene: Consultancy, Speakers Bureau; Millennium: Consultancy, Speakers Bureau; Onyx: Consultancy, Speakers Bureau. Duong:Celgene: Honoraria, Research Funding. Valent:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Reu:Celgene: Research Funding; Onyx: Speakers Bureau.