Addition Of Clarithromycin To Lenalidomide and Dexamethasone (BiRd) Is Effective In Multiple Myeloma After Progression On Lenalidomide and Dexamethasone

The combination of clarithromycin (biaxin), lenalidomide and dexamethasone (BiRd) has been previously shown by Niesvizky, R., et al as a very effective regimen in newly diagnosed myeloma (MM) with an overall response rate of 90.3% and a very good partial response (VGPR) rate of 73.6%. Long term follow up has shown a median progression free survival of 49 months. In a case control comparison, Gay, F., et al showed that BiRd has superior outcomes compared to lenalidomide and dexamethasone (Rd). Clarithromycin appears to optimize the pharmacologic effect of glucocorticoids by increasing the area under the curve and the maximum concentration levels of certain corticosteroids. Clarithromycin has immunomodulatory properties, partially mediated by the suppression of interleukin-6 and other inflammatory cytokines and may also have direct antineoplastic effects. Although the efficacy of BiRd in the frontline treatment of MM is well established, the effect of BiRd in patients who are refractory to Rd is unknown.

As part of an IRB-approved study we performed a retrospective analysis on all patients with MM in whom clarithromycin was added to Rd at the time of progression on Rd between January 2007 and March 2013. High risk MM was defined as having any one of the following: del(13q) by cytogenetics or t(4;14), t(14;16), t(14;20), -17p ,+1q21 on FISH/cytogenetics. International Staging System (ISS) stage was based on beta2 microglobulin and albumin at diagnosis of symptomatic myeloma. These data were available for 18 patients (75%). The definitions of progression, stable disease and response were as per the International Myeloma Working Group criteria. Event time distributions for overall (OS) and progression-free survival (PFS) were estimated with the method of Kaplan and Meier, and compared using the log-rank statistic, or the Cox proportional hazards regression model. Factors associated with BiRd response were selected based on cross tabulations and logistic regression modeling.

24 patients with MM who had disease progression on Rd had clarithromycin added to their regimen at the time of progression on Rd. Median age was 61 years (range: 41-80 years), 10 (41.6%) female, 11 (45.8%) had high risk features on cytogenetics or FISH, 6 (25%) had a prior stem cell transplant. All patients had shown evidence of disease progression on Rd prior to addition of clarithromycin. Median duration on Rd immediately prior to addition of clarithromycin was 5.2 months (range: 1.6-37.8 months). The regimen was well tolerated and only 2 patients needed a clarithromycin dose reduction. One patient developed dyspepsia, metallic taste, nausea and diarrhea. A second patient experienced grade 3 transaminitis. 10 patients, 41.6% (95% CI: 22.1, 63.4), achieved ≥PR. The clinical benefit rate (CR+VGPR+PR+MR) was 45.8% (95% CI: 25.6, 67.2). The median time to response was 4.4 months (range: 1-13.6 months) and the median duration of response was 17.3 months (range: 7.4-130.5 months). Median overall survival was 25 months with a median follow-up of 27.5 months. The median progression free survival (PFS) was 4 months. Age and prior therapy were significant risk factors for PFS. Patients over the age of 60 had a higher hazard of progression or death than patients under the age of 60 (HR 3.48 95% CI 1.09-11.09, p=0.04). The hazard of progression or death was increased by a factor of 1.59 for each additional prior therapy HR= 1.59 (95% CI: 1.19, 2.11), p=0.002. Patients initially responding to Rd (n=10) were more likely to respond to BiRd (n=6), 60% (95% CI: 26.2, 87.8) compared to patients that did not have an initial response to Rd (n=14) in whom the response to BiRD (n=4) was 28.6% (95% CI: 8.4, 58.1), OR=3.75, p=0.13. High risk genetics, prior stem cell transplant, and prior response to Rd did not correlate with PFS or response to BiRd, although the numbers are small.

Addition of clarithromycin to lenalidomide and dexamethasone (BiRd) can overcome resistance to lenalidomide and dexamethasone in a subset of patients and lead to clinical durable responses. This retrospective data may serve the basis for prospective evaluation of this effect.

Off Label Use: Addition of clarithromycin to overcome resistance to lenalidomide and dexamethasone.