The Impact of Cytogenetics on the Outcomes of Treatment with Lenalidomide Plus Dexamethasone in Relapsed or Refractory Multiple Myeloma.
Authors: Bahlis Nizar J , Song Kevin W. , Fu Tommy , Roland Birgitte J , Chang Hong , Horsman Doug , Mansoor Adnan , Chen Christine , Khan Esther Masih- , Trieu Young , Bruyere Helene , Stewart Douglas A. , Reece Donna E. 
Published: April 2020

Background: Lenalidomide improves survival for patients with relapsed or refractory multiple myeloma (MM). However, the benefit of this treatment in patients with highrisk cytogenetic abnormalities is not well studied. We have previously reported in an initial sub-analysis of a large, open-label study (MM016 study) the effects of the most common unfavorable cytogenetic abnormalities on outcomes in MM patients treated with lenalidomide plus dexamethasone. Since then we have performed an update of this sub-analysis within a larger cohort of patients and a longer median follow-up time of 19.6 months.

Methods: The MM016 is a multicenter single arm open label expanded access program for Lenalidomide in relapsed and refractory MM. Patients received dexamethasone orally (40mg, days 1–4; 9–12 and 17–20 for 4 cycles, then days 1–4 beginning with cycle 5) and Lenalidomide 25mg orally on days 1–21 of a 28 days cycle. Using fluorescence in situ hybridization, we examined the influence of three most common and recurrent cytogenetic abnormalities [del(13q), t(4;14), and del(17p13)] in 130 patients with FISH results available for the three genomic aberrations. Blade criteria were used to define RR. TTP and OS were defined according to the international uniform response criteria.

Results: The median age was 61 yrs (31–84), 55.4% had ISS stage II or III, median beta2-microglobulin was 3.125 mg/L (1.1–16.75), median number of prior treatments was 2 (1–6) with 53.8% previously treated with thalidomide, 45.9% with bortezomib and 73.3% with SCT. Del(13q), t(4;14) and del(17p13) were detected in 54 (41.5%), 28(21.5%) and 12 (9.2%) of patients, respectively. The overall response RR (CR+PR) to len-dex was 83.1% (13.1% CR and nCR) and 76.4% for the del13q, 78.6% for t(4;14) and 58.3% for del17p patients. In univariate analysis the time-to-progression (TTP) hazard ratio (HR) for del(13q) and for t(4;14) were 1.563 (P = .0479) and 1.680 (P = .0470) respectively. However in multivariate analysis, neither the presence of either del(13q) nor t(4;14) did adversely affect TTP. Similarly neither of these genomic aberrations did affect overall survival (OS) hazard ratio with HR= 1.472 (P= .1507) for del(13q) and HR=1.091 (P = .788) for t(4;14). TTP (HR 2.626, P = .0032) and OS (HR 3.213, P =0.0016) were significantly worse with del(17p13) in univariate and multivariate analysis. Among the other variables studied prior thalidomide exposure did result in a shorter TTP (HR= 2.330; P = .0004) but not OS (HR= 1.690; P = .0612).

Conclusion: Lenalidomide plus dexamethasone can overcome the negative prognostic effect of high-risk cytogenetic abnormalities conferred by the presence of del(13q) and t(4;14), and represents a good treatment option for relapsed or refractory MM patients with these adverse cytogenetic profiles. (Clinicaltrials.gov number, NCT00179647.)