Lenalidomide Overcomes Poor Prognosis Conferred by del13q and t(4;14) but Not del17p13 in Multiple Myeloma: Results of the Canadian MM016 Trial.
Authors: Bahlis Nizar J. , Song Kevin , Trieu Young , Roland Birgitte , Masih-Khan Esther , Chang Hong , Bruyere Helene , Mansoor Adnan , Horsman Douglas , Eliasziw Michael , Stewart Douglas , Reece Donna 
Published: April 2020

Abstract
The outcome of conventional therapy in MM is highly heterogeneous and appears to be largely dictated by the presence of recurrent genomic aberrations. Among these t(4;14), deletion 17p13 (TP53 locus), maf gene translocations and to a lesser extent del13q define a subgroup of patients with high risk disease. We here report on the efficacy (RR, PFS and OS) of lenalidomide and dexamethasone (len-dex) in relapsed MM patients according to their del13q, t(4;14) and del17p13 status. The MM016 is a multicenter single arm open label expanded access program for len in relapsed and refractory MM. Pts received dex orally (40mg, days 1–4; 9–12 and 17–20 for 4 cycles, then days 1–4 beginning with cycle 5) and len 25mg orally on days 1–21 of a 28 days cycle. FISH studies with commercially available probes detected the presence or absence of del13q, t(4;14)(p16;q32) and del17p13 on the interphase bone marrow aspirates. Blade criteria were used to define RR. PFS and OS were defined according to the international uniform response criteria. 159 patients with FISH results available for a least one of the genomic aberrations were included in this analysis: median age was 61 yrs (32–85), 50.3% had ISS stage II or III, median beta2-microglobulin was 3.055 mg/L (0.69–17.5), median number of prior treatments was 3 (1–6) with 50.3% previously treated with thalidomide, 43.7% with bortezomib and 73% with SCT. Del13q, t(4;14) and del17p13 were detected in 57 (37.3%), 21(19.1%) and 11 (11.6%) of patients, respectively. The overall response RR (CR+PR) to len-dex was 77.3% (14.4% CR and nCR) and 64.9% for the del13q, 76.2% for t(4;14) and 63.6% for del17p patients. The median PFS was 10.56 months (95%C.I.[6.65–14.48]). The median OS was not reached at the time of this analysis with 55.4% alive at a median follow-up of 16 months. PFS and OS were also similar when results were analyzed according to the presence or absence of del13q, t(4;14), ISS stage and prior SCT. In univariate analysis, prior thalidomide or bortezomib exposure, number of prior lines of therapy, depth of response (CR vs PR) and the presence of del17p13 by FISH did result in lower PFS and OS. However in multivariate analysis only the presence of 17p13 deletion and the depth of response correlated with PFS and OS (Table). Treatment with len-dex overcomes the poor prognosis conferred by t(4;14), high beta2-microglobulin and del13q in relapsed and refractory MM. Patients with deletion of the TP53 locus still fare very poorly despite a rapid initial response to len-dex. Confirmation of these results in patients with del17p13 with a larger prospective study is clearly warranted.
Variable PFS OS HR, 95% CI p value HR, 95% CI p value t(4;14) 0.92(0.29–2.13) 0.920 1.26(0.46–3.42 0.641 Del 13 0.90 (0.44–1.83) 0.783 0.56 (0.25–1.29) 0.179 Del17p13 6.26 (2.48–15.77) 0.000 3.83(1.34–10.93) 0.012 ISS III 2.03 (0.42–9.82) 0.376 1.72 (0.39–11.33) 0.378 Prior Thal 1.12 (0.51–2.44) 0.768 1.22 (0.53–2.82) 0.633 Prior Bortez 1.29 (0.61–2.74) 0.501 1.66 (0.74–3.71) 0.215 Response ≤ PR vs CR 3.031 (2.14–4.27) 0.000 2.17 (1.50–3.12) 0.000