Treatment of Patients with Relapsed/Refractory Multiple Myeloma (MM) with Lenalidomide and Dexamethasone with or without Bortezomib: Prospective Evaluation of the Impact of Cytogenetic Abnormalities.
Authors: Dimopoulos Meletios A. , Kastritis Efstathios , Christoulas Dimitrios , Migkou Magdalini , Gavriatopoulou Maria , Gkotzamanidou Maria , Iakovaki Marina , Roussou Maria , Efstathiou Eleni , Terpos Evangelos 
Published: October 2019

Abstract
Abstract 958
The addition of bortezomib (B) to lenalidomide and dexamethasone (RD) regimen seems to increase RD efficacy. In a prospective study conducted in the Department of Clinical Therapeutics of the University of Athens (Greece), patients with pre-existing peripheral neuropathy (PN) grade <2 received BRD, while patients with PN grade 2 received RD. The aim of the study was to assess the impact of cytogenetic abnormalities on response and time to progression. As of July 2009, 91 patients have been included, regardless of their performance status and renal function; the only exclusion criterion was prior treatment with R. Patients with PN grade <2, received B at a dose of 1 mg/m2 on days 1, 4, 8 and 11; R 15 mg on days 1-14 (or at a lower dose if creatinine clearance (CrCl) <30 ml/min) and D 40 mg PO on days 1-4, in a 21-day cycle. Patients with PN grade ≥2 received R on days 1-21 at a dose based on their CrCl and D 40 mg PO on days 1-4 and 15-18 for the first 4 cycles and only on days 1-4 thereafter, every 28 days. At baseline, conventional metaphase cytogenetics and FISH (after cell sorting) for del13q, del17p, add1q21, t (4;14), t (14;16) were performed in all patients. Poor risk cytogenetics were defined by the presence of at least one of the following: non-hyperdiploid karyotype, del13q by metaphase karyotype, del17p or add1q21 or t(4;14) or t(14;16) by FISH. Refractoriness to thalidomide (thal) or to B was defined as progressive disease during treatment with these agents or within 60 days after last dose. So far, 45 patients have received BRD and 46 RD. Median time from first treatment to this study was 35 months (range 1-217 months). Median number of prior treatments was 3 (range 1-8) and included prior therapy with thal: 76% (60% thal refractory), prior therapy with B: 84% (58% B-refractory) and prior treatment with D: 100% (60%D-refractory). Poor risk cytogenetics were present in 44% of patients: 31% had add1q21, 18% had non-hyperdiploid karyotype, 12% had del17p, 12% had t(4;14) and 9% had del13q by metaphase karyotype. Del13q detected by FISH was present in 31% of patients (6% as a sole anomaly). Twenty-four (26%) patients had baseline CrCl <50 ml/min, 18 (19%) had LDH >300 IU/dL (UNL=225 IU/dL) and 27 (29%) had ISS-3 MM. Patient characteristics and cytogenetic findings were similar between RD and BRD. On an intent to treat basis, 83 patients (43 in BRD and 40 in RD) are evaluable for response (IMWG criteria) so far: objective response (OR, i.e. PR or better) after BRD and RD was 61.9% and 60%, respectively (p=0.75). Sixteen (38%) of 42 thal-refractory patients achieved an OR. Median time to best response was 2 months (range 0-15 months) for RD and 1 month (0-13 months) for BRD (p=0.125). Factors associated with less than PR after treatment included thal-resistance (p=0.002), high LDH (p=0.008), non-hyperdiploid karyotype (p=0.004), presence of del17p (p=0.002) and poor-risk cytogenetics (p=0.014). However, add1q21 (p=0.576), t(4;14) (p=0.896) and poor-risk cytogenetics (p=0.42) could not predict for less than PR to BRD but they did for RD (p=0.009, 0.033 and 0.006, respectively). Median TTP was 7 months (range 0-17 months) and median OS was 16 months (range 0-28 months) with no differences observed between BRD and RD. Variables associated with shorter TTP in all patients included del17p (p<0.001), high LDH (p<0.001), poor-risk cytogenetics (p=0.001), non-hyperdiploid karyotype (p=0.004), thal resistance (p=0.002), del13q (p=0.027), and add1q21 (p=0.046). BRD seems to override the adverse prognostic impact of non-hyperdiploid karyotype (p=0.121), del13q (p=0.15) and add1q21 (p=0.404) on TTP, but not that of del17p (p=0.007). In RD arm, non-hyperdiploid karyotype (p=0.019), add1q21 (p=0.048) and del17p (p=0.021) predicted for shorter TTP. Poor-risk cytogenetics had only a borderline significant impact on TTP in BRD (p=0.042) compared to RD (p=0.012). In terms of OS, poor-risk cytogenetics predicted for inferior OS in both treatment groups (median: 11 months vs. not reached in standard risk cytogenetics group; p=0.001). We conclude that RD and BRD are clearly more active in patients with hyperdiploid karyotypes. The addition of B may overcome to a certain extend the adverse prognosis of cytogenetic abnormalities detected by FISH [t(4;14), del13q and add1q21] but not that of del17p.

Disclosures:
Dimopoulos: CELGENE: Honoraria.