High-Risk Cytogenetics in Newly Diagnosed Multiple Myeloma: Prognostic Relevance of Co-Segregations and Analysis of the Role of Double Versus Single Autotransplantation

Abstract

INTRODUCTIONCytogenetic analysis performed by FISH at diagnosis of Multiple Myeloma (MM) allows to stratify patients in groups at different risk of progression or death. We analyzed a large cohort of patients with newly diagnosed MM to evaluate the prognostic impact of multiple high-risk cytogenetic abnormalities (HRAs), detected either as a single lesion (e.g. isolated) or multiple lesions (e.g. co-segregated). METHODSProbes for FISH analysis of CD138+ bone marrow plasma cells were chosen to detect t(4;14), t(6;14), t(11,14), t(14;16), t(14;20), deletion of 1p32, 13q14, 17p13, gain of 1q21 and hyperdiploidy (HD). HRAs were defined by the presence of one or more of t(4;14), t(14;16), t(14;20), del(17p), gain(1q) and del(1p). The analysis was performed in a large cohort of patients who received the diagnosis of MM in Italian centers and were enrolled in the phase III EMNO2/HO95 study. By study design, patients were randomized to receive either standard-dose intensification treatment with bortezomib-melphalan-prednisone (VMP) or high-dose intensification treatment with melphalan at 200 mg/m2 (HDM) plus autotransplantation (ASCT), either single (ASCT-1) or double(ASCT-2). A second randomization to receive or not receive consolidation therapy was planned after the intensification phase, followed by lenalidomide maintenance in both arms. RESULTSA total of 461 patients were evaluable for all HRAs listed above. 151 of them were randomly assigned (stratification by ISS stage) to VMP and 310 to ASCT-1 or ASCT-2. HRAs were detected in 233/461 patients (50.5%): 155 (33.6%) gain(1q), 51 (11.1%) del(1p), 46 (10.0%) del(17p), 58 (12.6%) t(4;14), 20 (4.3%) t(14;16) and 6 (1.3%) t(14;20). 141/461 patients (30.6%) showed an isolated HRA: 76 (53.9%) gain(1q), 27 (19.1%) a high-risk translocation (HRT), 21 (14.9%) del(17p) and 17 (12.1%) del(1p). 81/461 patients (17.6%) carried 2 HRAs, most frequently a HRT co-segregating with gain(1q) (detected in 48.2%), while 3 HRAs were found in the remaining 11 (2.4%). With a median follow-up of 37.8 months, 3-year PFS estimates for patients without HRA or with 1, 2 and 3 HRAs were 80.3%, 53.5%, 45% and 21.8%, respectively (P<0.0001). The corresponding OS estimates were 95.4%, 81.7%, 73.5% and 40.9%, respectively (P<0.0001). All the HRAs, when evaluated either as isolated or in co-segregation, retained their adverse impact on PFS and OS in comparison with the groups lacking either 1 or more HRAs. Among isolated HRAs, del(17p) was the single lesion with the highest adverse impact on OS (HR=3.11; 95%CI=1.20-8.07; P=0.019). Notably, PFS benefit with ASCT-2 as compared with ASCT-1 was observed among the 148 patients with at least 1 HRA (3-year estimate: 61.8 vs 45.2; P= 0.0387). The corresponding OS rates with ASCT-2 vs ASCT-1 were 83.1 vs 67.6, P=0.04. Randomization to ASCT-2 significantly prolonged the 3-year PFS in comparison with ASCT-1 in patients with del(17p) (61% vs 38.7%; HR=0.27; CI=0.076-0.986; P=0.047). In comparison with isolated gain(1q), co-segregation of gain(1q) with a HRT was associated with significantly shorter 3-year PFS (33.3% vs 57.4%; HR 1.76; CI=1.02-3.03; P=0.041) and shorter OS rates (56.5% vs 85.7% ; HR=3.33; CI=1.52-7.30; P=0.027). Gain(1q) plus HRT was associated with lower OS (68.5% vs 89.6%; HR=4.78; 95%CI=1.09-20.93; P=0.038) compared with gain(1q) and del(1p). As expected, HD was more frequent in patients without HRA (59.2%) than in those with 1 HRA and 2 or more HRAs (53.2% and 34.8%). Differently from patients with 1 or ≥2 HRAs, PFS for patients with del(17p) and HD was significantly longer compared with that seen for patients with del(17) not associated with HD (43.9 vs 19.4 months, P=0.032). CONCLUSIONS50% of patients with NDMM presented with one or more HRA and 20% with two or more of them. In patients with at least 1 HRA, randomization to ASCT-2 was superior over ASCT-1 in terms of prolonged PFS and OS. The association of gain(1q) with a HRT was the most frequently observed co-segregation of 2 HRAs and was correlated with significantly shorter PFS and OS compared with isolated gain(1q) and gain(1q) plus del(1p). The association of HD with del(17p) mitigated the adverse PFS of del(17p). DisclosuresOffidani:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy. Boccadoro:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Honoraria; Amgen: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Research Funding.