CONTEXT: Multiple myeloma (MM) is characterized by recurrent chromosomal abnormalities (CA), which are known to affect patient survival. Translocation t(14;16) is associated with inferior survival, but the clinical features and outcomes of these patients have not been thoroughly described. OBJECTIVE: To characterize the baseline characteristics, response to first-line treatment, and survival outcomes of patients with t(14;16) multiple myeloma. DESIGN: We retrospectively reviewed databases of patients treated for multiple myeloma at participating medical centers in the United States, Italy, and Greece. Patients carrying t(14;16) as detected by FISH diagnosed between December 2006 and March 2017 were included. RESULTS: A total of 123 patients were evaluated. Median age at diagnosis was 66 years; 49% of patients presented with hemoglobin ≤10 g/dl and 11% with platelets ≤100 x10^9/L. Elevated lactate dehydrogenase (LDH), hypercalcemia and creatinine values >2 mg/dl were observed in 19%, 17% and 13%, respectively and 43% had ISS and R-ISS stage 3 disease. Eighty-two percent had at least one additional unfavorable CA, including del13q (71%), del17p (22%) and 1q gain (27%). Induction therapy consisted of an immunomodulatory drug, a proteasome inhibitor or a combination of both in 43%, 29% and 28%, respectively. Consolidation with autologous transplantation in first remission (ASCT-1) was performed in one-fourth of patients, and 43% received maintenance therapy. The best response to first-line treatment was ≥partial response (PR) in 83%, with 26% ≥complete remission (CR). Median progression-free survival (PFS) and overall survival (OS) for the entire cohort were 19 and 53 months, respectively. Among ASCT-eligible patients, those who received ASCT-1 had longer median PFS (31 vs. 10 months; HR: 0.35, p=0.003) and OS (58 vs. 34 months; HR 0.48, p=0.04) compared to those who did not. In ASCT-ineligible patients, median PFS and OS were 16 and 59 months. Maintenance therapy significantly prolonged median PFS (36 vs. 19 months, HR:0.56; p=0.03) compared to no maintenance. CONCLUSIONS: In the largest cohort of t(14:16) patients described to date, t(14;16) characterizes a group of high-risk MM patients with poor PFS and OS. ASCT-1 in first remission prolonged survival and maintenance therapy improved progression- free survival of patients with t(14;16). • The implementation of novel triplet-based induction regimens, consolidation with autologous stem cell transplant, and maintenance therapy has helped to improve outcomes significantly for patients with multiple myeloma, with median PFS ranging from 35 to 50 months [1,2] and overall survival rates reported as high as 75 months. [3] • However, for many patients with high-risk features and cytogenetics, outcomes remain poor. • Translocation (14;16) has been implicated as a high-risk recurrent cytogenetic abnormality seen in multiple myeloma, resulting in inferior outcomes including survival [4-6]. However, as it is a relatively infrequent event, occurring in approximately 5% of newly-diagnosed patients [4], the clinical features and outcomes of t(14;16) myeloma have not been fully described, particularly in the era of novel therapies. • The primary objective of this analysis was to describe the clinical characteristics, response to first-line therapy and survival outcomes of newly-diagnosed multiple myeloma patients (NDMM) harboring t(14;16) by FISH. Methods Abstract Background Outcomes Conclusions • In this large cohort of NDMM patients harboring t(14;16), almost all patients (99%) were exposed to novel agents (thalidomide, lenalidomide, bortezomib, carfilzomib, and ixazomib) as part of their upfront treatment. • t(14;16) myeloma frequently presents with high-risk features, such as ISS Stage 3 disease (53%) and additional cytogenetic abnormalities (82%). • Despite the wide use of novel agents, ASCT and maintenance, median PFS (19 months) and OS (53 months) of the overall population remain poor. • In transplant-eligible patients, upfront ASCT prolonged median PFS (31 vs. 10 months) and OS (58 vs. 34 months) compared with no transplant. • Continuous treatment (maintenance) also prolonged median PFS (36 vs. 19 months) versus no maintenance, without a significant improvement in OS. Translocation (14;16) Positive Multiple Myeloma: Clinical Features and Survival Outcomes of a High-risk Population Timothy Schmidt, 1 Roberto Mina, 1,2 Nisha S. Joseph, 1 Francesca Gay, 2 Ajay Nooka, 1 Efstathios Kastritis, 3 Stefano Spada, 2 Jonathan L. Kaufman, 1 Vittorio Montefusco, 4 Lawrence H. Boise, 5 Evangelos Terpos, 6 Sagar Lonial, 1 Mario Boccadoro, 2 Meletios A. Dimopoulos 3 1 Emory University, Atlanta, GA, USA; 2 Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy; 3 Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece; 4 Italian Multiple Myeloma Network, GIMEMA, Italy; 5 Division of BMT, Emory University, Atlanta, GA, USA; 6 Department of Clinical Therapeutics, University of Athens, Drosia, Greece Italian and EMN clinical trial databases N= 76 Winship Cancer Institute, Emory University, USA N= 29 Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Greece N= 18 N=123 NDMM patients t(14;16) positive by FISH Databases of three different institutions were utilized in this analysis. Patients diagnosed between December 2006 and March 2017 with t(14;16) by FISH were pooled together and analyzed. Clinical Characteristics Patient Characteristics N=123 Age, median (range) 66 years (38-87) Sex • Male • Female 57 (46%) 66 (54%) Isotype • IgG • IgA • FLC • Non-secretory 67 (54%) 32 (26%) 23 (19%) 1 (1%) ISS • 1 • 2 • 3 • NA 25 (20%) 41 (33%) 53 (43%) 4 (3%) Bone marrow plasma cells, median (range) 60% (0-100) Monoclonal protein, median (range) 3.3 gr/dl (0-11.6) Hemoglobin, median (range) 10 gr/dl (5.2-15.6) Platelets, median (range) 174 x 10 9 /mm3 (31-426) Calcium > upper level of normal 12 (17%) Serum Creatinine ≥ 2 mg/dl 16 (12%) FISH • Deletion 13q • Deletion 17p • Amplification 1q • translocation(4;14) • translocation(11;14) 87 (71%) 27 (22%) 33 (27%) 14 (11%) 6 (5%) First-line Treatments N=123 Induction therapy Immunomodulatory drug based • Lenalidomide • Thalidomide 53 (43%) 48 (39%) 4 (3%) Proteasome inhibitor based • Bortezomib • Carfilzomib 36 (29%) 30 (24%) 6 (5%) Proteasome inhibitor plus Immunomodulatory drug 34 (28%) Chemotherapy 1 (<1%) Autologous stem cell transplant 34 (28%) Maintenance 52 (43%) Progression-free survival Proportion of patients Proportion of patients Months Months Median PFS: 19 months; 95% CI 16-39 Median OS: 53 months; 95% CI 36-63 Overall Population Maintenance Therapy Median PFS: 31 vs. 10 months, HR: 0.35; p=0.003 ASCT-1 No ASCT-1 Median OS: 58 vs. 34 months, HR: 0.79; p=0.04 ASCT-1 No ASCT-1 Median PFS: 36 vs. 19 months, HR: 0.56; p=0.04 Maintenance No maintenance Progression-free survival Overall survival Overall survival Proportion of patients Proportion of patients Proportion of patients Proportion of patients Maintenance No maintenance Transplant-Eligible Patients Months Months Overall survival Progression-free survival Median OS: 69 vs. 58 months, HR: 0.79; p=0.5 Months Months Outcomes by Response to Induction Therapy Response Number of patients sCR 6 (5%) CR 18 (15%) VGPR 31 (25%) PR 44 (36%) SD 14 (11%) PD 6 (5%) NA 4 (3%) ORR 99 (80%) ≥ CR 24 (20%) sCR, stringent complete response; CR, complete response; VGPR, very good partial response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, overall response rate; CR/sCR PR/VGPR Progression-free survival Proportion of patients Months Median PFS: NA vs. 17 months, HR: 0.29; p<0.001 Univariate Multivariate PFS OS PFS OS HR p-value HR p-value HR p-value HR p-value Calcium > ULN 2.9 0.006 5 <0.001 1.8 0.11 3.5 0.005 B2M > 5.5 mg/dl 2 0.002 2 0.009 1.6 0.03 1.5 0.15 LDH > ULN 1.85 0.03 3 <0.001 2 0.03 2.3 0.02 1+ abnormality by FISH* 1.9 0.07 1.1 0.8 0.92 0.83 0.6 0.2 CR1 0.29 <0.001 0.56 0.1 0.27 <0.001 0.45 0.04 Prognostic Factors PFS, progression-free survival; OS, overall survival; HR, hazard ratio; ULN, upper level of normal; B2M, beta-2-macroglobulin; LDH, lactic dehydrogenase; FISH, fluorescent in situ hybridization; CR1, complete response at first line. * Including del17p, t(4;14) and gain 1q. FLC, free light chain; ISS, international staging system; NA, not available; FISH, fluorescent in situ hybridization; 1. Einsele, H., et al., Phase II study of bortezomib, cyclophosphamide and dexamethasone as induction therapy in multiple myeloma: DSMM XI trial. Br J Haematol, 2017. 179(4): p. 586-597. 2. Attal, M., et al., Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med, 2017. 376(14): p. 1311-1320. 3. Durie, B.G.M., et al., Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. The Lancet, 2017. 389(10068): p. 519-527. 4. Fonseca, R., et al., Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood, 2003. 101(11): p. 4569-75. 5. 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