Outcomes and Clinical Features of Patients with 1q+ Multiple Myeloma Treated with Lenalidomide, Bortezomib, and Dexamethasone

Introduction: Recurrent cytogenetic abnormalities have been well described in multiple myeloma and have important roles in the development and progression of myeloma, as well as prognostic implications for patient survival. Amplification of chromosome 1 (+1q) has been associated with inferior outcomes including survival. However, it is unclear whether this association is due to a primary effect of +1q on myeloma biology or secondary to its association with genomic instability and more advanced disease. Furthermore, the prognostic implication of +1q has yet to be determined in the setting of novel treatment regimens including triplet induction regimens incorporating an immunomodulatory agent and proteasome inhibitor backbone, with consideration of risk-adapted maintenance therapy. This study investigated the clinical characteristics and outcomes of a large population of multiple myeloma patients with +1q who were treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy.

Methods: We collected data for 1000 patients with newly diagnosed multiple myeloma who received RVD induction and were seen at Emory University/Winship Cancer Institute between July 1, 2005 and August 31, 2016. Baseline characteristics were determined, including age, sex, race, laboratory values at diagnosis (hemoglobin, creatinine, calcium, albumin, lactate dehydrogenase, beta-2-microglobulin, isotype, paraprotein, and serum free light chains) and molecular cytogenetics by fluorescent in-situ hybridization (FISH) for +1q, t(11;14), t(4;14), t(14;16), del(17p), del(13q), and hyperdiploidy. Patients were also categorized by their ISS stage, high-risk cytogenetics (defined as t(4;14), t(14;16), or del(17p)), and whether they were treated with autologous stem cell transplantation (ASCT). The primary outcomes were response to RVD induction by IMWG criteria (complete response (CR), very good partial response (VGPR), and partial response (PR)), progression free survival (PFS), and overall survival (OS) of patients with +1q compared to patients without +1q. Hazard ratios and p-values for PFS and OS were calculated using multivariate analysis accounting for presence of ISS stage 3 disease, t(4;14), t(14;16), and del(17p).

Results: Of 1000 total myeloma patients treated with RVD induction, 146 (14.6%) were noted to have +1q by FISH. Patients with +1q, compared to those without +1q, were more likely to be Caucasian (75.2% vs 60.1%, p=0.001) , have IgA isotype (29.8% vs 18.6%, p=0.049) , present with calcium > 10.5 (22.8% vs 14.3%, p=0.026) , and have concurrent high-risk abnormalities by FISH (59.6% vs 21.7%, p<0.001) . There was no significant difference in response to RVD induction, with responses of ≥CR/≥ VGPR /≥PR of 42.2%/67.2%/99.3% for patients with +1q compared with 36.1%/68.8%/97.8% for patients without +1q (p=0.693) . Median PFS was significantly shorter for patients with +1q compared with those without +1q (41.8 months vs 86.0 months , respectively, HR 2.39, p<0.001 ). OS of patients with +1q was significantly worse than patients without +1q (median not reached, HR 2.316, p=0.001 ).

Conclusion: In this retrospective, single-center analysis of multiple myeloma patients treated with RVD induction, patients with 1q amplification had similar responses to induction therapy, but significantly inferior PFS and OS compared to patients without +1q. Further investigation is required to determine if the timing of 1q gain, copy number of chromosome amplification, and/or association with other high-risk cytogenetics are important contributing factors to the prognosis of patients with +1q.