Dissecting the high-risk property of 1q gain/amplification in patients with newly diagnosed multiple myeloma.

1q gain/amplification (1q+) is the most common cytogenetic abnormality (CA), with a frequency of 30-50% in patients with newly diagnosed multiple myeloma (NDMM). Although accumulating evidence supports 1q+ as a "high-risk" CA (HRCA), several issues remain to be addressed to understand its true prognostic property. We retrospectively analyzed a cohort of 934 patients with NDMM from three centers in China, who had baseline data available for 1q+ [including 1q21 gain (3 copies) and amplification (> 3 copies)] detected by fluorescence in situ hybridization in isolated CD138+ cells, and who received first-line treatment with novel agents including proteasome inhibitors, immunomodulatory drugs, or both. Minimal residue disease (MRD) was assessed using next-generation flow cytometry. In this cohort, 1q+ patients accounted for 53% of all patients. 1q+ patients were characterized by larger tumor burden, more advanced diseases, adverse complications, and frequent concurrence of other CAs (particularly HRCAs) at diagnosis. Concurrence of HRCAs [del(17p), t(4;14), and t(14;16); known as double-hit MM], but not standard-risk CA, markedly worsened the outcome of 1q+ patients, compared to those with 1q+ only (progression-free survival/PFS: hazard ratio/HR 1.63, 95% confidence interval/CI 1.21-2.20, P = 0.0013; overall survival/OS: HR 1.96, 95% CI 1.40-2.74, P < 0.0001). 1q+ modulated the risk levels defined by the Revised International Staging System (R-ISS). Although the overall response rate was not significantly different between patients with or without 1q+, fewer 1q+ patients achieved complete response or better and minimal residue disease negativity (MRD-). MRD- attainment substantially prolonged PFS (HR 4.03, 95% CI 2.59-6.29, P < 0.0001) and OS (HR 3.72, 95% CI 2.24-6.19, P < 0.0001) of 1q+ patients. While 1q+ patients had relatively shorter MRD- duration, sustained MRD- significantly improved the PFS and OS of 1q+ patients. Together, 1q+ is an HRCA and a major component of double-hit MM, while the risk-adapted and MRD-tailored therapy may best help manage this high-risk population.