A Simple Risk-Scoring Model for Estimating the Prognostic Impact of 1q Gain in Patients with Newly-Diagnosed Multiple Myeloma

Introduction: 1q gain (+1q) is the most common high-risk cytogenetic abnormality (HRCA) in patients with newly-diagnosed multiple myeloma (NDMM). While bulk evidence support +1q as an independent risk factor, its prognostic value remains not fully defined in the era of novel agents. Recently, +1q has been integrated into several staging systems such as MASS and R2-ISS. However, the prognostic impacts of +1q seem highly heterogeneous. Thus, it would be important to re-stratify +1q patients with diverse outcomes. Materials and Methods: From a total of 1,329 NDMM patients from three centers, 934 patients who had baseline information of CAs (must have +1q), and must receive novel agents for frontline treatment were included as a training set. CAs were assessed using fluorescence in situ hybridization (FISH) in CD138+ cells isolated from bone marrow aspirates via routine diagnostic procedures. According to the IMWG consensus, 1q gain, del(17p), t[4;14], and t[14;16] were defined as HRCAs, while the FISH panels for routine laboratory examination in all three centers did not include t(14;20) due to its rareness. The minimal residue disease (MRD) status, including undetectable MRD (MRD−) vs. persistent MRD (MRD+), was determined by next-generation flow cytometry. In a total of 1,126 patients in the MMRF CoMMpass cohort, 726 patients eligible for this study were included as a validation set. All statistical analyses were conducted using SPSS software (version 22.0) and R packages survival and survminer in R/Bioconductor (version 3.6.1). Results: In our cohort, +1q was found in 496 cases, accounting for 53.1% of all patients, higher than 34.2% in the CoMMpass cohort. Compared to patients without +1q, +1q patients had significantly more IgA or IgD isotypes, more advanced diseases (e.g., ISS III or R-ISS III), larger tumor burden (e.g., BMPCs, b2-MG, and LDH), and higher frequency of concurrence with other CAs (especially HRCAs). With median follow-up of 44.1 months, +1q patients had significantly shorter PFS (P = 0.0001) and OS (P = 0.0003) than those without +1q. Considering the debate about whether +1q is a real risk factor of prognosis or just a byproduct of high-risk biology, the outcomes of patients with only +1q vs. non-HRCAs were further compared, to exclude the potential influence of other HRCAs. Survival of patients with only +1q were significantly shorter than those with non-HRCAs, including PFS (P = 0.0081) and OS (P = 0.0067), while similar to patients carrying other HRCAs. Multivariate Cox analysis demonstrated +1q as an independent risk factor for PFS (P = 0.014) and OS (P = 0.007). In +1q patients, 69.8% had concurrence of other CA(s), including HRCA (24.4%) and non-HRCA (45.4%). Compared to patients carrying only +1q, +1q patients with concurrent HRCAs, but not non-HRCAs, had significantly shorter PFS (P = 0.0294) and OS (P = 0.0381). Notably, concurrence of t(14;16) resulted in the worst outcome of +1q patients (PFS, P < 0.0001; OS, P = 0.0004 vs. those with only +1q). Multivariate Cox analysis identified ISS III, t(14;16), hypercalcemia, and elevated LDH as independent risk variates for both PFS and OS of +1q patients. Based on the scores of these four variates, a risk-scoring algorithm was created to estimate the outcomes of +1q patients. In the training set, +1q patients were classified into low (31.6%), intermediate (61.7%), and high risk subgroups (6.7%), with median PFS of 27.4, 18.1, and 6.1 months (intermediate vs. low: HR, 1.74, 95% CI, 1.32-2.29, P < 0.0001; high vs. intermediate: HR, 2.78, 95% CI, 1.77-4.37, P < 0.0001) and median OS of 59.8, 34.8, and 18.9 months (intermediate vs. low: HR, 2.36, 95% CI, 1.65-3.38, P < 0.0001; high vs. intermediate: HR, 3.20, 95% CI, 1.97-5.20, P < 0.0001). This model remained its ability to discriminate OS of +1q patients in the validation set and subgroups of patients who received the doublet therapy or transplant, as well as to predict early relapse. Although +1q patients had relatively lower rate of achieving undetectable MRD (MRD−) and shorter MRD− duration, attaining MRD− strikingly improved their PFS (P < 0.0001) and OS (P < 0.0001). Nonetheless, the risk-scoring model was still capable to discriminate OS of MRD− patients with different risk levels. Conclusion: +1q MM represents a heterogeneous group of patients with considerably different outcomes. A simple 3-tier risk-scoring model is thus proposed to help guide risk-adapted management for this subset of HRMM patients.