Clinical Outcome of Induction Treatment in the Era of Novel Agents and the Impact of the Number of High-Risk Cytogenetic Abnormalities (HRA) on Prognosis of Patients with Newly Diagnosed Multiple Myeloma (NDMM): Insights from a Multi-Center Study
Authors: Liang Dong , Feng Demei , Wang Qiaoli , Bai Shenrui , Zeng Min , Lu Bo , Li Xiaoqing , Sun Zhiqiang , Li Jianyun , Zhou Huanhuan , Zhang Jialu , Chen Xiaoqin , Xia Zhongjun , Liang Yang , Wang Hua 
Published: December 2024

Background：
The prognosis for multiple myeloma patients has significantly improved with the introduction of novel agents. Currently, induction treatments that include two or three novel agents, including daratumumab, are commonly used for newly diagnosed multiple myeloma. High-risk cytogenetic abnormalities (HRA) are linked to poor prognosis in multiple myeloma, with patients having two or more HRA considered at ultra-high risk according to the Mayo Clinic's mSMART definition. However, studies that examine the clinical outcomes of these novel agents and the impact of the number of HRA on prognosis of newly diagnosed multiple myeloma (NDMM) patients are still insufficient in a real-world setting.
Aim：
This study aims to evaluate the clinical outcomes of novel agents and the impact of the number of HRA on the prognosis of NDMM patients.
Methods：
Clinical data from Sun Yat-Sen University Cancer Center and six other hospitals were retrospectively analyzed for 734 NDMM patients between 2016 and 2023. Among the patients, 134 received daratumumab-based regimens, 337 received IMiD plus proteasome inhibitor (PI) regimens, and 263 received regimens based on either IMiDs or PIs. There were 327 patients without high-risk abnormalities (HRA), 156 with one HRA, and 46 with two or more HRA. In our study, 129 patients had 1q21 gain/amplification (1q21+) only, 19 had both 1q21+ and t(4;14), and 14 had both 1q21+ and t(14;16).
Results：
The median overall survival (OS) was 70 months (95% CI: 58-NR) for patients who received PI plus IMiDs, not reached for patients who received CD38 monoclonal antibody-based regimens, and 67 months (95% CI: 52-NR) for patients who received either IMiDs or PI. Patients in the IMiDs plus PI group (P=0.0424) and the CD38 group (P=0.0051) exhibited significantly better OS compared to those in the IMiDs or PI group. There was no significant difference in OS between the CD38 group and the IMiDs plus PI group. The median progression-free survival (PFS) was 54 months (95% CI: 43-NR) for the IMiDs plus PI group, 44 months (95% CI: 44-NR) for the CD38 group, and 44 months (95% CI: 38-54) for the IMiDs or PI group. Similar to the OS trend, significantly superior PFS was observed in patients who received the CD38 monoclonal antibody (P=0.0012) or IMiDs plus PI (P=0.0377) compared to those who received either IMiDs or PI alone. Additionally, there was a trend towards improved PFS in the CD38 group compared to the IMiDs plus PI group (P=0.0507).
Patients without HRA had significantly superior OS and PFS compared to those with one HRA and those with two or more HRA (P&lt;0.01). Additionally, having two HRA was associated with a worse OS outcome compared to having one HRA (P=0.0368). There was also a trend towards inferior PFS for patients with two HRA compared to those with one HRA (P=0.0787). We also found that transplantation, achieving minimal residual disease (MRD) negativity, and using a CD38 monoclonal antibody only partially mitigated the poor prognosis associated with HRA.
Patients with 1q21+ only had significantly better OS compared to those with 1q21+ and either 17p- (P=0.0112) or t(4;14) (P=0.0072). Similarly, patients with 1q21+ only had significantly better PFS compared to those with 1q21+ and 17p- (P=0.0145), and there was a trend towards improved PFS compared to those with 1q21+ and t(4;14) (P=0.0786).
Conclusion：
A total of 734 patients were included in this study. Patients treated with either a CD38 monoclonal antibody or a combination of IMiDs and PI had significantly better OS and PFS compared to those receiving IMiDs or PI alone. The CD38 monoclonal antibody also provided a PFS advantage over the IMiDs plus PI combination. HRA conferred a worse prognosis than no HRA, and having two HRA conferred a worse prognosis than having one. Patients with two or more HRA had an extremely poor prognosis and should be considered ultra-high risk in multiple myeloma. The CD38 monoclonal antibody, transplantation, and achieving MRD negativity only partially mitigated the poor prognosis in patients with HRA. Additionally, patients with 1q21 gain/amplification (1q21+) only had a significantly worse prognosis compared to those without HRA, and those with 1q21+ plus del17p or t(4;14) had an even worse prognosis compared to those with 1q21+ alone.