Survival Outcome of Salvage Therapy with Second-Generation Novel Agents in Patients with Relapsed and Refractory Multiple Myeloma in Routine Clinical Practice
Authors: Ozaki Shuji , Harada Takeshi , Udaka Kengo , Sekimoto Etsuko , Shibata Hironobu , Shigekiyo Toshio , Yagi Hikaru , Okamoto Yasunobu , Sogabe Kimiko , Oura Masahiro , Fujii Shiro , Nakamura Shingen , Miki Hirokazu , Kagawa Kumiko , Abe Masahiro 
Published: October 2019

Abstract
Survival outcome of patients with multiple myeloma (MM) has been markedly improved by the introduction of novel agents such as bortezomib, thalidomide, and lenalidomide over the past decade. Recent clinical studies have shown further improvement by second-generation agents, namely carfilzomib, ixazomib, pomalidomide, elotuzumab, and daratumumab. However, the prognosis of patients who became refractory to both bortezomib and lenalidomide was extremely poor, and the efficacy of the second-generation agents in such patient remains unclear in routine clinical practice. In this study, we analyzed the outcome of MM patients in terms of overall survival (OS) and survival time after salvage therapy. A total of 174 patients (89 male and 85 female) treated between 2003 and 2017 were enrolled. The median age was 69 years old (range 35-89). The type of M protein was IgG in 93, IgA in 35, IgD in 10, Bence Jones type in 30, and non-secretory type in 5 patients, respectively. The international staging system (ISS) stages I, II, and III were 32, 66, and 63 patients, respectively. There were 100 patients with normal serum LDH and 39 with high LDH. As for initial therapy, 62 patients were treated with conventional chemotherapy, 83 with bortezomib-based regimens, 7 with lenalidomide-based regimens, and 22 with bortezomib + lenalidomide + dexamethasone. Forty-seven patients received autologous stem cell transplantation in the upfront setting. During the observation period 120 patients relapsed and 6 were refractory to initial therapy, and 38 patients were treated with conventional chemotherapy and 58 with the first-generation novel agents such as bortezomib, lenalidomide, or thalidomide as salvage therapy. The remaining 30 patients were further treated with the second-generation novel agents such as carfilzomib in 21, ixazomib in 5, pomalidomide in 6, elotuzumab in 4, or daratumumab in 8 patients after refractory to bortezomib and lenalidomide. The median progression-free survival was 17.7 months and the median OS was 51.0 months from initial therapy. Regarding the outcome according to salvage therapy, the median OS was 22.0 months for conventional chemotherapy group, 46.4 months for first-generation agent group, and 98.7 months for second-generation agent group (p<0.0001). The survival of the second-generation group was longer compared with the first-generation group in both transplanted (median OS, 80.5 vs 118.3 months) and non-transplanted patients (39.2 vs 56.6 months). In patients who received the first-generation agents as initial therapy, the median OS was 45.1 months for the first-generation group and 71.5 months for the second-generation group. In the survival time after salvage therapy, the median survival was 18.6 months, and there was no significant difference by initial therapy (16.8 months for conventional chemotherapy group and 20.1 months for novel agent group). According to salvage therapy, the median survival after salvage therapy was 7.5 months for conventional chemotherapy group, 20.4 months for first-generation agent group, and 29.5 months for second-generation agent group (p<0.001, Figure). The survival benefit after salvage therapy with the second-generation agents was also observed in both transplanted (median survival after salvage, 29.5 vs 69.8 months) and non-transplanted patients (18.6 vs 23.6 months). In patients who received the first-generation agents as initial therapy, the median survival after salvage was 25.0 months for the first-generation group and 29.5 months for the second-generation group, and again survival time was longer in the second-generation group. Regarding the risk factors, the median survivals after second-generation novel agent therapy were not reached, 69.8, and 14.8 months in the ISS I, II, and III stages, respectively, and were 69.8 and 14.8 months in normal and high LDH groups, respectively. Thus, our results have demonstrated that the second-generation novel agents significantly prolonged survival in relapsed and refractory patients regardless of the use of the first-generation agents. However, the survival benefit was mostly observed in standard risk and transplanted patients but not in high-risk patients. Therefore, further studies are needed to establish more effective strategies using the next generation agents in routine clinical practice.
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Disclosures
No relevant conflicts of interest to declare.