Changing Trends in the Risk Factors of Secondary Primary Malignancies after Autologous Stem Cell Transplantation for Multiple Myeloma before and after the Introduction of Proteasome Inhibitors/Immunomodulatory Agents
Authors: Takamatsu Hiroyuki , Mizuno Shohei , Takahashi Tsutomu , Fuchida Shin-Ichi , Hanamura Ichiro , Nakamura Fumihiko , Mori Takehiko , Katayama Yuta , Doki Noriko , Tsukada Nobuhiro , Ichinohe Tatsuo , Kanda Yoshinobu , Atsuta Yoshiko , Sunami Kazutaka 
Published: November 2019

Background: Autologous stem cell transplantation (ASCT) combined with novel therapeutic drugs, including proteasome inhibitors (PIs)/immunomodulatory agents (IMiDs), can substantially improve the prognosis of patients with multiple myeloma (MM). Because MM patients survive longer, the incidence of secondary primary malignancies (SPMs) in long-term survivors is increasing. To date, only few studies have evaluated SPMs in real-world patients, particularly in those with MM in Asia.
Aims: To analyze the risk factors of SPMs in MM patients after ASCT before and after the introduction of PIs/IMiDs.
Methods: In this retrospective observational study, data from the Registry of the Japan Society for Hematopoietic Cell Transplantation were collected and analyzed. A total of 2340 newly diagnosed MM patients who underwent ASCT between 1993 and 2016 were enrolled in this study. Median age 58 at ASCT (range 22-72); males 1329 (56.8%), females 1011 (43.2%); IgG 1340 (57.3%), IgA 452 (19.3%), IgD 63 (2.7%), IgE 3 (0.1%), IgM 6 (0.3%), BJP 416 (17.8%), non-secreting 38 (1.6%), unknown 22 (0.9%); ISS1 774 (33.1%), ISS2 825 (35.3%), ISS3 455 (19.4%), not assessed 286 (12.2%). 1908 (81.5%) and 432 (18.5%) patients received single melphalan 200 mg/sqm (Mel200) and double Mel200, respectively as conditioning regimen before ASCT. Moreover, 771 (32.9%) and 1569 (67.1%) patients underwent ASCT from 1993 to 2006 and from 2007 to 2016, respectively. 659 (28.2%) patients received PIs, 73 (3.1%) IMiDs and 903 (38.6%) both PIs and IMiDs. Meanwhile, 38 (1.6%) patients received radiation treatment. The disease status at ASCT was as follows: 690 (29.5%), sCR/CR; 580 (24.8%), VGPR; 831 (35.5%), PR; 144 (6.2%), SD; 50 (2.1%), PD; and 45 (1.9%), unknown.
Results: The median follow-up from ASCT was 24 (range: 0-218) months. A total of 38 patients in this cohort developed SPMs, with a cumulative incidence of 0.8% [95% confidence interval (CI): 0.4%-1.2%] and 2.4% (95% CI: 1.6%-3.5%) at 24 and 60 months, respectively. Twenty-four solid (4, stomach; 3, breast; 5, lung; 2, liver; 2, pancreas; 2, colon; 1, uterus; 1, thyroid gland; 1, bladder; 2, sarcoma; and 1, basal cell carcinoma), 11 hematologic (7, myelodysplastic syndrome; 1, acute leukemia; 2, lymphoma; and 1, unknown), and 3 unknown tumors were observed. The cumulative incidence of hematologic and solid SPMs at 60 months was 0.8% and 1.7%, respectively. OS at 60 months after ASCT was 62.9%, and OS after the diagnosis of SPMs at 24 months was 70.7% for hematologic and 64.6% for solid SPMs (median follow-up of 23 months). Next, the risk factors affecting the incidence of SPMs were analyzed, which included age at ASCT (≤65 or >65 years), sex, PI/IMiD treatment, use of radiation, single/double ASCT, and period of ASCT (1993-2006 or 2007-2016). Because bortezomib, thalidomide, and lenalidomide were released for relapse/refractory MM treatment in Japan in December 2006, February 2009, and July 2010, respectively, we categorized the patients into two treatment cohorts: pre-novel agent era (1993-2006) and novel agent era (2007-2016). Univariate analysis showed that the novel agent era (1.7% vs 4.3% at 60 months; P = 0.013; Fig. 1) and use of radiation (2.3% vs 9.5% at 60 months; P = 0.027) were significant independent risk factors for SPMs. Multivariate analysis revealed that the use of radiation [hazard ratio (HR): 3.895; 95% CI: 1.163-13.050; P = 0.027] was a significant, independent risk factor for SPMs. The novel agent era (HR: 1.716; 95% CI: 0.857-3.438; P = 0.13) and IMiD without PI treatment (HR: 2.206; 95% CI: 0.787-6.189; P = 0.13) were likely high-risk factors for SPMs. In contrast, PI without IMiD treatment (P = 0.79) was not a risk factor for SPMs. The probabilities of developing SPMs and death due to other causes (mainly MM) at 60 months were 2.4% and 36.5% (Fig. 1), respectively, indicating that the risk for SPMs was lower than that for death from MM. Furthermore, OS between the pre-novel and novel agent era groups significantly improved (59.2% vs. 69.5%, P < 0.0001) at 60 months after ASCT.
Conclusions: The incidence of SPMs in patients with MM in Japan was consistent with that reported recently (Sahebi et al. BBMT, 2018). Although the risk for SPMs increased in the novel agent era group, the mortality rate of SPMs was lower than that of other causes (primarily MM). Considering the increase in the number of long-term survivors with MM, the early occurrence of SPMs should be cautiously monitored.

Disclosures
Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; Ono pharmaceutical: Honoraria, Research Funding; CSL Behring: Research Funding; SRL: Consultancy, Research Funding; Daiichi-Sankyo Company: Honoraria; Becton, Dickinson and Company: Honoraria; Sanofi: Consultancy, Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Fujimoto Pharmaceutical: Honoraria; Janssen Pharmaceutical: Consultancy, Honoraria; Abbvie: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Mizuno:Takeda Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb Corporation: Honoraria; Celgene Corporation: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Fuchida:Japan Blood Products Organization: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Daiichi-Sankyo Company: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Ono pharmaceutical: Honoraria; Kyowa Kirin: Honoraria; SEKISUI MEDICAL CO., LTD.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria. Hanamura:Asai Clinic: Research Funding; Yamada Yohojo: Research Funding; AbbVie: Honoraria; Chugai: Research Funding; Eli Lilly: Research Funding; Taiho: Research Funding; Sanofi: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Pfizer: Honoraria, Research Funding; Eisai: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Fukuyu Hospital: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Nihon Shinyaku: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Shionogi: Honoraria, Research Funding; Fujimoto: Research Funding; MSD: Research Funding; Zenyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Mundi: Honoraria. Nakamura:Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited: Research Funding; Eisai Co. Ltd.: Honoraria; Kyowa Kirin: Research Funding. Mori:Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical: Honoraria; Novartis Pharma K.K: Honoraria. Tsukada:Chugai Pharmaceutical Co.,Ltd: Honoraria; Kyowa Kirin: Honoraria; Celgene: Honoraria; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; MOCHIDA PHARMACEUTICAL CO., LTD.: Honoraria; Asahi Kasei Pharma Corporation: Honoraria; Ohtsuka Pharmaceutical: Honoraria; Fujimoto Pharmaceutical: Honoraria. Ichinohe:Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria. Kanda:Pfizer: Research Funding; Novartis: Research Funding; Mochida: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Nippon-Shinyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Tanabe Mitsubishi: Research Funding; Novartis: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria; Tanabe Mitsubishi: Research Funding; Asahi-Kasei: Research Funding; MSD: Research Funding; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Mochida: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Research Funding; CSL Behring: Research Funding; MSD: Research Funding; Otsuka: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Sanofi: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Sanofi: Research Funding; Taiho: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Celgene: Consultancy, Research Funding; Taiho: Research Funding. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Sunami:Takeda: Honoraria, Research Funding; GSK: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding; Ono: Honoraria, Research Funding; Alexion-pharma: Research Funding; Daiichi Sankyo: Research Funding; MSD: Research Funding; Abbvie: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Research Funding.