Second Primary Malignancies Among Patients with Multiple Myeloma
Authors: Cutshall Hannah P. , Arnold Kevin D. , Brown Elizabeth E. 
Published: November 2021

Abstract
Introduction. Treatment for multiple myeloma (MM) has undergone significant transformation in the past decade with the introduction of novel therapeutic agents, including proteasome inhibitors (PI), immunomodulatory imides (IMiD) and monoclonal antibodies (mAb), leading to significant improvements in drug tolerability, treatment response and overall survival. As overall survival improves, patients with MM are at increased risk of developing second primary malignancies. Therefore, we evaluated the incidence of second primary malignancies among patients with MM.
Methods. Using data from 30,630 1-year survivors of MM reported to 13 cancer registries that constitute the Surveillance, Epidemiology, and End Results (SEER) program (1992-2015; median survival time, 4.5 years), we calculated standardized incidence ratios (SIR) for all second primary malignancies, any solid and any hematologic malignancy and cancer sites among patients with MM, stratified by calendar year of first primary diagnosis consistent with advances in treatment for MM (1992-1999, 2000-2007, 2008-2015). Individual treatment data were unavailable. Excess absolute risk (excess cancer risk per 10,000 person-years) was calculated as ([observed cancers minus expected cancers]/person-years) multiplied by 10,000. Hazard ratios were calculated using Cox proportional hazards adjusted for confounders. Analyses were conducted using SAS v.9.4.
Results. Overall, among 30,630 1-year survivors of first primary MM, the standardized incidence of any second primary malignancy was significantly increased (n=1,962; SIR=1.15, 95% confidence interval [CI], 1.10-1.20; P&lt;0.0001) and SIRs were elevated in each of the three calendar periods (1992-1999, SIR=1.14; 2000-2007, SIR=1.11; 2008-2015, SIR=1.22). Of all the second primary malignancies, the incidence of any solid tumor was increased (n=1,584; SIR=1.05, 95% CI 0.99-1.10; P=0.09), albeit not significantly, with SIRs for specific solid tumor sites ranging from 0.80 to 2.23. In contrast, the incidence of any hematologic malignancy overall was significantly increased (n=317; SIR=2.28, 95% CI 2.03-2.54; P&lt;0.0001) with the largest SIRs observed for any leukemia (SIR=5.86, 95% CI 4.91-6.94; P=&lt;0.0001) and SIRs for leukemia subtypes ranging from 2.07 to 14.87. The SIR for any lymphoma was also increased but to a lesser extent (SIR=1.57, 95% CI 1.35-1.82; P&lt;0.0001). Notably, SIRs for any leukemia decreased over the three time periods (1992-1999, SIR=6.40; 2000-2007, SIR=5.77; 2008-2015, SIR=5.51) whereas SIRs for any lymphoma increased (1992-1999, SIR=1.21; 2000-2007, SIR=1.60; 2008-2015, SIR=1.81) leading to an excess absolute risk of any hematologic malignancy of 1.5 per 10,000 person-years in the latest calendar period. No differences were observed by sex or ancestry.
Discussion. We confirm that MM patients are at increased risk of second primary malignancies, and particularly other blood cancers. The transposition of leukemia and lymphoma incidence over time may reflect the effect of treatment changes in recent years. Additional studies, which include individual treatment data and longer follow up time from large and diverse populations, are required to further define these relationships.

Disclosures
No relevant conflicts of interest to declare.