Large registry analysis to accurately define second malignancy rates and risks in a well-characterized cohort of 744 consecutive multiple myeloma patients followed-up for 25 years

Abstract

Additional malignancies in multiple myeloma patients after first-line and maintenance treatment have been observed, questioning whether specific risks exist. Second primary malignancies have also gained attention since randomized data showed associations to newer drugs. We have conducted this large registry analysis in 744 consecutive patients and analyzed: 1) frequency and onset of additional malignancies; and 2) second primary malignancy- and myeloma-specific risks. We assessed the frequency of additional malignancies in terms of host-, myeloma- and treatment-specific characteristics. To compare these risks, we estimated cumulative incidence rates for second malignancies and myeloma with Fine and Gray regression models taking into account competing risks. Additional malignancies were found in 118 patients: prior or synchronous malignancies in 63% and subsequent in 37%. Cumulative incidence rates for second malignancies were increased in IgG-myeloma and decreased in bortezomib-treated patients (P<0.05). Cumulative incidence rates for myeloma death were increased with higher stage and age, but decreased in IgG-subtypes and due to anti-myeloma treatment (P<0.05). Cytogenetics in patients acquiring second primary malignancies were predominantly favorable, suggesting that indolent myeloma and long disease latency may allow the manifestation of additional malignancies. An assessment of the Surveillance, Epidemiology, and End Result Program of the National Cancer Institute and our data with long-term follow up of 25 years confirmed a prevalence of second malignancy of 10% at 25 years, whereas death from myeloma decreased from 90% to 83%, respectively. Our important findings widen our knowledge of second malignancies and show that they are of increasing relevance as the prognosis in myeloma improves and mortality rates decrease.

Figure 1.

Total of additional malignancies in myeloma patients: overview prior/synchronous (p/s) malignancies versus SPM and p/s versus SPM frequencies in hematologic-, solid- and skin-tumor entities. Hematologic malignancies occurred more frequently as SPM than p/s malignancies (albeit lymphomas were also frequent as p/s malignancies. Frequent solid tumors were colorectal, gynecological/urothelial and prostate cancer. Except for colorectal cancer, these all occurred more frequently p/s to the myeloma. Skin tumors, such as melanoma and basal-cell carcinomas, also occurred more often p/s to the myeloma, with basal-cell carcinomas appearing as SPM as well.

Figure 2.

Cumulative incidence rates for developing SPM for disease-, host- and treatment-specific factors. For second primary malignancies (SPM), cumulative incidence rates were increased in IgG myeloma (A), males (B), advanced Durie & Salmon stage (C) and in lenalidomide-treated patients (D). Age ≥65 years (E), anthracyclines (F), alkylators (G) and radiation (H) did not increase SPM. A decrease in SPM was noted with bortezomib (I) and thalidomide (J), the former (bortezomib) confirming prior retrospective analyses.^,

Figure 3.

Cumulative incidence rates for death from myeloma for disease-, host- and treatment-specific factors. Conversely, cumulative incidence rates of death from myeloma showed significant increases for advanced Durie&Salmon stages (A), patients ≥65 years (B) and thalidomide exposure (C), no increase with regard to alkylators (D) and sex (E) and decreases for IgG-myelomas (F) and in lenalidomide- (G), anthracycline- (H), bortezomib- (I) and with radiation (J) treated patients.

Figure 4.

Cumulative incidence rates of developing secondary primary malignancy (SPM) and death from causes other than second cancer. (A) Cumulative incidence rates of developing SPM and of death from all other causes (excluding second cancers): data based on 33,229 patients who received a diagnosis of myeloma, between 1973 and 2008 in the United States were taken from the Surveillance, Epidemiology, and End Result Program of the National Cancer Institute (SEER), showing incidence rates of 8% and 90% at 25 years, respectively. (B) Compared to these SEER data, cumulative incidence rates from our registry analysis involving 744 patients diagnosed with myeloma between 1997 and 2011 was 11.2% for SPM and 83% for death from causes other than second cancer at 25 years. This confirmed the cumulative incidence rate of second cancers after 25 years of approximately 10%, but also revealed that due to substantial advances in myeloma treatment, the risk of death is declining. This demonstrates that the development of second cancer in myeloma remains substantially lower than the risk of death from multiple myeloma, but that both curves detectably converge.