Introduction: Secondary primary malignancies (SPM) are an emerging issue in patients with multiple myeloma (MM) since the French IFM 99-02 trial has been closed as a consequence of a higher incidence of SPM in patients who had received lenalidomide as maintenance treatment compared to the patients in the placebo arm.
Methods: To evaluate the incidence of SPM in the group of patients, who were treated with high-dose therapy (HDT) followed by autologous peripheral blood stem cell transplantation (PBSCT), we retrospectively looked at a homogeneous group of 313 consecutive patients, who were diagnosed with MM and had received HDT and autologous PBSCT at our hospital between December 1994 and January 2009. Induction treatment consisted of conventional chemotherapy without novel agents in 95% of patients and maintenance treatment was given with interferon or thalidomide in 37% und 35% of patients, respectively.
Results:Within 313 patients with a median age of 55 (range: 31-74) years at diagnosis, we observed 18 (5.8%) patients who developed a SPM at various time points during the course of their disease. The number of patients who developed a solid neoplasm or a hematologic malignancy was identical. While the types of solid tumor observed varied greatly, we noted 8 patients with MDS/AML and only one patient with Hodgkins Disease. The median time from diagnosis of MM to the occurrence of SPM was 56 months (range: 14-127). The cumulative incidence of SPM was 19.7% with a rate of 0.7%, 5.8% and 15.7% at 2, 5 and 10 years after diagnosis without statistical differences between the group of patients with solid tumors (0.3%, 4.4%, 7.5%) and those with hematologic malignancies (0.4%, 1.8%, 9.3%). OS from the time of diagnosis in our group of 18 patients with SPM was not significantly different from that of patients without SPM with in median 70 and 83 months (p=0.7, HR 0.9 (0.5-1.7)), respectively. The same was true, when a landmark analysis was performed for patients alive after 2, 5 and 8 years with hazard ratios of 0.9 (95%CI 0.5–1.7, p=0.8), 0.6 (95%CI 0.3–1.4, p=0.2) and 1.0 (95%CI 0.2–4.3, p=1.0), respectively. In line with this finding, we found that survival time of more than 5 years from the time of diagnosis was the only prognostic parameter indicating a greater risk for the development of SPM (HR 4.7 (95%CI 1.1-19.8), p=0.04). In particular, we did not find any relationship to the incidence of SPM and the treatment with novel agents. The incidence rate of 206 patients, who were exposed to thalidomide was 6% (n=13, HR1.4 (95%CI 0.5-4.0), p=0.5), while of the 123 patients exposed to bortezomib 5 developed a SPM (4%, HR 0.4 (95%CI 0.1-1.1), p=0.1). There were two cases of SPM among the 71 patients following lenalidomide treatment (3%, HR 0.4 (95%CI 0.1-1.5), p=0.2). Having a closer look at the maintenance setting, which is associated with a longer duration of drug exposure, we did not find a higher incidence of SPM in patients treated with thalidomide maintenance after HDT in comparison to patients who had received interferon or no maintenance therapy (HR 1.0, 95%CI 0.3 – 3.2, p=1.0).
Conclusions: In conclusion, the incidence of SPM in patients with MM treated with HDT is increased, especially for patients with a prolonged life span. SPM were not related to various treatment modalities including maintenance treatment with thalidomide. As a consequence on the available data, physicians should be aware of the risk of SPM and diagnostic measures to detect SPM should be included in the daily clinical workup of patients with MM.