Risk of Second Primary Malignancies (SPMs) Following Bortezomib (Btz)-Based Therapy: Analysis of Four Phase 3 Randomized Controlled Trials in Previously Untreated or Relapsed Multiple Myeloma (MM)

MM patients have a significantly increased risk of developing certain SPMs subsequent to their initial diagnosis, including a 3.49-fold increased risk of leukemia and, specifically, an 8.32-fold increased risk of acute non-lymphocytic leukemia (but no overall increased risk of solid tumor SPMs; Surveillance, Epidemiology and End Results [SEER] data 1973–2000). The relative SPM risk increases with age and time after initial diagnosis; the risk of leukemia rises from a 1.22-fold increase within 1 year after diagnosis to 3.12-fold, 7.01-fold, and 5.45-fold increases at 1–4, 5–9, and ≥10 years, respectively. An elevated risk of SPMs may be particularly associated with the use of specific therapeutic agents, including conventional or high-dose cytotoxic chemotherapy. Here we report an analysis of data from four phase 3, randomized, controlled trials of Btz alone or in combination to determine whether Btz treatment is associated with an increased SPM risk.

Data were reviewed from: 1) the APEX study of Btz versus high-dose dexamethasone (Dex), and 2) the MMY-3001 study of Btz plus pegylated liposomal doxorubicin (PLD) versus Btz in patients with relapsed or refractory MM after 1–3 prior therapies; 3) the VISTA study of Btz plus melphalan-prednisone (VMP) versus MP in previously untreated transplant-ineligible patients; and 4) the HOVON65/GMMG-HD4 study of Btz, doxorubicin, and Dex (PAD) induction plus Btz maintenance post-transplant versus vincristine, doxorubicin, and Dex (VAD) induction plus thalidomide (Thal) maintenance in previously untreated transplant-eligible patients. Planned duration of Btz therapy was 39 weeks in APEX, 24 weeks in MMY-3001, 54 weeks in VISTA, and 9 weeks induction plus 2 years of maintenance in HOVON65/GMMG-HD4. For APEX, MMY-3001, and VISTA, clinical trial databases were reviewed for events within the MedDRA system organ class of ‘neoplasms’, and new malignancies developing during or after treatment were recorded (excluding non-melanomatous skin cancers and in situ malignancies). In addition, for VISTA, data were obtained from an SPM survey after a median follow-up of 5 years. For HOVON65/GMMG-HD4, data were prospectively collected; median follow-up was 42 months. The incidence rate (IR) of SPMs was expressed as the number per 100 patient-years (pt-yrs).

The risk of SPMs with Btz-based therapy appeared uniformly low across all four phase 3 studies in different MM patient populations (Table). A total of 25 SPMs were seen in 1718 Btz-treated patients, including three cases of acute myeloid leukemia/myelodysplastic syndromes, one B-cell malignancy, and one case of cutaneous T-cell lymphoma (in a patient with substantial prior alkylating agent exposure for treatment of MM), plus 20 reports of solid tumors (reflecting the higher overall incidence of these tumors). The IR ranged from 0 in the single-agent Btz arm of MMY-3001 to 1.66 with VMP in VISTA, with an IR of 0.88 in APEX and 0.3 in the PAD arm of HOVON65/GMMG-HD4; median age of Btz-treated patients was highest in VISTA, at 71 years. Overall rates (%) also appeared higher in VISTA, probably due to the longer follow-up and older population, plus the potential effects of concomitant chemotherapy. In the three studies with non-Btz control arms, the IR did not appear to be increased with Btz-based therapy versus the control arm, and across all Btz-containing arms in the four studies, the IRs for hematologic malignancies and solid tumors were consistent with SEER estimates (2004–2008 data) of the overall incidence of malignancies in the US population, of 1.1, 1.9, and 2.4 per 100 pt-yrs in individuals aged 55–64, 65–74, and 75–84 years, respectively.

Btz-based therapy for MM does not appear to be associated with an increased risk of either hematologic or solid tumor SPMs, with IRs consistent with SEER data for IRs in the overall US population.

San Miguel:Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc: Consultancy. Richardson:Celgene: Consultancy; Janssen Research & Development: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy. Orlowski:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Novartis: Consultancy; Onyx: Consultancy; Cephalon: Consultancy; Centocor: Consultancy; Celgene: Consultancy, Research Funding. Goldschmidt:Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy. Corzo:Millennium Pharmaceuticals, Inc.: Employment. Satler:Millennium Pharmaceuticals, Inc.: Employment. Esseltine:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership; Johnson & Johnson: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Ponsillo:Millennium Pharmaceuticals, Inc.: Employment. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. King:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Deraedt:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Desai:Janssen Global Services: Employment; Johnson & Johnson: Equity Ownership. Lutska:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Gifkins:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Liu:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership.