Author(s): D. E. Joshua, J. Bashford, J. Szer, N. Horvath, A. Spencer, M. S. Hertzberg, E. Ashurst, J. Wade, M. C. Copeman, H. M. Prince
Background: Chromosome 1q21 is amplified in 40% of myeloma and linked to lower response to single-agent bortezomib (Drach J. 2006). A retrospective analysis in patients with relapsed myeloma suggests that bortezomib-based combinations may overcome the negative prognosis of 1q21 (Sagaster V. 2007). Thus, a prospective trial was designed to assess the effect of 1q21 on response to PAD (PS341/bortezomib, doxorubicin, and dexamethasone) therapy in newly-diagnosed myeloma.
Methods: We conducted a multi-center, Phase II trial in 108 newly-diagnosed transplant-eligible myeloma patients. The primary endpoint was overall response rate (ORR; classified by IMWG uniform disease response criteria) after 4-cycles of PAD, stratified by baseline 1q21 by FISH (fluorescence in situ hybridisation). Patients were prescribed four 21-day cycles of PAD (bortezomib 1.3 mg/m2 on Days (D) 1,4,8 and 11; doxorubicin 20 mg/m2 on D1 and 4; and dexamethasone 20 mg on D1,2,4,5,8,9,11 and 12). Responding patients could proceed to stem cell harvest, high-dose melphalan (200 mg/m2) and autologous stem cell transplantation according to institutional protocols.
Results: Interim review (Dec 2009) of the first 32 of 108 patients enrolled showed ORR 97% (31/32), with 12.5% (4/32) stringent complete responses. No patient had progressive disease during PAD. Among the 24 of 32 patients evaluable for1q21, there was no difference in ORR between those with (7/7) compared to those without 1q21 amplification (16/17). By interim safety review (Dec 2009) 2 of 108 patients had died during PAD therapy (cardiac arrest and pulmonary embolus). Four others discontinued PAD early with painful neuropathy, dizziness, weakness and Sweet syndrome. Three further patients had severe adverse events considered related to PAD therapy: neutropenia, peripheral sensory neuropathy, and thrombocytopenia.
Conclusions: Preliminary results suggest that PAD induction therapy in front-line transplant-eligible myeloma may overcome bortezomib resistance associated with 1q21 amplification. Final data on overall response, stratified by 1q21 amplification, and safety of this PAD induction regimen will have adequate power to answer this question.