Response of newly diagnosed myeloma with 1q21 amplification to bortezomib-based PAD induction therapy.
Authors: D. E. Joshua, J. Bashford, J. Szer, N. Horvath, A. Spencer, M. S. Hertzberg, E. Ashurst, J. Wade, M. C. Copeman, H. M. Prince
Journal: Journal of Clinical Oncology (2010)

8028^ 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. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Janssen-Cilag Janssen-Cilag Johnson & Johnson Janssen-Cilag Janssen-Cilag In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.