Use of melphalan (M)/dexamethasone (D)/bortezomib in AL amyloidosis.
Authors: C. Gasparetto, V. Sanchorawala, R. M. Snyder, J. Matous, H. R. Terebelo, N. Janakiraman, M. Y. Mapara, C. Webb, J. Abrams, J. A. Zonder
Journal: Journal of Clinical Oncology (2010)

8024^ Background: AL amyloidosis is a monoclonal plasma cell disorder with progressive organ dysfunction and short survival. Standard non-transplant AL therapy is melphalan (M) + dexamethasone (D). As adding bortezomib (Bz) to M+ Prednisone improved outcomes in myeloma, we sought to determine if adding Bz to MD improves outcomes in AL. Methods: Eligibility: ECOG PS ≤ 3, Cr ≤ 5 mg/dL, T.Bili ≤ 2.5 × IULN, ALT/AST ≤ 3 × IULN, ANC ≥ 1.0 K/mm3, PLT ≥ 80 K/mm3, peripheral neuropathy (PN) ≤ Gr 2 (≤ 1 if painful), no lower limit for LVEF. Design: Two-stage phase II study. Stage I: 16 pts with biopsy-proven AL, light chain deposition disease (LCDD) or smoldering myeloma with amyloid (SMM). 1o endpoint: complete hematologic responses (cHR). If ≥5 cHRs observed, then 2nd stage with 17 more pts, giving 90% power to detect a true cHR rate of 50%. 2o endpoints: overall HR, organ response (OrR), and survival. Therapy: M (9 mg/m2 PO d 1-4; 6 mg/m2 if Cr > 2.5 mg/dL), Bz (1.3 mg/m2 IV d 1, 8, 15, 22; 1.0 mg/m2 if baseline PN) and D (40 mg PO/IV days of /after Bz; 20 mg if ≥ 70 yrs, edema, or CHF) in 4-6 wk cycles. PN assessed with the FACT/GOG-Ntx survey. Results: 30 pts enrolled (26 AL, 2 LCDD, 2 SMM). Med age: 65 (range: 47-83). Med # prior Rx: 1 (range: 0-4; 9 with prior ASCT). Tn-BNP stage 1/2/3: 11/9/10. PS 0-1/2-3: 27/3. Here, we update response data for the 16 pts comprising stage 1 of this study. One pt not evaluable for HR included in toxicity data (n=17). Med F/U: 10.6 mos. Med # cycles: 6 (range 3-17; 4 pts still on treatment). 15 pts had HR (9 cHR). Med # cycles to best response: 3 (range 2-9). 2/10 pts with cardiac AL had OrR. 7/8 pts with renal AL had ≥25% decrease in proteinuria. Abnormal FACT-GOG-Ntx Sensory/Dysfunction scores improved by cycle 4 in 6/12 pts. Two pts died (after 1 and 4.5 mos, from PD and pneumonia, respectively), and 1 stopped due to PN. Despite baseline dose adjustments, 12 pts needed further reductions of ≥ 1 study meds during therapy (10 Bz). Gr 3-4 heme AEs: ANC (2), PLTs (12). Gr 3-4 non-heme AEs (in ≥2 pts): edema (6), fatigue (4), infection (4), syncope (3), PN (3), SVT (2), dehydration (2), renal failure (3). Reversible cardiomyopathy attributed to Bz in 1 pt (cycle 8). Conclusions: MD-Bz is active vs AL: 94% HR (56% cHR). Toxicity is manageable with baseline/subsequent drug adjustments. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cepahlon, Millennium Cepahlon, Millennium Celgene, Facet Oncology, Johnson & Johnson, Millennium 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.