Orlowski, Robert Z.

AbstractThe role of high-dose therapy followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional chemotherapy to newer regimens incorporating the immunomodulatory derivatives thalidomide or lenalidomide and the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various doublet, triplet, and quadruplet regimens. Up-front use of these induction treatments, in particular 3-drug combinations, has affected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the depth of response, a gain that translates into extended progression-free survival and, potentially, overall survival. High activity shown by immunomodulatory derivatives and bortezomib before ASCT has recently led to their use as consolidation and maintenance therapies after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This article reviews the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current management of younger, transplantation-eligible MM patients.

Abstract It is essential that there be consistency in the conduct, analysis, and reporting of clinical trial results in myeloma. The goal of the International Myeloma Workshop Consensus Panel 1 was to develop a set of guidelines for the uniform reporting of clinical trial results in myeloma. This paper provides a summary of the current response criteria in myeloma, detailed definitions for patient populations, lines of therapy, and specific endpoints. We propose that future clinical trials in myeloma follow the guidelines for reporting results proposed in this manuscript.

Abstract Purpose: Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib. Experimental Design: In a phase 1 trial evaluating the safety and efficacy of carfilzomib in relapsed or refractory hematologic malignancies, eight dose groups of three to six patients received 5 consecutive days of carfilzomib i.v. push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, and 20 mg/m2 within 14-day cycles. Results: Twenty-nine patients enrolled that were relapsed or refractory after at least two prior therapies. Nonhematologic toxicities included fatigue, nausea, and diarrhea in more than one third of patientsmostly grade 1 or 2 in severity. At 20 mg/m2, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses 11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenstrm's macroglobulinemia). Conclusion: This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologic malignancies using consecutive-day dosing. (Clin Cancer Res 2009;15(22):708591)

Purpose To update the recommendations for the use of bisphosphonates in the prevention and treatment of bone disease in multiple myeloma. The Update Committee expanded the guideline to include a discussion of osteonecrosis of the jaw (ONJ). Methods For the 2007 update, an Update Committee composed of members from the full panel completed a review and analysis of data published since 2002. Searches of Medline and the Cochrane Collaboration Library databases were performed. Recommendations For multiple myeloma patients who have, on plain radiograph(s) or imaging studies, lytic destruction of bone or spine compression fracture from osteopenia, intravenous pamidronate 90 mg delivered over at least 2 hours or zoledronic acid 4 mg delivered over at least 15 minutes every 3 to 4 weeks is recommended. Clodronate is an alternative bisphosphonate approved worldwide, except in the United States, for oral or intravenous administration. New dosing guidelines for patients with pre-existing renal impairment were added to the zoledronic acid package insert. Although no similar dosing guidelines are available for pamidronate, the Update Committee recommends that clinicians consider reducing the initial pamidronate dose in patients with pre-existing renal impairment. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended in this setting. The Update Committee suggests that bisphosphonate treatment continue for a period of 2 years. At 2 years, physicians should seriously consider discontinuing bisphosphonates in patients with responsive or stable disease, but further use is at the discretion of the treating physician. The Update Committee also discusses measures regarding ONJ.