Development of Effective New Treatments for Multiple Myeloma

Abstract

Despite recent advances in basic biology and treatment, multiple myeloma remains incurable, and the need to develop effective new treatments remains urgent. The focused development of effective treatments for myeloma requires cooperation between patients, the US Food and Drug Administration, pharmaceutical sponsors, researchers working in both government and academia, and practicing oncologists. With approximately 50,000 people alive with myeloma annually in the United States, multiple myeloma represents a relatively small market compared with other oncology indications and areas such as cardiovascular disease. For this reason, pharmaceutical developers may be less apt to take on the full burden and risk of developing new drugs for this disease. Despite this limitation, multiple myeloma represents a unique and attractive opportunity for expedited new drug development for five reasons. First, there is a clear unmet medical need in myeloma. Second, the clinical end points for rapid new drug approval in myeloma have been clearly identified and can be measured using commercially available laboratory and radiologic tests. Third, the US Food and Drug Administration has identified response rate with substantial duration as a valid end point for regulatory approval of new myeloma agents under accelerated approval (AA; subpart H). Under these provisions, drugs used in serious and life-threatening diseases may be approved if they demonstrate an improvement over available therapy on the basis of a surrogate end point “reasonably likely to predict clinical benefit.” Subsequent randomized trials demonstrating clinical benefit are required after AA. The clinical profile of bortezomib (recently approved for the treatment of patients with relapsed and refractory myeloma), including an overall response rate 28%, with a complete response rate 3% and a median response duration of 12 months in patients refractory to all available treatments, has been accepted by US Food and Drug Administration as surrogate evidence deemed reasonably likely to predict clinical benefit and, therefore, as meeting criteria for AA. Fourth, for the approval of bortezomib, the US Food and Drug Administration accepted the criteria of the European Group for Blood and Marrow Transplant (EBMT), as set forth by Blade et al, for the definition of response in patients with myeloma. The EBMT criteria are now widely accepted as the standard criteria for the definition of complete and partial remission. Fifth, the determination of response according to the EBMT criteria depends on the measurement of the levels of myeloma protein (M-protein) in serum and urine. This assay is available in commercial laboratories and can be performed reproducibly using widely available laboratory techniques. Additional components of the EBMT criteria include the percentage of plasma cells in the bone marrow and the absence of evidence of new skeletal disease by conventional x-ray. These aspects of the EBMT criteria can also be measured easily and reproducibly. To address current challenges related to new myeloma drug development, a roundtable symposium, including members of From the Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA; and Office of Oncology Drug Products and Division of Oncology Drug Products, US Food and Drug Administration, Rockville, MD.