Excerpt

Multiple myeloma is a progressive, debilitating malignancy characterized by the proliferation and accumulation of cancerous plasma cells and the overabundance of monoclonal paraprotein. It is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures is common, as well as anemia, hypercalcemia, and kidney dysfunction. Although treatable, multiple myeloma is considered incurable and accounts for approximately 2 percent of all cancer deaths.¹ Historically, intermittent oral melphalan and prednisone (MP) was standard therapy for untreated symptomatic multiple myeloma. In more recent years, newer combination chemotherapy regimens have been used both as initial first-line chemotherapy and as salvage chemotherapy, with better response rates but little effect on overall survival.

Example combination chemotherapy programs include VBCMP (vincristine, carmustine, cyclophosphamide, melphalan, and prednisone) and VAD (vincristine, doxorubicin, and dexamethasone). There is a survival benefit when patients responding to chemotherapy such as VAD are treated with high dose chemotherapy plus single or double autologous stem cell transplantation. Nonetheless, over 80 percent of patients still relapse within 7 years. Treatment programs that include transplantation have limited applicability due to toxicity and associated age, performance status, and organ function requirements. Nearly all patients with multiple myeloma will eventually relapse and become resistant to further treatment. Median survival remains approximately 4 years.

Thalidomide, a glutamic acid derivative, was used as sedative in the late 1950s until it was withdrawn from the market because it caused severe birth defects. Thalidomide’s anti-angiogenic properties were appreciated in the 1990s and because bone marrow angiogenesis plays a substantial role in the development of multiple myeloma, thalidomide has been tried in multiple myeloma. Since the first publication documenting objective responses with thalidomide in patients with refractory myeloma was published in 1999, there has been a rapid proliferation of published and abstract reports on the use of thalidomide in multiple myeloma. In 1998, the Food and Drug Administration (FDA) approved thalidomide for use in treating leprosy (Hansen’s disease); it is not currently FDA-approved for multiple myeloma. Thalidomide can only be prescribed under the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) program, patented by Celgene Corporation.

The key questions for this review were developed with experts in the field of oncology, health economics, and health policy. The key questions are as follows:

1. For patients with relapsed or refractory multiple myeloma, what is the effect of thalidomide compared to standard chemotherapy regimens (e.g., VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone) and VAD (vincristine, doxorubicin, and dexamethasone)) on 2-year survival, disease-free survival, CR, PR (m-protein), and quality of life?
2. For patients with relapsed or refractory multiple myeloma, what is the effect of thalidomide compared to standard chemotherapy regimens (e.g., VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone) and VAD (vincristine, doxorubicin, dexamethasone)) on adverse effects, tolerability, and compliance?
3. What patient or tumor characteristics distinguish treatment responders from non-responders and have potential to be used to target therapy?

As there was emerging information regarding the role of thalidomide for newly diagnosed and smoldering multiple myeloma, these groups were also considered as part of this review.

Contents

• Executive Summary
• Introduction
  • Policy Context of the Current Technology Assessment
  • Clinical Context of the Current Technology Assessment
  • The Technology
  • Scope and Key Questions
• Methods
  • Search Strategy
  • Selection Criteria
  • Data Abstraction
  • Quality Assessment
  • Data Synthesis
• Results
  • Results
• Discussion
  • Current State of Clinical Use
  • Implications for Future Research
• References
• Included Articles
• Excluded Articles
• Appendix A MEDLINE Search Strategy
• Appendix B Quality Criteria

This report is based on research conducted by the Duke Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0025). The findings and conclusions in this document are those of the author(s) who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or of the U.S. Department of Health and Human Services.

The information in this report is intended to help health care decision-makers; patients and clinicians, health system leaders, and policymakers, make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients.

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.