Therapeutic and Pathogenetic Advances in Multiple Myeloma

By S. Vincent Rajkumar, M.D.

In the last five years, remarkable progress has been made in the pathogenesis and treatment of myeloma. For example, until 1998 alkylating agents and corticosteroids were the only agents known to have significant single-agent activity in the disease. Since then, thalidomide, bortezomib, and CC-5013 have emerged as active agents and have transformed the therapy of multiple myeloma. For those interested in catching up with the rapid progress in this field, today’s Education Program, Advances In The Biology and Therapy of Multiple Myeloma (2:00 p.m. – 3:45 p.m.) is a must. Several leading experts provide an update on cutting-edge developments in myeloma biology and treatment, and identify novel therapeutic strategies for future trials.

First, Dr. Michael Kuehl presents a new model for the molecular pathogenesis of multiple myeloma.He shows that approximately 50% of myeloma tumors have a primary translocation involving the immunoglobulin heavy chain locus on chromosome 14q32. The 5 recurrent partner chromosomes involved in this translocation include 11q13 (cyclin D1), 4p16.3 (FGFR-3 and MMSET), 6p21 (cyclin D3), 16q23 (C-maf), and 20q11 (mafB). Less frequently, primary translocations may involve the immunoglobulin lambda light chain locus (10-15%). Dr. Kuehl shows that progression of the disease is accompanied by secondary translocations (for example, involving c-myc) or mutations in RAS or other genes. He will also present data that classify myeloma into several molecular subtypes based on cytogenetic and gene array analysis. Finally, he discusses several novel strategies to exploit these developments in the treatment of multiple myeloma.

Next, Dr. Regis Bataille summarizes current data on bone disease in multiple myeloma. The pathogenesis of myeloma bone disease has been a subject of intense investigation over the last decade. Advances in our understanding of this process have revolutionized the treatment of myeloma with the routine use of pamidronate or zoledronic acid to treat myeloma bone disease. Dr. Bataille shows how overexpression of RANKL and inhibition of osteoprotegerin (OPG) are critical steps in increasing osteoclast activity and bone resorption in this disease (increased RANKL/OPG ratio). He also presents data on the role of MIP-1 a and b in simulating the expression of RANKL and consequent enhancement of bone resorption. New therapeutic strategies to prevent and treat bone disease in myeloma, including the role of bisphosphonates, RANKL and MIP-1 inhibitors will also be discussed.

At the same session, Dr. Robert Fenton presents an overview on the apoptotic pathways involved in multiple myeloma. He also will present data on novel targeting the various apoptotic pathways including clinical trials with BCL-2 antisense strategies. Finally, Dr. Bart Barlogie presents the current approach to treatment of multiple myeloma at the University of Arkansas. He summarizes available data on the role of stem cell transplantation, trials comparing single versus tandem transplantation, and therapy for high-risk disease. He sets the stage for several important presentations at tomorrow’s Simultaneous Session Autologous Transplantation: Multiple Myeloma (4:15 p.m. – 5:45 p.m.) that appear to challenge the role of autologous transplants in myeloma. Dr. Barlogie will also cover the recent advances in mini-allogeneic transplantation and indications for the use of several novel agents such as thalidomide, CC-5013, and bortezomib.

For those unable to attend today, the session is repeated tomorrow (7:30 a.m. – 9:15 a.m.).