By Rafat Abounour, MD
2008-12-06
What a journey it has been for multiple myeloma since the paper by Dr. Michael Rubistein, from the Montefiore Hospital in New York, was published 60 years ago. He investigated antimony compound in patients with multiple myeloma and wrote in the 1947 issue of Blood (2: 555-563) the following: “Multiple myeloma is a neoplastic, infiltrative disease of the bone marrow. The histologic origin of the myeloma cells is still a matter of discussion. It shares with the other neoplastic diseases both the mystery of its origin and the lack of any effective treatment.” Although we do not know the exact origin of myeloma cells, much is known about the pathways that dictate the biology of this disease. Several studies have identified cells expressing the identical immunoglobulin idiotype as the neoplastic plasma cells within the blood and bone marrow of patients that phenotypically display a wide range of B-cell maturation. However, the role of these cells in the pathogenesis of the disease has remained controversial. During the Education session on Plasma Cell Disorders (taking place today at 9:30 a.m and 4:00 p.m. in Halls B and C), Dr. Nikhil Munshi, of the Harvard Medical School, will discuss the significant chromosomal abnormalities that evolve over the disease course. Although virtually all myeloma patients have genomic rearrangement, only one-third of the patients have detectable abnormality at the time of diagnosis. Those patients with t(4;14), t(14;16), part or whole chromosome 13q deletion, and loss of 17p13 carry a poor prognosis, while hyperdiploidy and t(11;14) translocations are associated with better outcome. Gene expression profiling has defined specific pathways important in the multi-step transformation of normal plasma cells to MGUS and multiple myeloma, although appropriate validation is desperately needed. Dr. Munshi will review work by two groups that investigated expression profiles of myeloma cells and identified two different sets of genes that are associated with a high-risk profile. It is intriguing that these two groups did not find a common gene that is associated with a high-risk profile. Dr. Rubistein would say “I told you so”; the biology of myeloma continues to be mysterious.
Myeloma therapy has made huge leaps in the last decade. Dr. Rubistein went back to the periodic table and picked element 51. The natural sulfide of antimony, stibnite, was known and used in Biblical times as medicine, and in Islamic/Pre-Islamic times as a cosmetic. Dr. Rubistein noted that multiple myeloma shares with kala-azar, lymphogranuloma venereum, and schistosomiasis the presence of hyperglobulinemia, and since the latter three diseases responded well to antimony compounds, he started a clinical trial with these compounds in the spring of 1943 to reduce the hyperglobulinemia. Amazingly, he had control of the disease in a couple of patients. During the same education session, Professor Jean-Luc Harousseau, from the Centre Hospitalier Universitaire in France, will review current response criteria, the impact of the depth of response on survival and event-free survival, and the impact of IMIDs and proteasome inhibitors on the outcome. Fifty years later another element emerges as an important treatment in multiple myeloma. The boron atom in bortezomib binds the catalytic site of the 26S proteasome with high affinity and specificity. Bortezomib was used with dexamethasone prior to autologous transplant with a very good partial response (VGPR) and excellent side effects profile. Combination regimens including bortezomib and IMIDs have shown the highest response rate reported to date with more than 70 percent achieving at least a VGPR.
Sixty years later, progress has been made; however, the debate about biology and best initial therapy continues. Multiple myeloma has gone through major transformations. Those who paved the way and persevered when little could be offered are breathing a sigh of relief. ASH is recognizing two myeloma investigators this year. Dr. Robert Kyle, of the Mayo Clinic, will receive the Wallace H. Coulter Award on Sunday. We look at his long journey exploring the biology and therapy of multiple myeloma and MGUS with great admiration. He has inspired many of us to take care of patients with multiple myeloma and taught us how to be patient and passionate. Dr. Kenneth Anderson, of the Dana-Farber Cancer Institute, who brought us insight on the pathophysiology of the disease that helped in the development of novel agents with unprecedented activity against multiple myeloma, will be awarded the William Dameshek Prize on Tuesday. Progress has been made, and we are most likely closer to a cure than ever before.
Dr. Abonour indicated no relevant conflicts of interest.
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