Overview

Plasma cells represent the final stage of B-cell development and differentiation. They are professional antibody-producing cells normally present in small numbers in the bone marrow. Their precursors are activated B cells that can respond appropriately to infections and vaccinations and evolve into plasma cells. Aberrant plasma cells play roles in autoimmune disorders and hematologic malignancies and can also cause rejection of solid organ transplants. In hematologic malignancies, the character of the proteins made by the clonal plasma cells can cause direct damage to organs, such as the kidneys and heart, in AL. Our lab has pioneered strategies to disrupt the pathologic mechanisms of disease at the molecular, protein and cellular levels. Light chain proteins possess two domains: a variable region that contributes to the specific activity of the light chain and a constant region that provides structural stability. We initiated the molecular identification of the genes for the variable region domains of the light-chain proteins that form fibrillar AL amyloid deposits disrupting organ function. In myeloma cells, light chains often pair with heavy chains, and we have shown that the knockdown of light chain genes can trigger cell death because the heavy chain proteins cannot be secreted with their light chain mates. In AL, the clonal plasma cells often produce only light chains, so we have pursued the development of therapeutic monoclonal antibody constructs that can clear the pathologic light chains from the circulation, thereby preventing the fibrillar deposits from forming. In both myeloma and AL, the clonal plasma cells have a protein on their surface membrane that is the target of an FDA-approved monoclonal antibody called Darzalex. Our lab shares the patent with Janssen for its use in AL and also provided senior leadership in its clinical development to treat newly diagnosed patients with AL.

Principal investigator

Raymond Comenzo, MD has been a faculty member in the Division of Hematology-Oncology at Tufts Medical Center from 2009-present. He is a Professor of Medicine at Tufts University School of Medicine. He is principally responsible for the clinical care of all plasma cell disease patients and for clinical research for these diseases at Tufts Medical Center. He is also the Medical Director of the Blood Bank, Cell Therapy Lab and Apheresis Center. Dr Comenzo completed his Internal Medicine Residency at Boston City Hospital and Hematology-Oncology and Transfusion Medicine Fellowship at Tufts Medical Center. From 1999 to 2008, he was the medical director of the cell therapy laboratory, an attending member at Memorial Sloan Kettering Cancer Center in New York City, and a professor of medicine at Weil-Cornell School of Medicine. From 1992 to 1999, he was an attending physician in hematology, the founder of the Stem Cell Transplant Program, and the director of the Blood Bank at Boston Medical Center. Dr Comenzo is an internationally recognized expert in plasma cell diseases and has been the principal investigator of numerous clinical trials that have substantially improved their treatment.