Monoclonal antibodies designed against cell surface proteins such as CD20 (rituximab) or HER2 (trastuzumab), cytokines such as VEGF (bevacizumab), and now immune checkpoints such as PD1 (e.g., pembrolizumab) have transformed oncology care and are routinely used across nearly all tumor types. Although treatment options for multiple myeloma (MM) over the last decade have converted the disease into a chronic condition for many patients, it is only now that the potential of monoclonal antibodies in the treatment of MM is being recognized. These two agents are named Elotuzumab and Daratumumab.
Elotuzumab is a humanized recombinant monoclonal IgG1 Kappa antibody targeting SLAMF7 (signaling lymphocyte activation molecule), which is highly expressed on both normal and MM plasma cells. While as a single agent elotuzumab does not show significant clinical activity, when combined with lenalidomide and dexamethasone in a phase I/II trial (ELOQUENT-2) in relapsed or refractory MM the combination showed improvement in both overall response and progression-free survival. ELOQUENT-2 is the first study to show the benefit of adding a monoclonal antibody to conventional treatment in Multiple Myeloma.
Daratumumab is a human IgG1 Kappa monoclonal antibody which targets CD38, again highly expressed in Myeloma cells. It was evaluated in a phase I/II study where it demonstrated effectiveness as a single agent in heavily pretreated myeloma patients who were refractory to all available agents and showed modest response rate, including durable remission in some of these patients with very advanced myeloma. These findings establish daratumumab as the first monoclonal antibody to have single-agent activity, particularly in a challenging patient population with refractory disease.
Both of these medications were fairly well tolerated with manageable toxicity. More targeted antibodies are also in clinical development including antibodies targeted against CD138 (which is heavily expressed on the surface of myeloma cells) as well as antibody targeting a cytokine called interleukine 6 which is one of the most potent growth factor that helps myeloma cells grow. Given the encouraging efficacy and tolerably of elotuzumab and daratumumab, trials of combinations are also ongoing with immune modulatory drugs (like Lenalidomide) and proteasome inhibitors (like bortezomib), both in the relapsed setting and for patients with newly diagnosed disease. Their tolerability also raises the possibility of long-term use as maintenance therapy. Overall, elotuzumab and daratumumab (and future monoclonal antibodies), with their unique mechanism of action and limited toxicity, are poised to transform the treatment of Multiple Myeloma and may bring patients closer to the hope of a cure.