"A beacon of hope for relapsed multiple myeloma patients: TALVEY™".

Abstract

Dear Editor, Multiple myeloma, a significant hematological malignancy affecting about 10% of such cases globally, presents a substantial health challenge. Despite medical advancements, most patients eventually face relapse and resistance to treatment. Particularly, patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM), pretreated with immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies, have poor overall survival rates. Recent breakthroughs in immunotherapy, including CAR T-cell therapy and bispecific antibodies (BispAbs), offer promising options for RRMM management. CAR T-cell therapy is effective but has a timeconsuming manufacturing process. On the other hand, BispAbs are readily available and show remarkable efficacy in RRMM treatment. Recognizing this, the Food and Drug Administration (FDA) has recently given accelerated approval to Talquetamab, a pioneering second bispecific antibody that targets GPRC5D and CD3 receptors. This offthe-shelf therapy shows remarkable therapeutic achievement for heavily pretreated RRMM patients. Multiple myeloma (MM), the second most prevalent hematologic cancer after non-Hodgkin lymphoma, predominantly affects high-income countries. It is defined by the infiltration of bone marrow with monoclonal plasma cells, producing monoclonal immunoglobulins detectable in the blood or urine. The buildup of these immunoglobulins can result in organ dysfunction, commonly referred to as CRAB symptoms (hypercalcemia, kidney problems, anemia, and bone abnormalities), which signify the onset of symptomatic disease. TALVEYTM (talquetamab-tgvs), a GPRC5D-targeted therapeutic bispecific antibody, effectively engages T-cells and demonstrates the capacity to attach to both the CD3 receptor situated on T-cells and the G protein-coupled receptor class C group 5 member D (GPRC5D), which is present on the surfaces of both multiple myeloma cells and non-cancerous plasma cells. Furthermore, it also interacts with normal tissues such as epithelial cells in keratinized regions of the skin and tongue. In experimental settings, talquetamab-tgvs prompted the activation of T-cells, resulting in the emission of inflammatory signaling molecules and leading to the elimination of multiple myeloma cells. The effectiveness of TALVEY as a standalone treatment was assessed in patients with relapsed or refractory multiple myeloma. This evaluation took place in a study called MMY1001 (MonumenTAL-1) (NCT03399799, NCT4634552), involving 187 patients who had received at least four previous systemic treatments. Patients were given either talquetamab-tgvs 0.4 mg/kg subcutaneously weekly after initial step-up doses, or talquetamab-tgvs 0.8 mg/kg subcutaneously every 2 weeks following initial step-up doses. Treatment will be administered until either the disease advances or intolerable side effects occur. The main group under analysis consisted of patients who had undergone at least four prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. In the group receiving 0.4 mg/kg weekly, the overall response rate (ORR) was 73%, with a median duration of response (DOR) of 9.5 months. In the 0.8 mg/kg biweekly group, the ORR was 73.6%, and the median DOR was not estimable. About 85% of those who