In the last twenty years, there has been a major shift in available treatments for all indications of multiple myeloma (MM). The introduction of innovative treatments (e.g., proteasome inhibitors, immunomodulators, etc.) and autologous stem cell transplantation, has doubled MM patients’ five-year survival rate. Patients also have ample choice in treatment options as there are currently 41 approved medications. While strides have been made for MM patients, they eventually relapse or become resistant to a drug’s effects. In order to address this issue, biopharma companies have continued development of innovative treatments for MM in the hopes of continuing the increase in overall survival rates and potentially curing MM.

Background

Multiple myeloma is a type of cancer that forms in plasma cells, a type of white blood cell that is made in the bone marrow and produces an antibody that helps fight infections. Myeloma develops when plasma cells become cancerous, becoming myeloma cells. Myeloma cells multiply randomly and form tumors that accumulate, in the bone marrow and the surfaces of bones throughout the body. The tumors crowd the bone marrow and prevent it from making antibodies and other blood cells (i.e., red, white, and platelets). Myeloma cells also secrete chemicals that stimulate osteoclasts, cells that break down bone by removing calcium. Osteoclast stimulation can cause bones to become weaker and more brittle, engendering fractures. The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program estimates that more than 32,270 people living in the United States were diagnosed with multiple myeloma in 2020 and that 12,830 died of the disease. MM is more common in older people, especially men, and African Americans. The overall 5-year survival rate for people with MM is 54%. For the 5% of people who are diagnosed at an early stage, the 5-year survival rate is 75%. If the cancer has spread to a distant part of the body, the 5-year survival rate is 53%.

Methods

In order to project the state of development in MM, pipeline data was sourced from the BioPharmaCatalyst database. The database houses pipelines information for pharmaceutical companies listed on NASDAQ and NYSE, it covers nearly 550 companies and over 2000 drug entries. Therapies in development via partnerships were coded for each company and a therapy with multiple indications for MM (e.g. MM or relapsed/refractory MM) was coded for each indication. Molecule information sourced from BioPharma was categorized based on drug class and mechanism of action. Mechanism of action and drug class data was sourced from AdisInsights, a platform created by Springer Nature to provide information on drugs in commercial development and clinical trials.

Results

There are currently 53 molecules under development for MM. Early development is dominated by autologous & allogenic (A/A) transplant technology, with ninety percent (20 molecules) of these being CAR T-cell therapies. CAR Ts have been investigated in clinical trials for MM for a few years and have demonstrated efficacy and tolerability. Multiple organizations have begun development of CAR T therapy which could offer ample treatment options for patients in the future. Ide-cel, a bluebird bio & Bristol Myers Squibb’s collaborative effort, is the only CAR-T therapy in late-stage development. Ide-cel is currently under review by the Food and Drug Administration (FDA) and experts anticipate approval this year, for the indication of MM patients who have had at least 3 lines of prior therapy and have been exposed to the currently approved 3 main backbones of treatment. Interleukin inhibitors are the second largest drug-class in early-stage development. Interleukin-6 (IL-6), in particular, is a major survival factor for multiple myeloma (MM) cells preventing apoptosis induced by dexamethasone (DEX) or chemotherapy. IL-6 monoclonal antibodies saturate early and late-stage development; IL-6 inhibitors are a combination drug in nearly one-fourth of late-stage development programs.

Regarding novel technologies in development, BCMA-targeted Bi-specific T cell engagers (BiTEs), antibody–drug conjugates, and oncolytic viruses are promising new therapies to treat MM. BiTEs offer an efficacious therapeutic approach for people with numerous healthy T-cells as it boosts immune response. BCMA-targeting BiTEs redirect T-cells to BCMA-expressing MM cells for elimination. Several phase 1 studies show pronounced activity of BCMA-targeting bispecific antibodies, including teclistamab, AMG420 and CC-93269, in heavily pretreated MM patients. Based on preclinical findings, BCMA-targeting BiTEs combined with immunomodulatory drugs or CD38-targeting antibodies can make BiTEs more efficacious. BiTEs are currently in early-stage development via Amgen Inc. for two indications of MM.

BCMA targeting antibody-drug conjugates (ADC) provide a feasible treatment option for MM patients with a weaker immune response. ADCs are composed of three l components: a mAb that recognizes a tumor-specific antigen, a cytotoxic molecule often referred to as payload, and a chemical linker that connects the mAb and payload. Upon binding to the corresponding antigen on the surface of tumor cells, ADC is internalized first, and the linker is hydrolyzed inside of the lysosomes or endosomes, releasing the payloads that lead to cell death by damaging DNA or impeding microtubule assembly. ADC enhances targeted killing of tumors while sparing normal tissues, minimizing toxicity. ADC targeting BCMAs were first approved last year for GlaxoSmithKline Inc., it is now being evaluated in trials for combination therapies and other MM indications.

Oncolytic viruses (OV) provide tumor-targeted therapy by specifically infecting and replicating within cancerous cells. Oncolytic therapies destroy malignant cells and induce an anti-tumor immune response. All oncolytic virotherapies are derived from naturally occurring viruses, and many of the viruses in development are modified to increase their specificity for cancer cells or enhance their ability to promote tumor clearance. MM has several features that make it an ideal target for OV, these include mutations in signaling pathways that render MM more sensitive to viral infection and overexpression of cell surface proteins that are commonly used as viral entry receptors. Oncolytic Inc. is the only company developing oncolytic viruses for MM, and they are in early-stage development. There currently active trials are testing OV in combination with a checkpoint inhibitor (PD-1) and proteasome inhibitor (20S/26S).