Multiple myeloma (MM) is a hematologic malignancy characterized by the uncontrolled proliferation of abnormal plasma cells, a type of white blood cell that produces antibodies. These cancerous cells accumulate primarily in the bone marrow, crowding out healthy blood-forming cells and causing organ damage. Traditional treatments often struggle to achieve durable, long-term remission because MM cells can be highly resistant to standard chemotherapy protocols. Immunotherapy offers a modern approach by enhancing the body’s own immune system to specifically recognize and eliminate these persistent cancer cells, fundamentally changing the outlook for patients with this challenging disease.
Targeting Cancer Cells with Monoclonal Antibodies
Monoclonal antibodies (MoAbs) are the most straightforward form of immunotherapy for multiple myeloma, acting as “off-the-shelf” treatments that provide passive immunity. These laboratory-engineered proteins precisely recognize and attach to specific antigens, or targets, highly expressed on the surface of myeloma cells. Common targets include CD38, found abundantly on plasma cells, and B-cell maturation antigen (BCMA).
Once a monoclonal antibody binds to the myeloma cell surface, it initiates several powerful immune responses to destroy the cancer cell. One mechanism is Antibody-Dependent Cellular Cytotoxicity (ADCC), where the antibody marks the malignant cell for destruction by natural killer (NK) cells and cytotoxic T-cells. Antibodies also trigger Antibody-Dependent Cellular Phagocytosis (ADCP), where macrophages engulf and digest the coated cells. Furthermore, binding can activate the Complement-Dependent Cytotoxicity (CDC) pathway, leading to cell lysis, or directly trigger programmed cell death (apoptosis).
Activating T-Cells with Bispecific Engagers
Bispecific T-Cell Engagers (BiTEs) intensify the immune response by actively bridging the patient’s T-cells directly to the myeloma cells. These synthetic molecules are engineered with two distinct binding domains, acting as a physical link between the immune system and the cancer. One arm binds to CD3, a protein complex found on the surface of T-cells, recruiting them to the tumor site. The second arm simultaneously binds to a target antigen on the myeloma cell, such as BCMA or GPRC5D.
By forcing this close proximity, the BiTE creates an artificial immune synapse. This forced interaction bypasses the complex process typically required for T-cell activation, ensuring a localized and potent immune attack. When the T-cell contacts the myeloma cell, the BiTE activates the T-cell, causing it to release cytotoxic granules that induce rapid cell death. This approach represents a powerful step up from monoclonal antibodies because it actively redirects the body’s most potent immune cells toward the malignancy.
Reprogramming the Immune System: CAR T-Cell Therapy
Chimeric Antigen Receptor (CAR) T-cell therapy is a highly personalized form of treatment that involves genetically reprogramming a patient’s own immune cells to create a “living drug.” The process begins with leukapheresis, where the patient’s blood is drawn to isolate and collect their T-cells. The remaining blood components are then returned to the patient.
Once harvested, these T-cells are sent to a specialized laboratory for genetic engineering. Scientists use a viral vector to introduce a new gene into the T-cells’ DNA, causing them to express the Chimeric Antigen Receptor (CAR) on their surface. This engineered receptor is specifically designed to recognize a target antigen on the myeloma cell, most commonly BCMA.
The newly engineered CAR T-cells are then expanded in the laboratory over several weeks to create a large army of cancer-fighting cells. Before the final infusion, the patient typically receives a brief course of chemotherapy to prepare the body by reducing existing immune cells. Finally, the modified cells are infused back into the patient intravenously, where they circulate to seek out and destroy myeloma cells with the targeted antigen.
Patient Monitoring and Managing Immunotherapy Side Effects
The immune activation achieved by bispecific engagers and CAR T-cell therapy necessitates close patient monitoring due to the risk of severe side effects. The most common toxicity is Cytokine Release Syndrome (CRS), which results from the rapid and systemic release of inflammatory signaling proteins as T-cells activate and destroy cancer cells. CRS symptoms range from mild, flu-like symptoms such as fever and chills, to severe manifestations like hypotension and difficulty breathing.
Another serious complication is Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), involving neurological symptoms that occur hours to days after treatment. ICANS can manifest as confusion, cognitive impairment, seizures, or difficulties with language. Because these toxicities can onset and escalate rapidly, patients often require specialized medical care and inpatient observation during the initial days following the infusion or the start of treatment.
Management of these immune reactions relies on a structured approach using anti-inflammatory medications. For CRS, standard treatment often involves the anti-interleukin-6 receptor antibody tocilizumab, which blocks the effects of a major inflammatory cytokine, sometimes combined with corticosteroids. ICANS is primarily managed with corticosteroids, though other agents like anakinra, an interleukin-1 receptor antagonist, may be used in more severe cases.