Immunotherapy treats multiple myeloma by training or directing your immune system to recognize and destroy cancerous plasma cells. Unlike chemotherapy, which kills fast-growing cells indiscriminately, immunotherapies lock onto specific proteins found on the surface of myeloma cells and either flag them for destruction or deliver immune cells directly to the tumor. Several types of immunotherapy are now approved for myeloma, each using a different strategy to accomplish this, and they’ve produced some of the highest response rates ever seen in patients with advanced disease.
The Surface Proteins That Make Myeloma Vulnerable
Every immunotherapy for myeloma works by targeting a specific molecule on the outside of myeloma cells. Two targets dominate current treatment: CD38 and BCMA (B-cell maturation antigen). Both are heavily expressed on cancerous plasma cells, which makes them useful addresses for therapies to find and attack the right cells while largely sparing healthy tissue.
CD38 is a protein found on the surface of most myeloma cells at high levels. It’s the target for monoclonal antibodies like daratumumab and isatuximab, which were among the first immunotherapies to transform myeloma care. BCMA sits on the surface of mature plasma cells and is the target for newer, more complex therapies including CAR T-cell treatments, bispecific antibodies, and antibody-drug conjugates. A third target, GPRC5D, is gaining ground for patients whose myeloma has stopped responding to BCMA-directed treatments.
How Monoclonal Antibodies Kill Myeloma Cells
Monoclonal antibodies are lab-made proteins designed to attach to a single target. In myeloma, daratumumab and isatuximab bind to CD38 on the surface of myeloma cells. Once attached, they kill cancer cells through several coordinated mechanisms. The antibody’s tail region (called the Fc region) acts as a beacon, recruiting different branches of the immune system to finish the job.
Natural killer (NK) cells are the primary responders. When they detect the antibody sitting on a myeloma cell, they release toxic proteins called granzymes and perforins that puncture and destroy the cancer cell. This process is called antibody-dependent cellular cytotoxicity. Daratumumab also strongly activates the complement system, a cascade of blood proteins that forms pores in the myeloma cell membrane and kills it directly. On top of that, immune cells called macrophages can engulf and digest antibody-coated myeloma cells whole.
These antibodies are now a cornerstone of myeloma treatment. Combination regimens that include daratumumab or isatuximab are approved for patients who have received as few as one to three prior lines of therapy, making them one of the earliest immunotherapies a myeloma patient is likely to encounter.
CAR T-Cell Therapy: Reprogramming Your Own Immune Cells
CAR T-cell therapy takes a more radical approach. Instead of adding an antibody to flag cancer cells, it genetically reprograms your own T-cells to hunt myeloma on their own. Two CAR T-cell products are approved for multiple myeloma: idecabtagene vicleucel (ide-cel, brand name Abecma) approved in March 2021, and ciltacabtagene autoleucel (cilta-cel, brand name Carvykti) approved in February 2022. Both target BCMA.
The process starts with collecting T-cells from your blood through a procedure similar to blood donation. Those cells are shipped to a manufacturing facility where they’re engineered to carry a chimeric antigen receptor, a synthetic sensor that recognizes BCMA on myeloma cells. The modified cells are then expanded in the lab over one to two weeks, though the total time from collection to infusion is often longer due to shipping, quality testing, and clinical preparation. Before the cells are infused back into your body, you receive a short course of chemotherapy called lymphodepletion, which clears space in your immune system so the new CAR T-cells can take hold and multiply.
Once infused, the engineered T-cells circulate through your body, latch onto BCMA-expressing myeloma cells, and kill them. In a multicenter study comparing the two products, cilta-cel produced an overall response rate of 93% compared to 79% for ide-cel. At 10 months, 82% of cilta-cel patients had not seen their disease progress, versus 47% for ide-cel. Both products were initially approved for patients who had already tried at least four prior lines of treatment, including standard drug classes like immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies.
Bispecific Antibodies: Bridging T-Cells to Tumor Cells
Bispecific antibodies, sometimes called T-cell engagers, work like molecular bridges. One arm of the antibody grabs a protein on the myeloma cell (usually BCMA or GPRC5D), while the other arm grabs CD3, a receptor on T-cells. By physically linking a T-cell to a myeloma cell, the antibody forces an immune attack without needing the T-cell to naturally recognize the cancer first. This bypasses the normal process that T-cells use to identify threats, which myeloma cells often learn to evade.
Three bispecific antibodies have reached approval or late-stage development for myeloma. Teclistamab and elranatamab both target BCMA on myeloma cells and CD3 on T-cells. Talquetamab takes a different approach by targeting GPRC5D instead of BCMA, giving doctors an option for patients whose myeloma has already been treated with BCMA-directed therapies.
These treatments are given as injections, typically once a week or once every two weeks. Treatment starts with small step-up doses to reduce the risk of a sudden immune overreaction, then moves to a maintenance schedule. In real-world practice, many patients on teclistamab who achieve a deep response can eventually space their doses to every two weeks. Talquetamab patients most commonly receive doses every two weeks, with that schedule becoming more predominant the longer treatment continues. Unlike CAR T-cell therapy, which is a one-time infusion, bispecific antibodies are given on an ongoing basis until the disease progresses.
Side Effects to Expect
The most common side effect across nearly all myeloma immunotherapies is cytokine release syndrome, or CRS. When immunotherapy activates large numbers of immune cells at once, those cells flood the bloodstream with signaling molecules called cytokines. This can cause fever, chills, low blood pressure, and difficulty breathing. In clinical trials of talquetamab, CRS occurred in roughly 75% to 79% of patients. The severity varies widely. Most cases are mild to moderate, peaking within the first few days of treatment and resolving with supportive care. Severe CRS is less common but requires hospital management.
CRS risk is highest during the initial doses, which is why bispecific antibodies use a step-up dosing strategy and why CAR T-cell therapy patients are closely monitored in the days following infusion. Other potential side effects depend on the specific therapy. Treatments targeting GPRC5D, like talquetamab, can cause skin-related effects and changes in taste because GPRC5D is also expressed on some normal tissues. CAR T-cell therapies carry a risk of neurological side effects, including confusion and difficulty speaking, caused by immune activity in the brain.
Infections are another significant concern. Many immunotherapies reduce healthy immune cell populations alongside myeloma cells, leaving patients more vulnerable to bacterial and viral infections for weeks to months after treatment.
How These Therapies Fit Into Treatment
Not every myeloma patient receives immunotherapy right away. The treatment landscape is organized in lines of therapy, and when you become eligible for specific immunotherapies depends on how your disease has responded to earlier treatments. Anti-CD38 monoclonal antibodies like daratumumab have moved earliest in the treatment sequence and are now routinely used in combination with other drugs for newly diagnosed and early-relapse patients.
CAR T-cell therapies and bispecific antibodies were initially reserved for patients who had exhausted multiple prior treatments, typically four or more lines. As clinical trial data matures, some of these therapies are moving into earlier use. The practical difference between them matters for patients: CAR T-cell therapy is a one-time treatment that requires a manufacturing period and a hospital stay, while bispecific antibodies are ongoing outpatient treatments that can start relatively quickly. For patients whose disease is progressing rapidly and can’t wait for CAR T-cell manufacturing, bispecific antibodies may be a more immediate option.
The availability of multiple targets, particularly BCMA and GPRC5D, also means that patients who relapse after one type of immunotherapy may still respond to another that attacks a different protein on the myeloma cell surface. This sequencing of immunotherapies is becoming an increasingly important strategy for extending survival in patients with relapsed disease.