Immunotherapy for Multiple Myeloma

Immunotherapy has fundamentally reshaped the treatment of multiple myeloma over the past decade, moving from a disease managed primarily with chemotherapy and stem cell transplants to one where the immune system can be trained, redirected, or armed to attack cancer cells directly. The options now span several distinct classes of therapy, including monoclonal antibodies, CAR-T cells, bispecific antibodies, and antibody-drug conjugates, each with different mechanisms, side-effect profiles, and practical trade-offs. But the landscape is complicated, and understanding which therapies do what, and what their limitations are, matters for anyone navigating or learning about this disease.

CD38-Targeting Monoclonal Antibodies

The first immunotherapies to become standard treatment in multiple myeloma were monoclonal antibodies aimed at CD38, a protein found on the surface of myeloma cells. Two drugs in this category, daratumumab and isatuximab, are now widely used in both newly diagnosed and relapsed disease, often combined with other drugs rather than used alone. Both work by flagging myeloma cells for destruction by the immune system, but they do so through somewhat different mechanisms. Daratumumab relies more on immune-cell-driven killing and reshaping the immune environment around the tumor, while isatuximab binds closer to the active site of CD38 and generates more direct toxic effects on the cancer cell, including through reactive oxygen species.

These mechanistic differences are not just academic. Isatuximab’s ability to inhibit CD38’s enzymatic activity and suppress a protein called FOXM1 may give it an edge against myeloma cells that carry a specific genetic alteration known as 1q21 amplification, a change associated with more aggressive disease. Daratumumab, on the other hand, strips CD38 and a molecule called VLA-4 from cell surfaces through a process called trogocytosis, which can weaken the cancer cell’s ability to cling to the bone marrow and resist other drugs. Daratumumab’s immune-remodeling effects may also set the stage for other immunotherapies to work better later in treatment.

BCMA as the Central Immunotherapy Target

If CD38 antibodies were the first wave, the protein B-cell maturation antigen (BCMA) has become the single most important target for newer myeloma immunotherapies. BCMA sits on the surface of mature plasma cells, including malignant ones, and is involved in cell survival signaling. Its relatively restricted expression pattern makes it a useful bullseye: it is present on myeloma cells and normal plasma cells but largely absent from most other tissues, reducing the risk of widespread collateral damage.

Three major classes of immunotherapy now aim at BCMA: CAR-T cell products, bispecific antibodies, and antibody-drug conjugates. Each approaches the target differently. CAR-T cells are engineered from a patient’s own immune cells to recognize and kill BCMA-expressing myeloma cells. Bispecific antibodies physically link a T cell to a myeloma cell by binding BCMA on one end and a T-cell receptor component on the other. And antibody-drug conjugates deliver a toxic chemical payload directly to BCMA-expressing cells.

CAR-T Cell Therapy

Two CAR-T cell products are approved for relapsed or refractory multiple myeloma: idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). Both target BCMA, but cilta-cel uses a different binding structure and generally produces deeper, more durable responses. In a real-world comparison, overall response rates at three months were around 91% for cilta-cel versus about 77% for ide-cel, and median progression-free survival was roughly 18 months compared to about 17 months, though these differences did not reach statistical significance in the cohort studied. The researchers found that clinical response correlated with how quickly CAR-T cells expanded after infusion, not with the dose of cells given.

The process of receiving CAR-T therapy is involved. Your T cells are collected through a blood draw, shipped to a manufacturing facility, genetically modified, expanded into large numbers, and shipped back. This takes weeks, during which you may need “bridging therapy” to keep the disease in check. Manufacturing delays, the need for specialized treatment centers, and the risk of severe side effects all limit who can receive this treatment and when.

Quality of life temporarily worsens after CAR-T infusion. In a real-world observational study of patients with heavily pretreated myeloma, those who received CAR-T cells experienced declines in quality-of-life scores and worsening disease symptoms through the first two to three months, followed by gradual recovery. Some patients eventually exceeded their pre-treatment quality of life. Patients receiving non-CAR-T therapies, by contrast, had more stable but modestly declining quality-of-life scores over six months.

Bispecific Antibodies

Bispecific antibodies are a fundamentally different approach. Rather than reengineering your own immune cells, these are off-the-shelf drugs given by injection that grab a T cell with one arm and a myeloma cell with the other, forcing them together so the T cell can do what it does naturally: kill the target. Teclistamab, which binds CD3 on T cells and BCMA on myeloma cells, became the first bispecific antibody approved for relapsed or refractory myeloma in 2022. Several others are in late-stage development, including elranatamab and linvoseltamab, which also target BCMA.

The practical advantages are significant. Bispecific antibodies do not require the weeks-long manufacturing process of CAR-T cells and can be started relatively quickly. This makes them a preferred option for patients who are too frail for CAR-T, whose disease is progressing too rapidly to wait, or who are treated at centers without CAR-T capabilities. They are administered on a regular schedule, typically via subcutaneous injection, and treatment continues until the disease progresses or side effects become unmanageable.

The flip side of continuous dosing is continuous T-cell stimulation, which can eventually wear out the immune cells that bispecific antibodies depend on. Chronic exposure to these drugs has been linked to T-cell exhaustion, a state in which T cells lose their killing ability. This raises questions about how long treatment should continue and whether planned breaks might preserve T-cell fitness. Researchers are actively working through the optimal dosing schedule and duration, and the issue remains unresolved.

Targets Beyond BCMA

Not all myeloma cells express BCMA at high levels, and some patients relapse because their cancer evolves to lose BCMA expression entirely. This has driven interest in alternative targets, particularly GPRC5D and FcRH5. GPRC5D is a protein found at high levels on myeloma cells but also on hair follicles, skin, and the tongue. Talquetamab, a bispecific antibody targeting GPRC5D, is in clinical use and under continuing study. Cevostamab, targeting FcRH5, is another bispecific antibody in trials.

Talquetamab’s activity against a non-BCMA target makes it useful after BCMA-directed therapies fail, but GPRC5D’s expression on normal tissues produces a distinctive side-effect profile. Patients commonly experience changes in taste, difficulty swallowing, dry mouth, rashes, and nail problems. These side effects are generally manageable but can significantly affect daily life, and their management requires specific attention. Because these effects stem directly from where GPRC5D is normally expressed in the body, they are somewhat predictable, occurring in tissues like the tongue and skin.

Antibody-Drug Conjugates

Belantamab mafodotin is an antibody-drug conjugate that targets BCMA and delivers a potent cell-killing chemical called MMAF directly into myeloma cells. The antibody acts like a guided missile: it locks onto BCMA, gets pulled inside the cell, and releases its toxic payload. The drug had a turbulent regulatory history, initially gaining accelerated approval and later being voluntarily withdrawn before returning to the market based on updated trial data.

The most distinctive side effect of belantamab mafodotin is eye toxicity. MMAF damages corneal epithelial cells, leading to changes in vision, dry eyes, and blurred vision in a substantial number of patients. This is an off-target effect: the drug’s toxic payload affects corneal cells that take it up, likely through normal cellular processes rather than BCMA expression. Regular eye exams with an ophthalmologist are required during treatment, and dose adjustments or treatment pauses are common to manage the corneal damage.

Cytokine Release Syndrome and Acute Risks

Almost every form of T-cell-engaging immunotherapy in myeloma can trigger cytokine release syndrome (CRS), an inflammatory response caused by the rapid activation of immune cells. When T cells start killing myeloma cells en masse, they release a flood of signaling molecules including IL-6, IL-2, IFN-gamma, and others. At its mildest, CRS causes fever and fatigue. At its worst, it resembles sepsis, with dangerously low blood pressure, organ dysfunction, and the potential for death.

A meta-analysis comparing CRS across treatment types found that CAR-T therapies produce higher overall CRS rates than bispecific antibodies (about 88% versus 59%), higher rates of severe CRS (roughly 7% versus 2%), longer CRS episodes (five days versus two), and more frequent use of tocilizumab, the IL-6 blocker used as rescue therapy (44% versus 25%). Within the bispecific antibody category, subcutaneous injection appeared to produce lower rates of severe CRS compared to intravenous delivery. In a detailed analysis of cilta-cel specifically, CRS occurred in all patients studied, with a median onset of six days after infusion. About two-thirds of those patients experienced grade 3 or worse CRS, which is the severe end of the spectrum.

Management of CRS relies on early recognition and a combination of supportive care, tocilizumab, and corticosteroids. The challenge is that severe CRS can look like an infection, especially in patients whose immune systems are already compromised. Treatment centers with experience managing these side effects are essential, which is one reason these therapies are concentrated in specialized hospitals.

Infections After Immunotherapy

All BCMA-directed therapies share an on-target side effect that has nothing to do with inflammation: because BCMA is expressed on normal plasma cells, the antibody-producing cells of the immune system, treatments that kill BCMA-expressing cells also deplete healthy plasma cells. The result is low immunoglobulin levels, a condition called hypogammaglobulinemia, which leaves patients vulnerable to infections.

Rates of low immunoglobulin levels are similar between CAR-T cell recipients and bispecific antibody recipients, but the infection risk plays out differently. A comparison of infectious complications found that during periods of low immunoglobulin levels, patients on bispecific antibodies had a higher risk of severe infections than those who had received CAR-T cells. The likely explanation is the duration of immune suppression: CAR-T is a one-time treatment after which the immune system can gradually rebuild, whereas bispecific antibodies suppress plasma cells continuously for as long as the patient is on treatment. These findings have led to guidelines recommending that immunoglobulin replacement therapy (intravenous immunoglobulin, or IVIG) be especially considered for patients on ongoing bispecific antibody treatment.

How Myeloma Escapes Immunotherapy

Even when immunotherapy produces deep responses, relapse remains common, and researchers have mapped several routes of escape. The most straightforward is antigen loss. Myeloma cells can evolve to simply stop producing the protein being targeted. One well-documented case involved a patient whose myeloma relapsed after anti-BCMA CAR-T therapy because the tumor acquired what is called biallelic BCMA loss: one copy of the BCMA gene was deleted, and the remaining copy picked up a mutation that created an early stop signal, effectively shutting down all BCMA production. The CAR-T cells were still active and functional, but they had nothing left to recognize.

Beyond complete antigen loss, myeloma can also develop mutations in the targeted protein that alter its shape enough to reduce how well the therapy binds. Research has shown that different mutations confer different sensitivities to various anti-BCMA therapies, meaning a mutation that blocks one drug may not block another. This has practical implications for sequencing treatments: the specific way BCMA changes could determine which therapy to try next. Antigen escape has been documented for GPRC5D-targeted therapies as well, suggesting that the problem is not unique to any one target.

The other major resistance pathway is not about the tumor at all but about the immune cells doing the killing. T-cell exhaustion, the progressive loss of T-cell function from chronic stimulation, has been observed after both CAR-T and bispecific antibody therapy. Single-cell profiling of T cells in myeloma patients has revealed that the abundance of exhausted CD8+ T cells correlates with treatment failure. Patients who did not respond to T-cell-engaging therapies had fewer functional effector T cells and more cells expressing exhaustion markers. Loss of MHC class I on tumor cells, which makes them invisible to T-cell surveillance, has also been described as a tumor-intrinsic adaptation.

Predicting Who Will Respond

Given the expense, toxicity, and variable outcomes of these therapies, there is intense interest in identifying biomarkers that could predict who will benefit most. Soluble BCMA, a form of the protein that gets shed into the blood, appears to interfere with the ability of bispecific antibodies to connect T cells to myeloma cells. Laboratory experiments showed that high levels of soluble BCMA reduced the cell-killing efficiency of the bispecific antibody teclistamab but did not affect a different type of T-cell-engaging construct, suggesting that measuring soluble BCMA levels before treatment could help guide drug selection.

Broader immune profiling at diagnosis is also yielding insights. In newly diagnosed patients treated with daratumumab-containing regimens, genomic and immune signatures predicted clinical outcomes. Higher natural killer cell numbers before treatment, greater T-cell receptor diversity, and specific patterns of immune-cell change over time were all associated with sustained remission. On the tumor side, certain genomic features, including high activity of a mutation-generating process called APOBEC and specific chromosomal deletions, predicted earlier progression despite immunotherapy. These findings point toward a future in which treatment selection is informed by both the tumor’s genetic profile and the patient’s immune fitness.

Combining Immunotherapies With Other Drugs

Rather than using immunotherapies in isolation, researchers are exploring combinations that could boost their effectiveness. One promising strategy involves adding immunomodulatory drugs like lenalidomide to bispecific antibody therapy. Laboratory studies showed that lenalidomide enhanced the killing ability of CD8+ T cells activated by bispecific antibodies, even at very low ratios of immune cells to tumor cells. The drug appeared to achieve this by increasing IL-2 production, essentially giving the T cells more fuel. The magnitude of the boost was comparable to adding a targeted 4-1BB activating signal, which is a dedicated T-cell stimulatory approach.

The logic of combination extends further. Because daratumumab’s immune-remodeling effects may enhance subsequent T-cell-redirecting therapies, there is interest in sequencing CD38 antibody treatment before bispecific antibodies or CAR-T cells. Clinical trials exploring combination and sequencing strategies are ongoing, and the treatment paradigm is shifting toward thinking of these therapies not as standalone options but as building blocks that might work better together than alone.

Off-the-Shelf and Next-Generation Approaches

One of the biggest practical barriers to CAR-T therapy is that each product must be manufactured individually from the patient’s own cells. Allogeneic, or “off-the-shelf,” CAR-T products aim to solve this by using donor cells that can be manufactured in advance and given to any patient without a custom production run. CB-011 is one such product: an allogeneic anti-BCMA CAR-T cell that incorporates a technology called immune cloaking, designed to prevent the recipient’s immune system from rejecting the foreign cells. Early-phase trial results have shown high response rates in heavily pretreated patients.

Another avenue under development moves beyond T cells entirely. CAR-NK cell therapies, which use natural killer cells instead of T cells as the immune effector, are being explored as a way to avoid some of the toxicity associated with T-cell activation, particularly CRS. One product, CIB315, uses CAR-NK cells derived from induced pluripotent stem cells (iPSCs) to target GPRC5D. Because iPSCs can be expanded indefinitely in the laboratory, this approach could theoretically produce unlimited quantities of standardized therapeutic cells, bypassing both the manufacturing bottleneck of autologous CAR-T and the rejection issues of allogeneic T-cell products.

Access and Practical Realities

The transformative potential of these therapies is tempered by real-world barriers. CAR-T cell products carry list prices in the hundreds of thousands of dollars, require certified treatment centers, and involve weeks of manufacturing time during which patients may deteriorate. Bispecific antibodies are more accessible in terms of logistics, since they can be given off the shelf, but they require ongoing administration, typically every one to two weeks, for an indefinite period. The cumulative cost of continuous bispecific antibody treatment can rival or exceed the one-time cost of CAR-T over a long enough timeframe.

For patients who are frail, elderly, or being treated at community oncology practices rather than academic medical centers, bispecific antibodies have become the more practical immunotherapy option. Their manageable safety profile, immediate availability, and subcutaneous delivery make them accessible in settings where CAR-T cell logistics are not feasible. The trade-off is the need for continuous treatment, regular monitoring for infections, and the risk of T-cell exhaustion over time. These practical considerations are often as important as efficacy data in determining which therapy a patient actually receives, and the field is increasingly acknowledging that the best therapy is one the patient can realistically access and tolerate.

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