Bispecific antibodies are a type of multiple myeloma treatment that work on both immune cells and cancer cells. For some people, these drugs stop working to treat the myeloma.
At the 2026 Controversies in Multiple Myeloma (COMy), Dr. Nizar Bahlis shared what his team is learning about resistance to bispecific antibodies and four strategies that may help people regain control of their disease.
How do bispecific antibodies work?
Bispecific antibodies are drugs that grab two things at once: a myeloma cell and a patient's own T cell. T cells are immune cells that can kill cancer.
By pulling them together, the drug helps the immune system destroy the cancer. CAR T-cell therapy works on a similar principle, but uses engineered T cells.
Dr. Bahlis explained that not every T cell pulls its weight. To learn which ones matter most, his team looked at the immune cells of people treated with bispecifics one cell at a time. This isa method called single-cell sequencing.
They found that after treatment, one specific type of T cell grew in number much more than the others. These were CD8 effector T cells, the kind built to attack and kill other cells. The ones that multiplied most carried a marker on their surface called CX3CR1.
This finding prompted lab experiments. Researchers sorted naive T cells from effector memory T cells. Naive T cells are younger immune cells that have never been activated. Effector memory T cells are more mature immune cells that have been activated before. They cultured both with myeloma cells. Only the effector memory cells killed the myeloma cells. The naive T cells did not.
He also pointed out that to kill a single myeloma cell, one or two hits are usually not enough. Several T cells need to strike it in quick succession, within less than 50 minutes of each other, so the damage builds up faster than the cell can repair it. That timing matters because spacing treatments too far apart could weaken the response.
Two types of bispecific antibody resistance and four strategies to fight it
There are two types of bispecific antibody resistance. Primary resistance and acquired resistance.
Primary resistance is when a treatment never works well from the start. This is mostly driven by high disease burden, which is when there is a lot of myeloma in the body. A high disease burden lowers the ratio of T cells to cancer cells.
Acquired resistance is when a treatment that worked begins to fail. This is mostly driven by antigen loss. This means the myeloma cells lose the very targets the drug is designed to find. In a study of more than 100 patients using whole-genome sequencing (WGS), Dr. Lee from the same group found antigen loss in roughly 80% of cases involving BCMA and nearly 70% of cases involving GPRC5D. These losses happen either through complete deletion of the gene or through smaller mutations that change the binding region.
Researchers presented four strategies to delay resistance.
Strategy 1: Debulk the cancer first
When there is too much myeloma, the cancer cells outnumber the immune cells the drug depends on. Lowering the amount of myeloma, before or alongside the bispecific, can tip that balance back.
Dr. Bahlis shared the story of a patient whose myeloma had stopped responding to a bispecific antibody. When she later relapsed with only a small rise in kappa free light chains, her team gave her the same bispecific plus a second drug, lenalidomide. She has now been in remission for nearly two years.
Strategy 2: Restore T cell function
One way to delay or stop resistance is restoring T cell function with medication. Researchers suggested two different medications that could be given alongside bispecific antibodies to help.
Daratumumab (Darzalex) is a monoclonal antibody that targets CD38 on myeloma cells. It also depletes Tregs, which are regulatory T cells that suppress immune attack. Adding daratumumab to bispecific antibodies could improve immune function.
CELMoDs are such as mezigdomide were shown in research published in Blood to expand CD8 and CD4 effector memory T cells and reduce exhausted T-cells. Exhausted T cells are immune cells worn out from chronic stimulation, marked by proteins like PD-1 and TIGIT.
Strategy 3: Help T cells reach "cold" tumors
Some tumors have almost no T cells inside them, so the immune treatment that boosts T cells has nearly no effect on them. Doctors call these "immune cold," and they are common when myeloma grows outside the bone marrow (an extramedullary plasmacytoma)
Dr. Bahlis described a case of a patient with highly refractory disease whose plasmacytoma permeating the skull completely melted away within days of adding lenalidomide (Revlimid).
These tumors can be hard to hit for one more reason. The drugs work by locking onto a target, a marker on the surface of the myeloma cell that acts like a flag the drug can grab. Outside the bone marrow, the cancer can hide these flags, and it does this in two ways. For the target called GPRC5D, the cell turns off the gene that makes it, like flipping a switch, even though its DNA does not change. Doctors call this epigenetic silencing. For the target called BCMA, the cell clears the flag off its surface using its protein recycling system, the proteasome. The hopeful part is that demethylating agents (such as decitabine and 5-azacytidine) may flip the GPRC5D switch back on, bringing that flag back so the treatment can find the cancer again. These drugs are being actively researched in trials and might become an option for patients soon.
Strategy 4: Dual targeting to prevent resistant clones
Myeloma can escape by dropping the single target the drug is built to find. Hitting two targets at once means that losing one still leaves the other. Resistance also tends to affect just one specific drug rather than the whole class, so a different bispecific may still work after the first one fails. In the MajesTEC-3 trial, pairing a bispecific with daratumumab produced no resistance mutations even at 36 months, when they would normally be expected within the first year on a single drug.
A surprising twist on how long to stay on treatment
A controversial question is how long people should stay on bispecifics. Researchers once worried that long-term exposure would cause resistance, so the LimiTec trial tested stopping bispecific therapy after 6 to 9 cycles in patients who reached deep responses.
At first the news looked encouraging. Most patients who stopped kept their responses, just as if they had stayed on the drug. But there was a catch. Out of the 15 patients who restarted Teclistamab after their disease came back, only 1 was able to regain a response.
"This disturbing finding suggests we shouldn't be rushing to shorten the duration of therapy," Dr. Bahlis said. He explained that continuous treatment may actually recruit bystander T cells that help block mutant clones from emerging in the first place.
Questions to ask your care team about bispecific antibodies
Bispecific antibodies are a powerful tool against myeloma, but they do not work forever for everyone, and researchers like Dr. Bahlis are actively working on ways to make them last longer. Most of those ideas are still being tested, so they are not all available yet. But this research points to a few things worth discussing with your own care team now.
The biggest one is timing. Dr. Bahlis's main message was that stopping treatment early may not be as safe as it once seemed. In the LimiTEC trial, among patients who stopped and later relapsed, only 1 of 15 was able to get their response back after restarting. That does not mean stopping is always wrong, but it is a decision worth discussing carefully with your doctor.
So if you are on a bispecific antibody, or thinking about one, these are good questions for your next visit:
How long is the plan for me to stay on treatment?
If we ever pause, what is the plan to catch and treat a relapse early?
Are there combination treatments or clinical trials that might fit my case?
Asking these questions is one of the best ways to stay on top of your own care.
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