Advances in Multiple Myeloma Research

Research in Multiple Myeloma Treatment

Multiple myeloma is not considered curable. However, with recent advances in treatment, it can be managed like a chronic disease in some people.

The mainstays of treatment for multiple myeloma have been chemotherapy followed by stem cell transplant for people healthy enough to tolerate the procedure. Targeted therapies and immunotherapies have also been used, either to prepare people for a stem cell transplant or in place of one. Recent advances in immunotherapy have changed the way many people are treated, especially those unable to have a stem cell transplant.

Immunotherapy

Immunotherapy is treatment that helps the body’s immune system fight cancer more effectively. Types of immunotherapies being used or tested for multiple myeloma include:

CAR T Cells

CAR T cells are an immunotherapy in which a patient's T cells, a type of immune cell, are changed in the lab so they will better attack cancer cells and then returned to the patient’s bloodstream.

Two types of CAR T cells have been approved by the FDA to treat multiple myeloma that has come back after previous treatments:

• Idecabtagene vicleucel (Abecma) for people with multiple myeloma that is not responding to treatment or has returned after treatment.
• Ciltacabtagene autoleucel (Carvykti) for adults with multiple myeloma that is not responding to treatment or has returned after treatment.

Researchers are now testing whether some patients may benefit from getting CAR T-cell therapy instead of a stem cell transplant as their initial treatment.

Currently, CAR T cells must be created from scratch for each patient, making them the most personalized of therapies. But this process is complicated and expensive. Researchers have been testing the use of so-called off-the-shelf CAR T-cell therapies, which could potentially be made in bulk and used immediately.

An ongoing trial at NCI is also testing another type of immunotherapy using T cells, called TCR T-cell therapy, in people with multiple myeloma who have at least one tumor that can be removed surgically.

Bispecific T-Cell Engagers (BiTEs)

BiTEs are drugs that latch onto both tumor cells and T cells. By bringing T cells and cancer cells close together, they help the T cells recognize and destroy the cancer cells.

Three BiTEs have been approved by the FDA to treat adults with multiple myeloma that came back or did not get better after treatment with several other anticancer therapies:

• teclistamab (Tecvayli)
• elranatamab (Elrexfio)
• talquetamab (Talvey)

Researchers are now studying whether giving these drugs to people with multiple myeloma who have received only one previous treatment can help keep the disease at bay for longer. They’re also making sure the potential side effects, such as an increased risk of dangerous infections, don’t outweigh the potential benefits.

Ongoing trials are also testing whether using more than one BiTE at the same time can keep multiple myeloma in remission for longer than using a single BiTE. Additional trials, including one sponsored by NCI, are investigating combinations of other new myeloma therapies with BiTEs.

Immunomodulating Drugs

Immunomodulating agents are drugs that either stimulate or suppress parts of the immune system to help the body fight cancer. These types of drugs, including lenalidomide (Revlimid) and pomalidomide (Actimid), have been used for decades to treat some people with multiple myeloma.

Studies are now testing a new generation of immunomodulating drugs that have been developed for use once resistance to current drugs occurs. These include iberdomide and mezigdomide.

Targeted Therapies

Targeted therapy treats cancer by shutting down proteins that control how cancer cells grow, divide, and spread. Some of the earliest targeted therapies, drugs called proteasome inhibitors, were developed for use in multiple myeloma. These drugs, such as bortezomib (Velcade), block the action of proteasomes, large protein complexes that help destroy other cellular proteins when they are no longer needed.

But resistance to proteasome inhibitors eventually develops and multiple myeloma starts to grow again. So researchers are searching for new ways to shut down multiple myeloma cells using targeted drugs.

Approaches being tested include:

Picking very specific populations for treatment. For example, studies found that adding venetoclax (Venclexta)—a drug that has shown promise in treating some types of leukemia—to other multiple myeloma drugs actually made myeloma grow faster. However, further research suggested that people whose multiple myeloma tumors harbor a rare genetic mutation may benefit from venetoclax. Clinical trials are now testing the drug only in people with this specific gene change.

Targeting a family of genes called RAS. After pancreatic cancer and colorectal cancer, multiple myeloma is the third most likely cancer type to be driven by changes in RAS. RAS used to be considered “undruggable,” that is, that it couldn’t be shut down with targeted therapies. But over the last decade, drugs have been developed that can shut down RAS and stop tumor growth. Clinical trials, including one at NCI, are now testing such drugs in people with multiple myeloma.

Targeting epigenetic regulation of cancer cells. Epigenetics refers to changes in the way genes are switched on and off that don’t involve changes in the actual DNA sequence. Drugs that shut down cancer cells by targeting their epigenetic regulation are now being tested in multiple myeloma.

Monoclonal antibodies (Mabs). Mabs are versions of immune system proteins that are created in the lab and bind to cancer cells. They can kill cancer cells directly or indirectly, by engaging the immune system to kill the cancer cells. 

A Mab called daratumumab (Darzalex) binds to a protein found on the surface of myeloma cells and helps immune cells kill myeloma cells. Daratumumab is FDA approved to be used with some drug combinations for newly diagnosed multiple myeloma, as well as myeloma that has relapsed, and is being tested in addition to other combinations.

For example, a recent study tested adding daratumumab to the standard chemotherapy drugs given after an initial diagnosis of multiple myeloma. Patients treated with daratumumab lived substantially longer without their cancer getting worse or dying than those who received the standard treatment only. An ongoing study is now testing whether giving people with newly diagnosed multiple myeloma a treatment regimen that includes daratumumab can lengthen the time before a stem cell transplant is needed.

FDA has also approved another Mab, called isatuximab (Sarclisa), to be given along with the drugs bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone. The approval was based on a clinical trial called IMROZ, which showed that the four-drug regimen substantially increased the time patients lived without evidence of their cancer coming back or getting worse.

Elotuzumab (Empliciti) is another monoclonal antibody approved by for myeloma that has relapsed after previous treatment. This Mab targets a different protein on myeloma cells than the one targeted by daratumumab and isatuximab, so it may be effective after other antibodies stop working. Elotuzumab is currently being tested in combinations with other targeted therapies and with immunotherapies.

Advances in Stem Cell Transplant

Despite advances in immunotherapy and targeted therapies, autologous stem cell transplant is still used to treat many people with multiple myeloma. But often, too few stem cells can be successfully collected from a patient, making transplant impossible. Researchers are working to make stem cell transplant an option for more people with this cancer type.

For example, a clinical trial funded in part by NCI tested the injection of a drug called motixafortide (Aphexda) in addition to injections of G-CSF, the drug most widely used to “mobilize” stem cells from the bone marrow to the blood. People who received motixafortide had a markedly increased number of stem cells that could be collected for transplant compared with people who received G-CSF alone. Motixafortide received FDA approval in 2023 for use as part of preparation for an autologous stem cell transplant.

Research in the Treatment of Precursor Conditions

Multiple myeloma is a slow-growing cancer. It can develop silently for years without causing symptoms. The most common such precursor condition to multiple myeloma is called monoclonal gammopathy of undetermined significance, or MGUS. People with this condition have abnormal levels of certain blood markers. In some people, MGUS can progress to a condition called smoldering myeloma, which also doesn’t have symptoms. From there, it may turn into multiple myeloma. But it also may not cause full-blown cancer in a person’s lifetime.

Both MGUS and smoldering myeloma are usually found incidentally, by blood tests looking for other problems. If this happens, people are usually monitored and not given treatment right away. However, researchers have wondered if they can predict which people with MGUS or smoldering myeloma will eventually progress to myeloma. And, if progression can be predicted, would giving treatment before multiple myeloma develops help them live longer? Or would it only expose them to the side effects of treatment earlier without providing any benefit?

• In a recent clinical trial called AQUILA, which was funded by the manufacturer of daratumumab, people with smoldering myeloma at high risk of progressing to multiple myeloma were randomly assigned to either receive the drug for up to 3 years or to undergo monitoring. Fewer patients receiving daratumumab progressed to multiple myeloma during the study, though they also experienced more side effects.
• An ongoing trial at NCI is testing daratumumab as part of a multidrug regimen in people with smoldering myeloma at high risk of progressing to multiple myeloma.

NCI-Supported Research Programs

Many NCI-funded researchers working at the NIH campus and across the United States and the world are seeking ways to address multiple myeloma and other plasma cell neoplasms more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer. And some is more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s research efforts in multiple myeloma and related plasma cell tumors.

The Multiple Myeloma Specialized Programs of Research Excellence (Myeloma SPOREs) are designed to quickly move basic scientific findings into clinical settings. The Myeloma SPOREs support the development of new treatments for multiple myeloma and related, rarer conditions such as Waldenstrom’s macroglobulinemia.

The National Clinical Trials Network funds clinical trials testing new treatments for multiple myeloma as well as precursor conditions such as smoldering myeloma. 

The Cancer Intervention and Surveillance Modeling Network (CISNET) is a consortium of NCI-sponsored investigators who use simulation modeling to improve our understanding of cancer control interventions in prevention, screening, and treatment and their effects on population trends in incidence and mortality. Investigators within CISNET's Multiple Myeloma Working Group are developing such models to assess the value of guideline-recommended therapies and novel intervention strategies for myeloma prevention and control.

The Genomic Data Commons (GDC) provides the cancer research community with a unified repository and cancer knowledge base that enables data sharing across cancer genomic studies in support of precision medicine. The Multiple Myeloma Research Foundation has made genomic data from a large clinical trial of precision medicine for multiple myeloma, called The Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study (CoMMpassSM) available to the research community through the GDC.

Clinical Trials for Multiple Myeloma and Other Plasma Cell Cancers

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Treatment clinical trials are available for multiple myeloma and other plasma cell cancers.

Multiple Myeloma Research Results

The following are some of NCI's latest news articles on multiple myeloma research:

• FDA Approvals Expand Initial Treatment Options for Multiple Myeloma
• Trial Results Support Adding Daratumumab to Initial Treatment for Multiple Myeloma
• Motixafortide May Improve Stem Cell Transplants for People with Multiple Myeloma
• Teclistamab Shows Promise for People with Heavily Pretreated Multiple Myeloma
• Carvykti Approval Marks Second CAR T-Cell Therapy for Multiple Myeloma
• FDA Approves BCMA-Targeted CAR T-Cell Therapy for Multiple Myeloma

View the full list of Plasma Cell Neoplasm Research Results and Study Updates.