Immunotherapy for Multiple Myeloma

Learn how immunotherapy is transforming the treatment of multiple myeloma

What Is Multiple Myeloma?

Multiple myeloma is the second most common blood cancer worldwide, accounting for approximately 10% of all hematologic malignancies. Globally, an estimated 188,000 new cases were diagnosed, and 121,000 deaths occurred in 2022, according to the latest GLOBOCAN report. In the U.S., about 36,000 new cases and 10,850 deaths are expected in 2026.

Multiple myeloma is a cancer of plasma cells, a type of white blood cell found in the bone marrow that normally helps your body fight infections. In multiple myeloma, plasma cells grow out of control and can crowd out healthy blood cells, while also producing abnormal proteins that can damage your bones, kidneys, and immune system.

These cancerous plasma cells make large amounts of an abnormal antibody called M protein, which accumulates in your blood and urine. Over time, this buildup can lead to different health problems, which doctors often describe using the acronym “CRAB”: high Calcium levels, Renal (kidney) problems, Anemia (low red blood cells), and Bone disease.

Although multiple myeloma is considered a long-term, treatable cancer for most patients, advances in treatment — including novel targeted agents, stem cell transplantation, and, more recently, immunotherapy — have significantly improved survival and expanded options for care. The five-year survival rate has nearly doubled since the mid-1990s, rising from 32% to 62%. This reflects the transformative impact of new immunotherapy approaches including monoclonal antibodies, chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies.

---

What Is Multiple Myeloma Screening, and How is Multiple Myeloma Detected?

There is currently no routine screening test recommended for multiple myeloma in people of average risk. It is often detected incidentally through routine blood or urine tests ordered for other reasons, such as an unexpectedly elevated protein level or abnormal kidney function.

People diagnosed with MGUS or SMM are monitored over time with regular blood and urine tests to watch for changes. If active multiple myeloma is suspected, doctors may use additional tests — such as a bone marrow biopsy and imaging scans — to confirm the diagnosis and understand how advanced the disease is.

If you have MGUS, SMM, or other risk factors, talk with your health care team about what monitoring or next steps may be right for you.

What Are the Symptoms of Multiple Myeloma?

Multiple myeloma often develops slowly and may not cause symptoms at first. When symptoms do develop, they can include:

• Bone pain, especially in the spine, ribs, hips, and skull, is often the first symptom noticed
• Fatigue and weakness
• Frequent infections
• Kidney problems
• High calcium levels (hypercalcemia) from bone destruction, causing nausea, thirst, constipation, and confusion
• Unexplained weight loss
• Numbness or tingling in the hands or feet

Because these symptoms can overlap with many other conditions, multiple myeloma may be difficult to recognize early. Regular blood work and awareness of these symptoms are important for earlier detection.

If you are experiencing ongoing or unusual symptoms, talk to your health care team.

---

Can Multiple Myeloma Be Prevented?

There is currently no known way to prevent multiple myeloma. Most known risk factors, including age, race, sex, and family history, cannot be modified. Keeping a healthy weight may help lower your risk of developing multiple myeloma, as obesity has been linked to a higher chance of the disease.

For people with MGUS or SMM, ongoing monitoring by a health care team is the most important step. Early detection allows treatment to begin at the right time. Clinical trials are also investigating whether early intervention in high-risk SMM can delay or prevent progression to active multiple myeloma.

How Is Multiple Myeloma Treated?

Treatment for multiple myeloma depends on the stage of disease, a patient’s overall health, and whether they are eligible for a stem cell transplant. A stem cell transplant is a common treatment option for some people with multiple myeloma because it helps replace damaged bone marrow with healthy blood-forming cells. Other standard treatment options include chemotherapy, targeted therapy, immunotherapy, radiation therapy, and autologous stem cell transplantation (in which a patient’s own stem cells are collected and reinfused after high-dose chemotherapy). Immunotherapy has become a cornerstone of myeloma treatment, with multiple types now approved across all stages of the disease.

Immunotherapies Used to Treat Multiple Myeloma

Immunotherapy is a type of cancer treatment that uses your body’s immune system to recognize and attack cancer cells. It works by helping your immune system overcome cancer’s defenses, enabling immune cells to better identify and fight the disease.

For patients with relapsed or refractory multiple myeloma, immunotherapy has become a cornerstone of treatment, with options expanding rapidly over the past decade. Several types are now approved by U.S. Food and Drug Administration (FDA) — including monoclonal antibodies, CAR T-cell therapies, and bispecific antibodies — and some are being used earlier in treatment for newly diagnosed patients.

CAR T-cell therapies:
CAR T-cell therapy is a type of adoptive cell therapy. It involves collecting a patient’s own T cells, genetically engineering them to recognize and attack myeloma cells, and infusing them back into the patient. Because CAR T-cell therapies are manufactured from a patient’s own cells, they require several weeks of processing time before treatment can begin. Both FDA-approved CAR T-cell therapies for multiple myeloma target BCMA (B-cell maturation antigen), a protein found on the surface of myeloma cells.

• Idecabtagene vicleucel (Abecma®): Approved for patients with relapsed/refractory multiple myeloma (RRMM) after two or more prior lines of therapy. It was the first BCMA-directed CAR T-cell therapy approved for multiple myeloma.
• Ciltacabtagene autoleucel (Carvykti®): Approved for patients with relapsed/refractory multiple myeloma after one or more prior lines of therapy. It is a BCMA-directed CAR T-cell therapy that targets two different regions of BCMA to make a stronger, more secure connection.

Bispecific antibodies:
Bispecific antibodies are engineered proteins with two binding arms — one that attaches to a target on myeloma cells and one that attaches to T cells — physically bridging the two cells and triggering the immune system to attack the cancer. All FDA-approved bispecific antibodies for multiple myeloma target CD3, a protein found on the surface of T cells. Unlike CAR T-cell therapy, bispecific antibodies are ready-to-use treatments that do not require manufacturing from a patient’s own cells.

• Teclistamab (Tecvayli®): Approved for patients with RRMM after four or more prior lines of therapy as monotherapy, or after one or more prior lines of therapy in combination with daratumumab. It is the first bispecific antibody approved for multiple myeloma, targeting BCMA on myeloma cells and CD3 on T cells.
• Elranatamab (Elrexfio®): Approved for patients with RRMM after four or more prior lines of therapy. It is a BCMA-directed bispecific antibody.
• Talquetamab (Talvey™): Approved for patients with RRMM after four or more prior lines of therapy. It is a bispecific antibody targeting a protein called GPRC5D, making it an option for patients whose disease has stopped responding to BCMA-targeted therapies.
• Linvoseltamab (Lynozyfic™): Approved for patients with RRMM after four or more prior lines of therapy. It is a BCMA-directed bispecific antibody.

Immuno-modulating agents:
Immuno-modulating agents are treatments that enhance immune activity against myeloma cells while directly inhibiting tumor growth. Examples include lenalidomide (Revlimid®), pomalidomide (Pomalyst®), and thalidomide (Thalomid®).

Immuno-modulating agents are approved for patients with multiple myeloma across different stages of disease, from first-line (the first treatment given after diagnosis) and maintenance treatment to relapsed/refractory settings. They can be used alone or in combination with other treatment types.

Targeted Therapies Used to Treat Multiple Myeloma

Targeted therapies are designed to interfere with specific molecules involved in cancer cell growth and survival. Unlike immunotherapy, which activates the immune system, these treatments directly block the pathways tumors rely on to grow and spread. They include:

• Anti-CD38 monoclonal antibodies: Targeted treatments that bind to CD38, a protein found at high levels on the surface of myeloma cells, and mark them for destruction. These therapies are approved across different stages of the disease and include daratumumab (Darzalex®, Darzalex Faspro®) and isatuximab (Sarclisa®). Darzalex Faspro was also the first treatment approved for patients with high-risk SMM.
• Anti-SLAMF7 monoclonal antibody: Elotuzumab (Empliciti®), a targeted treatment that binds to SLAMF7, a protein found on the surface of myeloma cells. It is approved in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone for patients with RRMM.
• Antibody-drug conjugate: Belantamab mafodotin (Blenrep®), a targeted treatment that uses an antibody to deliver a cytotoxic agent directly to myeloma cells. It targets BCMA on myeloma cells and is approved in combination with bortezomib and dexamethasone for patients with RRMM after two or more prior lines of therapy.

---

Are There Clinical Trials for Patients with Multiple Myeloma?

If standard treatments for patients with multiple myeloma haven’t worked or aren’t available, clinical trials may offer access to promising new therapies. Clinical research is advancing rapidly across several areas of immunotherapy for multiple myeloma:

---

How Is CRI Advancing Multiple Myeloma Research?

CRI-funded scientists have been at the forefront of discovering how the immune system can be harnessed to fight multiple myeloma, from identifying new therapeutic targets and improving CAR T-cell therapies to developing novel detection technologies and exploring how to prevent disease progression. Today, CRI continues to invest in the next-generation of multiple myeloma immunotherapy research, including:

• CRI CLIP Investigator Matteo Maria Bellone, MD, at Vita-Salute San Raffaele University is investigating how changing the gut microbiome with specific types of bacteria can prevent SMM from progressing to active disease. His goal is to develop probiotic-based strategies that work in combination with immunotherapy.
• CRI CLIP Investigator Yubin Kang, MD, at Duke University, is exploring how blocking an enzyme called sphingosine kinase-2 (SK2) can improve the durability and potency of CAR T-cell therapies to help patients with multiple myeloma who relapse after initial treatment.
• CRI Esther M. Baird Technology Impact Investigator Nadia Guerra, PhD, at Imperial College London, is developing a nanobiosensor platform that can detect and monitor multiple myeloma through blood and urine samples to enable earlier diagnosis and more personalized treatment decisions.
• CRI Irvington Postdoctoral Fellow Shannon McGettigan, PhD, at University of Pennsylvania, is investigating a novel survival mechanism in plasma cells, focusing on how these cells sense ATP, a molecule released by nearby bone marrow cells. By inhibiting this ATP sensing pathway, she aims to uncover new therapeutic targets for multiple myeloma.