• Relapsed/refractory multiple myeloma (RRMM) is an aggressive form of myeloma that can be hard to treat and lead to poor outcomes.
• Most people with myeloma experience a relapse, in which the cancer returns after being treated.
• Myeloma often becomes refractory (resistant to treatment), and new approaches may need to be tried.
• Researchers are developing therapies to better treat RRMM and are improving outcomes for many people with myeloma.

Multiple myeloma is a blood cancer that affects the plasma cells, a type of white blood cell. Myeloma is difficult to treat and usually can’t be cured.

Over time, myeloma becomes more advanced. People with this cancer usually experience a relapse, in which the myeloma comes back and symptoms worsen after being initially treated. Multiple myeloma can also become refractory, in which the cancer stops responding to treatment, and therapies no longer keep cancer cells under control. People may have myeloma that is relapsed, refractory, or both.

Relapsed/refractory multiple myeloma is typically harder to treat. People may experience less symptom relief once their condition reaches this stage. They may also have a worse outlook after being diagnosed with relapsed or refractory disease. However, researchers are continuously developing therapies that may work better to treat RRMM.

Relapsed Multiple Myeloma: An Overview

After being diagnosed with myeloma, people generally begin first-line (or front-line) therapy — the initial treatment given for a cancer. These medications aim to kill cancer cells, decrease myeloma symptoms, and help extend life. First-line therapy may include a combination of chemotherapy, targeted therapy, immunomodulatory drugs, and corticosteroids such as dexamethasone.

These medications work well to get the myeloma under control for more than 9 in 10 people. The goal of first-line treatment is remission, a period of time in which there are few signs of cancer. Remission lasts an average of four years.

However, most people will eventually relapse. In one study, researchers looked at people with myeloma who began treatment between 2006 and 2014. About 16 percent of people experienced a relapse within one year. Researchers continued following the participants for an average of three years and eight months, and about two-thirds of people had gone through at least one relapse during this period.

Many people go through a cycle of experiencing a first relapse, having their myeloma improve, and then undergoing additional relapses. The time between relapses may shorten as the myeloma comes back more aggressively.

It is important to note that relapses are not inevitable. A little more than 14 percent of people with myeloma live 20 years or more with the condition, according to the International Myeloma Foundation. Half of these individuals still have myeloma cells in their body, but their immune system works well enough to keep the cancer under control and prevent a relapse.

How Do You Know If You Have a Myeloma Relapse?

A doctor may diagnose a multiple myeloma relapse if a person meets certain conditions, such as:

• Increased plasma cells in the bone marrow (spongy tissue in which new blood cells are made)
• Higher levels of monoclonal antibodies or M protein (a protein made by cancerous plasma cells) or more pieces of M protein called serum-free light chains
• Newly formed or growing plasmacytomas or bone lesions (tumors in the bone)
• Low levels of hemoglobin (a protein found in red blood cells that helps move oxygen through the body)
• High levels of creatinine (a waste product normally removed by the kidneys)

Anemia (low levels of red blood cells), kidney failure, and hypercalcemia (high calcium levels) also indicate relapsing disease.

While you are being treated for myeloma, your doctor will likely order regular follow-up testing to look for these signs of a relapse. You may need to undergo blood, urine, or imaging tests.

What Causes a Myeloma Relapse?

Cancer is thought to come back because the treatments weren’t able to kill all the cancer cells. Although treatments are becoming more effective, they aren’t perfect. For example, some medications work by preventing cancer cells from dividing and forming new cells. However, cancer cells sometimes go through a period of rest. During cancer treatment, the drug may leave resting cells alone and allow them to survive.

Myeloma cells that remain in the body after treatment are known as minimal residual disease (MRD). Sometimes, so few cells may be left that they can’t be detected with diagnostic tests. However, even a single cell can grow and divide, causing the cancer to come back. The fewer cells remaining after treatment, the longer remission is likely to last.

Myeloma cells may survive in the body because they have developed abnormalities that allow them to better resist treatment. If these cells grow and take over, the prior therapy may not work as well as it did before.

If you relapse more than six months after trying a treatment, your doctor may recommend using that same therapy again. On the other hand, if you experience a relapse within six months, you may need to try a different approach.

Refractory Multiple Myeloma: What You Should Know

Refractory myeloma doesn’t respond to therapy. Most cases of myeloma will eventually become resistant to treatment. How often this occurs depends on the type of therapy. For example, a 2021 study performed in the United Kingdom found that 72 percent of people with myeloma had disease that was no longer sensitive to lenalidomide (Revlimid), an immunomodulatory drug.

People with lenalidomide-refractory myeloma now have many treatments to choose from. If myeloma cells become refractory to one therapy, another medication or regimen may work better.

How Do You Know If You Have Refractory Myeloma?

If you don’t see much improvement after first beginning treatment, that doesn’t necessarily indicate refractory disease — first-line treatments don’t always work, and you may have other options. However, if you try multiple treatments and your myeloma signs and symptoms never improve, you may have primary refractory myeloma.

Myeloma may also start getting better with treatment and then become resistant after it relapses. Experts refer to this as relapsed/refractory multiple myeloma. You have RRMM if you improve during first-line therapy and then either:

• Stop getting better or begin worsening while undergoing additional treatments
• Stop seeing improvements within 60 days of your last treatment

The same types of tests that help detect a relapse can also identify signs that myeloma is getting worse. If tests show that myeloma signs persist after treatment, you may have refractory disease.

Read more about what to expect if the first myeloma treatment you try fails.

What Causes Refractory Myeloma?

Refractory myeloma develops as a result of cancer cells making certain changes. The longer cancer cells live, grow, and divide, the more gene changes (mutations) they collect. Some of these mutations can help protect the cancer cells from being killed by medications. For example, some mutations may allow cancer cells to pump cancer drugs out, preventing the medication from doing its job.

Additionally, myeloma cells cause bone marrow changes that make it easier for the cells to survive. By modifying their environment, the cells may be able to “hide” from cancer drugs and the immune system. As a result, myeloma becomes more difficult to treat.

New Treatments for Relapsed/Refractory Myeloma

In recent decades, new treatment options have more than doubled myeloma survival rates. In the 1990s, people with myeloma lived an average of three to four years, while people being diagnosed now are expected to live more than eight years. These advances are largely due to the development of next-generation treatments that work much better than previous options.

However, myeloma is still an incurable disease, and the treatment of relapsed/refractory myeloma can be particularly challenging. More effective medications and new drug combinations can continue to help people with this condition live longer and enjoy an improved quality of life. In recent years, the U.S. Food and Drug Administration (FDA) has approved multiple treatments, including:

• New monoclonal antibodies drugs like daratumumab hyaluronidase-fihj (Darzalex Faspro), which can recognize and attack myeloma cells
• Immunochemotherapy combinations such as belantamab mafodotin (Blenrep), in which a monoclonal antibody delivers chemotherapy
• Groundbreaking immunotherapy options like chimeric antigen receptor T-cell therapy
• Drugs that take new approaches to fighting cancer cells, including selinexor (Xpovio)

Experts are continuing to develop additional treatment options through laboratory research and studies called clinical trials. Read more about new therapies for RRMM.

Talk With Others Who Understand

MyMyelomaTeam is the social network for people with multiple myeloma and their loved ones. On MyMyelomaTeam, more than 16,000 members come together to ask questions, give advice, and share their stories with others who understand life with myeloma.

Have you been diagnosed with relapsed or refractory multiple myeloma? Have you and your health care provider discussed new treatment possibilities? Share your experience in the comments below, or start a conversation by posting on your Activities page.