Multiple myeloma is a blood cancer that affects plasma cells, a type of white blood cell. Myeloma is difficult to treat and usually can’t be cured. When myeloma is relapsed or refractory, treating it becomes even more challenging. However, new treatments and combination therapies can improve your chances of remission (a period in which there are few or no signs of cancer).

Here are the most important facts to know about relapsed versus refractory myeloma.

What Are Relapsed and Refractory Myeloma?

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

Most people will respond well to initial myeloma treatment and may enter remission, which can last for months or even years. One MyMyelomaTeam member shared words of encouragement: “I have been in remission for five years and feel fine. I just have a doctor phone call every 13 weeks. Good luck to everyone.”

Maintenance therapy can help prolong remission, but remission usually doesn’t last forever. Most people with myeloma experience one or more relapses, when myeloma comes back and symptoms get worse after being initially treated. Over time, myeloma becomes more advanced.

Multiple myeloma can also become refractory — 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.

Both relapsed and refractory myeloma can affect your physical and mental health. These conditions can lead to a range of health complications including kidney issues, a weakened immune system, and anemia (low levels of red blood cells). Long-term treatment or use of multiple drugs can also lead to complications, so it’s important to work with your oncologist (cancer doctor) as your myeloma changes over time.

In this article, we’ll review key similarities and differences between relapsed and refractory myeloma.

1. Myeloma Can Be Both Relapsed and Refractory

Myeloma may respond to initial treatment but can become resistant over time, especially after a relapse. This is called relapsed/refractory multiple myeloma (RRMM). You are considered to have RRMM if you improve during first-line therapy and any of the following apply:

• Your disease stops getting better or begins to worsen while you’re still receiving treatment.
• You stop seeing improvements within 60 days of your last treatment.
• You don’t achieve at least a minimal response with a given therapy.

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

2. Your Disease Status Will Change

All people with multiple myeloma will experience either relapsed myeloma, refractory myeloma, or RRMM. Just because your myeloma is relapsed, refractory, or even in remission now doesn’t mean it’ll stay that way. You can expect to have several cycles of remission and relapse as you go through multiple myeloma treatment.

Coming to terms with myeloma changes may make it easier to accept new developments in your disease. One MyMyelomaTeam member said, “I was advised that at some point I will likely relapse since MM acts like a light switch and turns on with no obvious reason. However, I’m comforted by others I know who have relapsed and returned to remission.”

How Changes Lead To Refractory Myeloma

Refractory myeloma develops when cancer cells make certain changes. The longer cancer cells live, grow, and divide, the more they mutate (change genetically). Some mutations can help protect the cancer cells from being killed by medications. For example, certain mutations may allow cancer cells to pump cancer drugs out, preventing the medication from doing its job.

Additionally, myeloma cells alter the bone marrow (spongy tissue in which new blood cells are made) to create an environment that helps them survive. By changing their surroundings, these cells can “hide” from cancer drugs and the immune system. As a result, myeloma becomes more difficult to treat.

3. Relapsed and Refractory Myeloma Have Some Similar Risk Factors

Several known risk factors can help your oncologist provide preventive care to reduce your risk of relapse or treatment resistance. You’re more likely to experience relapsed or refractory myeloma if:

• Your remission periods are short.
• Your myeloma advances quickly.
• You’ve had an aggressive relapse in the past.
• You have specific genetic mutations.
• Your immune system is impaired.
• You have another type of cancer, such as plasma cell leukemia.

4. Relapsed and Refractory Myeloma Share Signs and Symptoms

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.

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

• Increased plasma cells in the bone marrow
• 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, kidney failure, and hypercalcemia (high calcium levels) also indicate relapsing disease.

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

Even before testing, you might notice some signs of relapse. Symptoms of multiple myeloma relapse can vary. Be sure to tell your oncology team if you notice new or worsening symptoms or if you don’t feel that a treatment is helping.

5. New Treatments Offer Hope for Relapsed/Refractory Myeloma

Learning that you have relapsed or refractory myeloma can feel overwhelming, but advances in therapy are improving outcomes. Over the past few 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. Today, newly diagnosed people are expected to live more than eight years, thanks to next-generation treatments that work much better than older options.

However, myeloma is still an incurable disease, and the treatment of relapsed/refractory myeloma can be particularly challenging. New and more effective treatments and drug combinations can help people live longer with multiple myeloma. In recent years, the U.S. Food and Drug Administration (FDA) has approved multiple treatments, including:

• Monoclonal antibodies such as daratumumab and hyaluronidase-fihj (Darzalex Faspro) and isatuximab-irfc (Sarclisa), which can recognize and attack myeloma cells
• Chimeric antigen receptor (CAR) T-cell therapy, which modifies a person’s T cells to better target myeloma cells
• Teclistamab-cqyv (Tecvayli), the first bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager, which helps T cells find and destroy myeloma cells
• Elranatamab-bcmm (Elrexfio), a BCMA-directed CD3 T-cell engager approved in 2023
• Talquetamab-tgvs (Talvey), a bispecific T-cell engager
• Selinexor (Xpovio), which disrupts cancer cell function, and other therapies that take new approaches

New treatment options are being developed through laboratory work and clinical trials, with the goal of extending overall survival and quality of life. Read more about life expectancy with relapsed/refractory myeloma.

New and more effective treatments and drug combinations can help people with relapsed or refractory myeloma live longer and enjoy an improved quality of life.

How Relapse Can Guide Treatment

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.

Talk With Others Who Understand

MyMyelomaTeam is the social network for people with multiple myeloma and their loved ones. On MyMyelomaTeam, more than 26,000 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, start a conversation by posting on your Activities page, or connect with like-minded members in Groups.