After you receive a multiple myeloma diagnosis, first-line therapies are used to control the cancer and help you achieve remission. However, after a time of being in remission, most people will relapse, which means their cancer has returned.

If you have a relapse, your hematologist-oncologist (a doctor specializing in blood cancer) will develop a new treatment plan to help you achieve remission again. Most people experience multiple relapses, depending on their specific multiple myeloma case. Knowing what to expect if and when your myeloma relapses can help you prepare for future treatments.

What Is Relapsing Multiple Myeloma?

The International Myeloma Foundation defines a multiple myeloma relapse as “the reappearance of signs and symptoms of a disease after a period of improvement.” Relapses occur when some myeloma cells remain after treatment, known as minimal residual disease (MRD). These leftover cells can continue to grow and divide. The goal of treatment is to reduce MRD as much as possible. Although myeloma treatments are generally effective and kill off most myeloma cells, just a few surviving cells can result in an eventual relapse.

The Relapse Rate for Multiple Myeloma

Relapsing multiple myeloma is common. In a 2016 study, 16 percent of people with multiple myeloma relapsed within one year. After about four years, almost 66 percent of participants had experienced a relapse.

Testing and Diagnosing a Relapse

Sometimes a multiple myeloma relapse is diagnosed because you notice new symptoms, such as bone pain. In most cases, your hematologist-oncologist may suspect a relapse after performing blood work or imaging tests. A relapse is diagnosed based on test results that show changes in blood globulin levels, formation of bone lesions, and an increase in plasma cells in the bone marrow.

Doctors may use the CRAB criteria to look for a relapse of multiple myeloma. The CRAB criteria are:

• Calcium — Increased calcium levels, also known as hypercalcemia
• Renal — Kidney impairment
• Anemia — A decrease in your hemoglobin levels
• Bone disease

MRD testing can also be done after treatment to monitor remission. This method uses next-generation sequencing (technologies to look for genetic changes) or flow cytometry to look for myeloma cells in the bone marrow. Flow cytometry uses special antibodies that bind to proteins on the surface of cells to identify them as myeloma cells. If MRD can be detected after treatment is complete, a relapse may occur sooner rather than later.

Early Relapses

Most people with multiple myeloma respond well to their first-line therapy (the first regimen used to treat their cancer) for around two or three years but eventually have a relapse. After the initial relapse, you can expect to undergo periods of response to new medications followed by subsequent relapses.

First or second relapses may be considered early relapses if they occur soon after initial therapy ends. A small number of people relapse within a year after initial treatment. A very early relapse may develop if you do not respond well to initial therapy, have high-risk disease (known as primary refractory disease), or relapse during maintenance therapy.

After your first relapse, your hematologist-oncologist will reevaluate your treatment plan. Several factors go into changing a plan or developing a new one, including:

• Your overall health
• The first-line therapies you received
• How well these treatments worked
• How long you were in remission

Treatment Options for a First or Second Relapse

If you’ve relapsed for the first time, your doctor may recommend using one of your original therapies again or trying a new approach. If you get a new treatment plan, you may start one of many classes of drugs, including alkylating agents, immunomodulatory imide drugs (IMiDs), proteasome inhibitors, and monoclonal antibodies. Some of these medications are approved as first-line therapies and can also be used after early relapses. Others, including the alkylating agent cyclophosphamide (Cytoxan) and the IMiDs lenalidomide and thalidomide (Thalidomid), are approved for use only after other therapies have failed.

Here are nine possible treatment options for a myeloma relapse. Your doctor will help you make the best treatment plan for your individual needs.

1. Restarting Your Original Therapy

In some circumstances, your hematologist-oncologist may recommend restarting your original therapy that led to remission. This is typically done if remission lasted at least six months to one year after treatment ended. Reintroducing initial therapy is successful around 50 percent of the time and leads to remission, especially in people who were in remission for at least a year.

2. Another Bone Marrow Transplant

If you previously had an autologous bone marrow transplant, or ASCT, and then several years of remission, your hematologist-oncologist may recommend another ASCT. They will discuss the pros and cons of this procedure with you and whether it’s worth trying again. They may also adjust your maintenance therapy, such as adding dexamethasone combined with lenalidomide (Revlimid).

3. Proteasome Inhibitors

Certain proteasome inhibitors are more likely to be recommended after relapses, or if earlier treatments didn’t work. These include:

• Bortezomib (Velcade)
• Ixazomib (Ninlaro)
• Carfilzomib (Kyprolis)

4. Monoclonal Antibodies

Monoclonal antibodies, which are also known as biologic drugs, may be another option for treating relapsed multiple myeloma. These include:

• Daratumumab (Darzalex)
• Daratumumab and hyaluronidase-fihj (Darzalex Faspro)
• Elotuzumab (Empliciti)
• Isatuximab-irfc (Sarclisa)
• Belantamab mafodotin-blmf (Blenrep)

5. Combination Therapies

The U.S. Food and Drug Administration (FDA) also has approved the following drug combinations for treating early relapsed multiple myeloma:

• Bortezomib, daratumumab, and dexamethasone
• Lenalidomide, daratumumab, and dexamethasone

Later Relapses

Many people will continue to relapse after new treatments, undergoing several periods of remission and then relapse. With each new relapse, your hematologist-oncologist will change your treatment plan to include new drugs. Eventually, this leads to myeloma cells that become increasingly resistant to more drug combinations. This may make it more difficult to treat multiple myeloma relapses.

Your hematologist-oncologist may use genetic testing to look at the mutations in your myeloma cells. This test may reveal changes in certain genes that can be targeted with treatments, making them more effective. Genetic testing can also show if you have high-risk multiple myeloma, a more aggressive form of the disease. Knowing if you have high-risk multiple myeloma helps determine which treatments you’ll receive. Staging tests to show the extent of your cancer include blood work, urine tests, imaging studies, and a bone marrow biopsy.

Treatment Options for Third or Later Relapses

Several drugs can be used to treat later relapses. Many people with multiple myeloma eventually become resistant to IMiDs, proteasome inhibitors, and monoclonal antibodies, so they are treated with new classes of therapies. Specifically, these therapies are approved for treating people with multiple myeloma that has relapsed after at least four lines of therapy.

6. BCMA-Targeted Antibodies

One drug class that is used to overcome resistance includes antibodies that target B-cell maturation antigen (BCMA). These antibodies bind to the BCMA protein on the outside of myeloma cells.

Three BCMA-targeted antibodies have been approved by the FDA for treating relapsed multiple myeloma. The first, belantamab mafodotin-blmf, received approval in August 2020.

7. CAR T-Cell Therapies

The other two BCMA-targeted antibodies are used in a type of treatment known as chimeric antigen receptor (CAR) T-cell therapy, which involves teaching the immune system’s T cells to attack myeloma cells. The FDA approved idecabtagene vicleucel (Abecma) in March 2021 and ciltacabtagene autoleucel (Carvykti) in February 2022.

8. Bispecific T-Cell Engagers

Bispecific T-cell engagers (BiTEs) are a newer approach to treating relapsed or refractory multiple myeloma that involves antibodies that can bind to two antigens at once. The FDA approved the BiTE teclistamab-cqyv (Tecvayli) in 2022 for treating people who had previously tried three prior lines of therapy.

BiTEs work by targeting BCMA, a protein on the outside of myeloma cells, and the CD3 protein found in T cells. As a result, teclistamab-cqyv causes tumor cell lysis (destruction).

Read more about bispecific T-cell engagers and how they work to treat relapsed or refractory multiple myeloma.

9. Clinical Trials for Multiple Myeloma

For those who have had multiple relapses and generally exhausted their treatment options, clinical trials may be a good option. These studies test novel agents (new treatments) that are not yet FDA-approved for treating multiple myeloma but show promise.

Clinical trials may also use new combinations of already-approved drugs that haven’t yet been tested together.

If you’re interested in learning more about clinical trials for relapsing multiple myeloma, talk to your hematologist-oncologist. They will be able to recommend studies for which you may be eligible and discuss the benefits and risks of clinical trials.

Prognosis for Relapsed Multiple Myeloma

In general, the five-year survival rate for multiple myeloma is 58 percent. Approximately 33.6 percent of people diagnosed with myeloma are alive 10 years after their initial diagnosis. The time from the end of treatment to the first relapse strongly predicts survival. For example, one study found that people who initially relapsed within one year of treatment had, on average, a survival rate of just under two years. Those who relapsed later had a survival rate of approximately 10 years.

As research continues, myeloma treatments continue to improve overall survival rates and quality of life. Talk to your doctor about what to expect with a multiple myeloma relapse and what treatment options may work best for your individual condition.

Read more about life expectancy with relapsed or refractory myeloma.

Equal Access to Effective Treatment Options

Health outcomes haven’t improved equally for everyone with multiple myeloma. In the U.S., survival rates for Black people with multiple myeloma have not improved as much as survival rates for white people, likely due to less access to treatment. For instance, Black and Hispanic people are less likely to undergo bone marrow transplant than white people. They’re also underrepresented in clinical trials studying new treatments for multiple myeloma, compared with white and Asian people.

When everyone has equal access to care, Black and Hispanic people have similar or better survival rates than white people. To make sure you get access to the most effective treatment options for you, stay engaged with your health care team. Don’t hesitate to ask questions, and make sure your oncology team understands your goals for treatment.

Find Your Team

On MyMyelomaTeam, the social network for people with multiple myeloma and their loved ones, more than 20,000 members come together to ask questions, give advice, and share their stories with others who understand life with myeloma.

Have you experienced myeloma relapses? What would you say to someone who has yet to have a relapse? Share your experience in the comments below, or start a conversation by posting on your Activities page.