When you’re first diagnosed with multiple myeloma, your doctor will prescribe first-line treatments to help control symptoms, slow disease progression, and reduce or reverse complications. However, in some cases, myeloma cells can become resistant to treatment.

If myeloma doesn’t respond — or stops responding — to treatment, it’s known as “refractory myeloma.” If you develop refractory myeloma, it’s important to know what to expect and what your next treatment options are.

First-Line Treatments for Multiple Myeloma

In multiple myeloma, plasma cells (a type of white blood cell) grow rapidly and abnormally, causing damage to the bone marrow. Most people who get a diagnosis of myeloma will be prescribed a first-line treatment regimen to reduce the number of myeloma cells in the body while preventing damage to the organs.

The standard first-line treatment for multiple myeloma involves triplet combinations of chemotherapy, immunomodulatory drugs, and proteasome inhibitors (PIs). This is known as “induction therapy.”

The most common combination of drugs used for induction therapy is lenalidomide (Revlimid), bortezomib (Velcade), and the corticosteroid dexamethasone. If this combination is successful, lenalidomide can also be used for maintenance therapy for multiple myeloma.

There are more than a dozen other combinations that may be prescribed, including:

• Carfilzomib (Kyprolis), lenalidomide, and dexamethasone
• Daratumumab and hyaluronidase (Darzalex Faspro), bortezomib, lenalidomide, and dexamethasone
• Cyclophosphamide, bortezomib, and dexamethasone
• Thalidomide (Thalomid), bortezomib, daratumumab, and dexamethasone
• Daratumumab and hyaluronidase, bortezomib, prednisone, and melphalan (Alkeran)

After induction therapy, you may also undergo an autologous bone marrow transplant. This procedure uses your own healthy cells to replace the cancerous marrow destroyed during induction therapy. For this procedure, your healthy bone marrow cells are collected and stored before treatment. After induction therapy, these healthy cells are given back to replace your bone marrow cells.

While these initial therapies may be effective for some time, most people with myeloma eventually will relapse, meaning symptoms will return or worsen. This is known as “relapsed myeloma.”

If your doctor suspects your treatment plan is no longer working, they will run a series of tests. These may include blood work to measure calcium levels and look for the presence of M protein (an abnormal protein secreted by myeloma cells), as well as a bone marrow biopsy to look for myeloma cells. They may also perform minimal residual disease testing, which looks at blood or bone marrow samples. These extremely sensitive tests can detect whether you need to restart treatment or try another therapy.

Read more about the relapse rate for multiple myeloma.

How Doctors Decide What To Recommend Next

If a treatment does not work against myeloma, the myeloma is considered refractory. Some people may have a complete response (no remaining signs of myeloma in the body) to the first-line treatment, but over time their myeloma relapses.

If you’re diagnosed with relapsed or refractory myeloma, your doctor will discuss your next treatment options with you. These will depend on a few factors, including what treatment you had for first-line therapy, along with your age and overall health. Some treatments — like high-dose chemotherapy — are more intense than others and have side effects that may be difficult for some people to handle. The median age of myeloma diagnosis is 70 years, and age can affect organ function and overall health.

To determine which treatment options will be most effective, certain tests are recommended, including:

• Testing to identify mutations on chromosomes (cytogenetic testing)
• Checking kidney function and bone health

Together, you and your doctor will consider all of the results and form a new treatment plan.

Treatment Options for Refractory Myeloma

Receiving a refractory myeloma diagnosis can be overwhelming, but there are several other treatment options available to help. These include other types of PIs, immunomodulatory drugs, and immunotherapy, along with newer treatments to help control myeloma. A new treatment regimen will depend on the drugs you had previously, as well as how long it took for the myeloma to relapse or become refractory.

Receiving a refractory myeloma diagnosis can be overwhelming, but there are several treatment options available to help.

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1. Immunomodulatory Drugs

For those who were treated with thalidomide or lenalidomide and have progressed to refractory myeloma, there is a third immunomodulatory option available. Pomalidomide (Pomalyst) is similar to these medications, but it can be used in combination with dexamethasone and other drugs to treat refractory disease.

2. Proteasome Inhibitors

In cases where first-line PIs like bortezomib fail, there are other options. Ixazomib (Ninlaro) is an oral PI approved by the U.S. Food and Drug Administration (FDA) to treat refractory myeloma. It’s often combined with dexamethasone and lenalidomide.

Carfilzomib is another PI that can be given alone to people with refractory myeloma who were treated with at least one other therapy. It can also be used in a few different combinations to treat refractory myeloma after trying one to three other lines of therapy. These combinations include:

• Dexamethasone
• Dexamethasone and lenalidomide
• Dexamethasone and daratumumab

While not yet approved, marizomib is a third PI undergoing clinical studies for treating myeloma. It shows early promise, and trials continue to investigate it.

3. CAR T-Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy is a cancer treatment in which the T cells from your immune system are changed so they can better recognize cancer cells. These changed cells are then infused back into your bloodstream to help fight cancer.

In early 2021, the FDA approved Abecma — a formulation of idecabtagene vicleucel — to treat refractory myeloma in people who have tried four or more lines of treatment, including PIs, immunomodulatory drugs, and monoclonal antibodies. It is specialized to each individual with myeloma, using their own T cells. Studies show that 28 percent of people achieved complete response on idecabtagene vicleucel, and 65 percent of those maintained the response for at least 12 months.​​

Another CAR T-cell therapy, ciltacabtagene autoleucel (Carvykti) is approved for people with relapsed or refractory multiple myeloma who’ve received at least one other line of therapy and for whom lenalidomide didn’t work.

4. Monoclonal Antibodies

Monoclonal antibodies are specialized antibodies that have been engineered to recognize certain markers on immune cells and cancer cells.

Elotuzumab (Empliciti) was the first FDA-approved monoclonal antibody for treating relapsing/refractory multiple myeloma. It is not prescribed on its own in treatment. Instead, it’s used in three different combination therapies to treat refractory myeloma. The first is with dexamethasone and lenalidomide, and the second is with bortezomib and dexamethasone. Both combinations are used to treat people who have already received one to three lines of treatment. The last combination is with dexamethasone and pomalidomide to treat those who have received at least two therapies (lenalidomide and PIs).

While daratumumab is often used as first-line therapy, the drug can also be used to treat refractory myeloma that is resistant to both PIs and immunomodulatory drugs. It’s administered alone to treat refractory myeloma after a person has tried at least three lines of therapy (including an immunomodulatory drug and PIs).

The FDA has approved isatuximab-irfc (Sarclisa) to treat refractory myeloma in people who previously received one to three lines of treatment. It can be combined with dexamethasone and carfilzomib or dexamethasone and pomalidomide to be as effective as possible.

5. Bispecific T-Cell Engagers

Bispecific T-cell engagers (BiTES) are one newer option for treating refractory multiple myeloma. Teclistamab-cqyv (Tecvayli) was approved in 2022 to treat people with multiple myeloma who have previously received four or more lines of therapy. Teclistamab-cqyv is the first BiTE to be indicated for myeloma. The FDA granted the drug accelerated approval due to its performance in clinical studies.

CAR T-cell therapies and BiTES are two newer types of treatments approved to fight refractory myeloma.

Since then, the FDA has approved two new BiTES: elranatamab-bccm (Elrexfio) and talquetamab (Talvey).

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

6. Clinical Trials for Treating Refractory Myeloma

While there are many therapies currently available, researchers and doctors are always looking for the next effective refractory myeloma treatment. These include novel drugs that are not yet approved or new combinations of available drugs, such as selinexor (Xpovio), dexamethasone, and carfilzomib.

You may be eligible to join clinical trials for refractory myeloma and get access to novel drugs or new combinations of available drugs.

If you’re interested in learning more about ongoing clinical trials, you can take a look at those supported by the National Cancer Institute or ask your hematology specialist. Clinical trials are available for all types and stages of blood cancers, including leukemia, lymphoma, and myeloma.

Stay Engaged To Get the Most Effective Treatment Options

While things are changing slowly, it’s an unpleasant truth that not everyone has equal access to care for multiple myeloma. For instance, Black and Hispanic people are underrepresented in clinical trials studying new treatments for multiple myeloma, compared with white and Asian people. Given equal access to care, Black and Hispanic people with myeloma 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.

Talk With Others Who Understand

MyMyelomaTeam is the social network for people with myeloma and their loved ones. More than 25,000 members come together to ask questions, give advice, and share their stories with others who understand life with myeloma.

Are you living with refractory multiple myeloma? What kinds of treatments have you received? Share your experience in the comments below, or start a conversation by posting to your Activities feed.