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When you’re first diagnosed with multiple myeloma, your doctor will typically recommend first-line treatments to help control symptoms, slow disease progression, and reduce or reverse complications. But over time, the myeloma cells may stop responding to these therapies.
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.
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In multiple myeloma, white blood cells known as plasma cells 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 their body while preventing damage to the organs.
First-line treatment for multiple myeloma involves triplet (three-drug) or quadruplet (four-drug) regimens, known as “induction therapy.” Myeloma experts usually recommend a quadruplet regimen that involves chemotherapy, immunomodulatory drugs, and medications called proteasome inhibitors (PIs).
The most common combination of drugs used for induction therapy is daratumumab (Darzalex), 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:
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.
If your doctor suspects your treatment plan is no longer working, they may order a series of tests to learn how your myeloma is responding. Health experts use a set of criteria developed by the International Myeloma Working Group (IMWG) to assess treatment response. These are based on the CRAB criteria, which focus on signs of organ damage caused by myeloma. CRAB stands for:
Doctors will also consider your levels of M protein — an abnormal monoclonal protein made by myeloma cells. A bone marrow biopsy can look for myeloma cells in the bone marrow.
Read more about the symptoms of multiple myeloma relapse.
While first-line 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 a treatment doesn’t 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 refractory multiple myeloma treatment options with you. Most people will be prescribed a new combination of drugs that’s different from the first. However, if your relapse occurs one year or more after your initial therapy, your doctors may recommend the same regimen.
Together, you and your doctor will consider all of the results and form a new treatment plan.
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.
For those who were treated with thalidomide or lenalidomide and have progressed to refractory myeloma, there’s a third immunomodulatory option. Pomalidomide (Pomalyst) is similar to these medications, but it can be used in combination with dexamethasone and other drugs to treat refractory disease. Pomalidomide is typically used after at least two prior therapies — including lenalidomide and a proteasome inhibitor — have been unsuccessful. Lenalidomide may also be used in some cases of refractory myeloma, as part of combination therapy.
In cases where first-line PIs like bortezomib fail, there are other options. Ixazomib (Ninlaro) is a PI approved by the U.S. Food and Drug Administration (FDA) to treat refractory myeloma. It’s often combined with dexamethasone and lenalidomide and is the only PI that can be taken by mouth.
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 combinations to treat refractory myeloma after trying one to three other lines of therapy. These combinations include:
Chimeric antigen receptor (CAR) T-cell therapy is a personalized cancer treatment in which the T cells from your immune system are changed so they can better recognize cancer cells. These modified 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. It’s approved to treat adults who’ve tried two or more previous myeloma treatments, including PIs, immunomodulatory drugs, and monoclonal antibodies.
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. This treatment may be considered in people in their first relapse.
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 can be used in combination with lenalidomide and dexamethasone for people who’ve tried one to three lines of treatment. It can also be used alongside pomalidomide and dexamethasone for people who have tried at least two other treatments, including lenalidomide and a PI.
While daratumumab is often used as first-line therapy, the drug can also be used alone or in combination with other treatments for refractory myeloma. 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) or when someone doesn’t respond to both a PI and an immunomodulatory drug.
The FDA has approved isatuximab-irfc 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.
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.
Since then, the FDA has approved three new BiTES:
Read more about bispecific T-cell engagers and how they work to treat relapsed or refractory multiple myeloma.
Antibody-drug conjugates (ADCs) pair a targeted antibody with a chemotherapy‑like drug to deliver treatment directly to myeloma cells while limiting damage to healthy cells.
Belantamab mafodotin‑blmf (Blenrep) is an ADC that targets BCMA, a protein found on myeloma cells. It was first approved in 2020 but was withdrawn in 2022 after a follow-up study didn’t confirm its benefit. In 2025, the FDA reapproved the drug in combination with bortezomib and dexamethasone for adults with relapsed or refractory myeloma who’ve had at least two prior treatments.
Nuclear export inhibitors block the movement of proteins around the cell, which can trigger cell death in myeloma cells. Selinexor (Xpovio) is the first nuclear export inhibitor approved by the FDA for myeloma. It’s used in combination with bortezomib and dexamethasone in people who have tried at least one prior therapy. It can also be used in combination with dexamethasone for people who have tried at least four other treatments, including two PIs and two immunomodulatory drugs, and a monoclonal antibody.
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.
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.
While things are changing slowly, it’s an unpleasant truth that not everyone has equal access to care for multiple myeloma. For instance, in the United States, 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 refractory multiple myeloma therapy options for you, stay engaged with your healthcare team. Don’t hesitate to ask questions, and make sure your oncology team understands your goals for treatment.
On MyMyelomaTeam, people share their experiences with myeloma, get advice, and find support from others who understand.
Are you living with refractory multiple myeloma? Which treatments have you received? Let others know in the comments below.
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After My Chemotherapy Treatment With Velcaide I Was Placed On Revlimid+Dexamethasone; But Later Dexamethasone Was Stopped; Why?
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In October 2022, l went through the ABECMA Car-T therapy treatment for my Multiple Myeloma. My oncologist said l should get at least a year without any type of treatment. I wound up getting 50 weeks… read more
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