What Is Refractory Multiple Myeloma?

Written by Stephanie Booth
Medically Reviewed by Brunilda Nazario, MD on December 15, 2025

Refractory multiple myeloma means that your blood cancer isn’t responding to treatment. Your doctor may also refer to this as “progressive disease.” Hearing that your treatment isn’t slowing the spread of cancer cells in your body can be hard to hear. It’s important to remember that another type of cancer treatment might work better.

Multiple myeloma is a rare disease. Your average lifetime risk of being diagnosed is less than 1%. About 36,110 people are expected to be diagnosed in the U.S. this year. 

A significant number of people with multiple myeloma need to have three or more kinds of treatment.

Doctors use a few terms to describe refractory multiple myeloma based on the types of cancer treatment that you have had and the duration of your cancer’s response.

Primary refractory multiple myeloma is when you didn’t have a response to your first treatment.

Double refractory multiple myeloma describes cancer that has spread during or after you were treated with protease inhibitor or immunomodulator drugs.

Triple-class refractory multiple myeloma, or triple-class refractory disease, means that your cancer also didn’t respond to monoclonal antibodies.

Experts still don’t know what causes multiple myeloma. It starts in your plasma cells, a type of white blood cell that helps your body fight infection. Multiple myeloma causes a normal  plasma cell to mutate (change) and build up in your bone marrow, destroying it and crowding out other healthy cells.

You’re at higher risk for multiple myeloma if you:

  • Have a family history of multiple myeloma or plasma cell diseases
  • Have obesity
  • Are over 65 years old
  • Are Black
  • Are male
  • Have been exposed to radiation or toxic chemicals

What causes multiple myeloma to resist treatment?

Myeloma cells change over time. If one cancer treatment doesn’t wipe them all out, then the ones that are left can find new ways to survive and spread. That resistance may grow with each treatment that’s tried.

Many new, exciting treatments for multiple myeloma are available than ever before. That’s great news, but it can also make it hard for your doctor to know which ones will work best for you.

Refractory multiple myeloma causes the same symptoms as multiple myeloma. These symptoms either don't go away or return after treatment.

The most common symptoms are usually:

  • Bone pain
  • Shortness of breath
  • Fatigue

Your bones may also break very easily. And you could get sick easily because your immune system isn’t working like it should.

Once you start treatment, your doctor will do regular tests and scans to see if your cancer has responded. That usually includes:

Blood tests. A complete blood count (CBC) is a test that measures the amount of red blood cells, white blood cells, and platelets in your blood. Multiple myeloma can lower the numbers of these cells.

Blood chemistry tests check levels of proteins and other substances in your blood. Multiple myeloma can cause high calcium levels and low levels of the protein albumin.

Other blood tests detect high or low levels of certain antibodies that multiple myeloma can affect. Antibodies are immune system proteins that help your body fight infections. They are normally made by plasma cells. Myeloma cells make antibodies called M proteins.

Urine tests. This test looks for an abnormal protein that’s made by myeloma cells. You may need to collect all of your urine for 24 hours.

Imaging tests. These tests let your doctor look inside your body to see whether your cancer has gotten smaller or if it has grown. Some tests you might get are:

  • An X-ray, which uses radiation in low doses to make images of your bones. It can show areas of bone loss from multiple myeloma.
  • An MRI, which uses powerful magnets and radio waves to make 3D pictures of your soft tissue and bone marrow.
  • A CT scan combines X-rays from different angles to make a detailed image of your bones. That helps them find any areas of cancer.
  • A PET scan uses radioactive sugar that your cancer cells quickly absorb. Then a special camera takes pictures to show clusters of cancer in your body.

When you see your doctor for follow-up visits, it's helpful to have a list of questions ready. You can also bring along a family member or friend to help you guide the conversation and write down your doctor's answers.

Some questions you might ask:

  • What new treatment do you suggest, and why?
  • When would I start it and how long does it last?
  • How will I know if the next treatment is working?
  • What side effects could I have?
  • What are some symptoms that you need to know about right away?
  • If another treatment doesn't help or it stops working, what other treatments will you try?
  • If I’m worried about finances or getting to and from my treatment, who can I talk to?
  • Should I join a clinical trial?

You may decide to get a second opinion about the next cancer treatment that you try. This is a common practice when you have a complex condition like multiple myeloma. Many treatment options are available and doctors often have different approaches.

To find another oncologist:

Ask for word-of-mouth recommendations. Your primary care doctor may be able to suggest someone. You could also ask someone you trust who has gone through cancer treatment. 

Check with your health plan. Your insurance may only pay for you to see certain doctors, which could narrow your options.

Look for a treatment center that specializes in multiple myeloma. They may have more access to certain treatments or new types of testing.

Get advice from a national myeloma organization. For instance, both the International Myeloma Foundation and Blood Cancer United offer free help in finding a blood cancer specialist.

As you continue with your cancer treatment, your care team could also grow to include a:

  • Nephrologist, a kidney specialist
  • Orthopedist or orthopedic oncologist, to help with any bone issues
  • Radiation oncologist, if radiation is part of your treatment plan
  • Physical therapist, to help you gain strength and range of motion
  • Palliative care doctor, who can help manage your symptoms and make you more comfortable

To figure out the best next steps for you, your doctor will take many things into account, including:

  • Treatments that you’ve already had
  • How the cancer cells responded to them 
  • Your general health
  • Multiple myeloma symptoms that you’re having 

Several types of medications can be used to treat refractory multiple myeloma. These include:

Chemotherapy. It uses strong medicine to kill cancer cells or stop them from dividing. Examples include bendamustine (Bendeka), cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), and melphalan (Alkeran).

Targeted therapy:

  • Proteasome inhibitors, such as bortezomib (Velcade), carfilzomib (Kyprolis), or ixazomib (Ninlaro), which slow the multiplying of myeloma cells.
  • Monoclonal antibodies such as daratumumab (Darzalex), daratumumab and hyaluronidase (Darzalex Faspro),  elotuzumab (Empliciti), and isatuximab (Sarclisa). These are lab-made versions of proteins that your body makes. They attack specific targets (proteins) on the surface of myeloma cells to kill them directly and help your immune system get involved in the fight. 
  • Antibody-drug conjugate (ADC). This treatment links a monoclonal antibody to a chemotherapy drug. That way, the antibody can deliver chemotherapy directly to cancer cells. 
  • Nuclear export inhibitor. Selinexor (Xpovio) is a new kind of medication. It blocks a protein that myeloma cells need to stay alive.
  • T-cell engagers (TCEs). These newer medications can attach to both a T cell (a type of immune cell) and a myeloma cell at the same time, causing an immune attack on the cancer cell. Your doctor may prescribe a TCE when other treatments haven’t worked. Elranatamab (Elrexfio), linvoseltamab (Lynozyfic), talquetamab (Talvey), and teclistamab-cqyv (Tecvayli) are bispecific T-cell engagers.
  •  Cereblon E3 ligase modulatory drugs (CELMoDs). This is a new drug class of medications that target specific proteins in cancer cells and break them down, helping to stop cancer cell growth and causing the cells to die. Iberdomide (Zenbexus) was recently FDA-approved in combination with daratumumab and hyaluronidase-fihj and dexamethasone (ZDd) for treatment of multiple myeloma in adults who have received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.

Immunomodulatory drugs, such as lenalidomide (Revlimid), pomalidomide (Pomalyst), and thalidomide (Thalomid), try to stop myeloma by changing how your immune system works.

Cellular immunotherapy. Chimeric antigen receptor (CAR) T-cell therapy is a type of immunotherapy. Your doctor removes T cells from your body. Those cells go to a lab, which modifies and multiplies them so they can find and attack your cancer cells. Examples include ciltacabtagene autoleucel (Carvykti) and idecabtagene vicleucel (Abecma).

People with refractory multiple myeloma sometimes take a combination of two to four kinds of medicine. That can include a steroid medicine to kill more myeloma cells or help lessen treatment side effects. For example, if you have relapsed or refractory multiple myeloma and have received at least one prior line of therapy, teclistamab-cqyv (Tecvayli) plus daratumumab and hyaluronidase-fihj (Darzalex Faspro) might be an option.

Your doctor can try different combinations of these drugs to see what works best against your cancer. If one combination doesn't help, you can switch to another one.

Other treatment options include:

Stem cell transplant. This is a common procedure to treat multiple myeloma, especially if your health is good. First, you’ll have chemotherapy to kill cells in your bone marrow, where all new cells are made. Then, you'll be given new healthy stem cells in an IV to replace them.

Clinical trial. A clinical trial gives you access to a new treatment that you wouldn’t otherwise get, as well as extra health care. There’s no cost to join a clinical trial. Ask your doctor if they know of one that might be right for you.

Multiple myeloma can lead to other health issues like:

  • Blood clots
  • Bacterial infections
  • Broken bones
  • Nerve damage and pain
  • Hypercalcemia (too much calcium in your blood)
  • Amyloidosis (a build-up of abnormal proteins in your organs)
  • Cryoglobulinemia (damage and inflammation of your blood vessels)
  • Myelopathy (compressed spinal cord)
  • Hyperviscosity syndrome (when your blood is too thick to flow easily through your body)
  • Kidney failure

Your doctor will work closely with you to try to prevent these complications from happening and manage them if they do.

Try to take care of yourself as best as you can. Making healthy choices every day can help. It can also help you tolerate your next treatment better and lessen its side effects.

For instance, you can:

Give up smoking. Tell your doctor if you need help quitting.

Get regular exercise. Ask your doctor which types are safe for you to try. Usually, walking and swimming are good options.

Eat a healthy diet. Focus on “real” foods like fruits, vegetables, fish, lean proteins, and whole grains. Try to limit added sugars and ultra-processed foods.

Drink plenty of water. It can help with side effects like constipation and keep you from getting dehydrated.   

Try not to get sick. Your immune system is weaker than usual when you go through cancer treatment. Wash your hands often, and stay updated on your vaccines.

Staying organized 

Keeping track of doctor visits, prescription refills, and insurance claims is another way to practice self-care and reduce stress. To stay on top of all the information related to your cancer treatment, divide it into five groups:

  • Articles and research
  • Personal health information, like test results
  • Schedules and contact information 
  • Health insurance and billing 
  • Legal documents, like your will

Keep these files together in a safe place at home or store them on your computer. Make sure that a loved one knows how to find them, too.

There’s still no cure for multiple myeloma, but treatments can try to slow down how fast it spreads, manage your symptoms, and improve your quality of life. 

Having a good response to your first treatment is linked to a better outcome.

According to the National Cancer Institute, the five-year survival rate for multiple myeloma is nearly 60%. About 31.6% of people survive 10 years after their diagnosis.

Talk to your doctor about your own outlook and what you can expect. 

Unlike many other types of cancer, multiple myeloma is a “relapsing and remitting” cancer. Even a complete response to treatment can’t make it go away for good. At some point, the myeloma cells will return and start spreading. When they do, you’ll need treatment again.

Treatments for multiple myeloma keep getting better, but any cancer treatment can be physically and emotionally draining. How many treatments you choose to pursue is your personal decision.

If you have questions about what will happen if you stop treatment, talk to your doctor.  

It's important to reach out to others to get the emotional backing you need. Family and friends are a good place to start. You can talk to them or ask them to help you with everyday tasks like cooking and cleaning when you don't feel well. 

Multiple myeloma support groups are another place to turn. They help you meet other people with the same kind of cancer. They may have advice to help you manage your condition and can relate to how you’re feeling.

You can find a support group through an organization like the American Cancer Society, Multiple Myeloma Research Foundation, or the International Myeloma Foundation.

Although your doctor’s focus will be on your physical health, remember that it’s crucial to care for your mental health, too. Living with multiple myeloma can be a challenge.

 You may find it helpful to:

Get more information. Learning more about refractory multiple myeloma and different treatments can give you a better idea of what to expect. Bring a loved one to a doctor’s visit so they can help write down what the doctor tells you. You could also ask your doctor for information handouts that you can take home with you.

Take control. There’s a lot about cancer that is uncertain. Try to focus instead on all the things in your life that you can control. You may find it comforting to make to-do lists, plan activities you enjoy, and schedule regular time with loved ones.

Try a mindfulness-based practice. Being mindful means trying to stay in the present, without judgment,  instead of jumping ahead into the future and asking “What if?” or trying to replay the past. Making time to do this every day may help you feel more calm. Ways you can be more mindful include meditation, deep breathing exercises, and guided imagery.

Get more support. Anxiety and depression are common in people with multiple myeloma. If you feel sad or can’t stop worrying,  talk to your doctor. They can connect you to a mental health expert, like a counselor or therapist. You may find it useful to talk to someone who has experience helping people who live with cancer. 

Caring for someone with refractory multiple myeloma is an important job. You may be scheduling your loved one’s doctor visits, driving them to appointments, picking up their prescriptions, helping them be comfortable at home, giving them emotional support, and relaying news to family members and friends.

It’s common to feel frustrated at times over how much you’re doing or feel guilty that you’re not doing more. To keep from getting overwhelmed, you might:

Ask friends and family to help. Some people are happy to pitch in, but don’t offer until they’re asked. It may help to assign specific tasks.

Don’t take on more than you need to. Let your loved one keep doing the things they’re capable of, even if you can do them faster or better.

Look for local resources. Talk to your loved one’s doctor about where and how you can get support. For instance, there may be a local volunteer group that can drive them to a doctor’s visit or bring over dinner so you can get a small break.

Respect your loved one’s choices. You may not agree with some of the decisions that they make, whether it’s a lifestyle choice or something that has to do with their treatment. Respect their wishes unless it puts them or someone else in danger.

Refractory multiple myeloma means that your cancer treatment didn’t work and myeloma cells are still spreading in your body. That can be very hard news to hear, but your doctor can discuss other treatments that you can try. Do your best to take care of yourself. That includes managing your stress, eating healthy foods, trying to get enough exercise and sleep, and talking honestly with loved ones about what you’re going through. 

What’s the difference between relapsed and refractory multiple myeloma?

Relapsed multiple myeloma means that your cancer returned after you finished cancer treatment. Refractory multiple myeloma is when your cancer doesn’t respond to cancer treatment.

What is primary refractory multiple myeloma?

If you have primary refractory multiple myeloma, your cancer didn’t respond to the first cancer treatment you had. Some doctors also refer to this as “very early relapse” or “functional high risk.” 

Can CAR-T cell therapy treat refractory multiple myeloma?

CAR-T cell therapy can be a good option for refractory multiple myeloma. Data shows that this type of treatment can have a 67% to 83% response rate.

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