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Refractory Myeloma: What To Expect When the First Treatment Fails

Posted on December 13, 2022
Medically reviewed by
Richard LoCicero, M.D.
Article written by
Emily Wagner, M.S.

  • When myeloma treatment doesn’t work or stops working, this is known as refractory myeloma.
  • Refractory myeloma can be treated with different combinations of medications that may work better.
  • Clinical trials are currently investigating new treatments to give people with refractory myeloma more options.

After a multiple myeloma diagnosis, your doctor will work with you to develop a treatment plan. Typically, this will involve first-line treatments commonly prescribed to help control myeloma, slow disease progression, and reduce or reverse complications.

However, 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. Everyone who gets a diagnosis of myeloma is prescribed a first-line treatment regimen aimed at reducing the number of myeloma cells in the body while preventing damage to the organs.

The standard first-line treatment option 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.

Other combinations include:

  • Cyclophosphamide (Cytoxan), bortezomib, and dexamethasone
  • Thalidomide (Thalomid), bortezomib, and dexamethasone
  • Daratumumab and hyaluronidase (Darzalex Faspro), 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.

While these initial therapies may be effective for some time, eventually most people with myeloma will relapse, meaning symptoms will return or worsen. If your doctor suspects your treatment plan is no longer working, they will run a series of tests. These may include blood work to look for the presence of M protein — an abnormal protein secreted by myeloma cells — and measure calcium levels, and 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.

Considering Next-Line Treatment Options

Once a treatment no longer works against myeloma, the myeloma is considered to be refractory. A person may have had a complete response (no remaining signs of myeloma in the body) to the first-line treatment, but over time their myeloma became resistant.

If you’re diagnosed with refractory myeloma, your doctor will discuss your next treatment options with you. These will depend on a few factors, including what treatment plan was used 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 are best after a relapse, certain tests are recommended, including:

  • Restaging according to the Revised International Staging System (R-ISS)
  • Testing cytogenetics to identify mutations on chromosomes in plasma cells
  • Checking organ health (such as kidney function)

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

While not widely used currently, genetic testing is being studied as a way to monitor treatments for those with multiple myeloma. The MATCH screening trial is a phase 2 clinical trial examining genetic testing to influence treatment decisions for refractory myeloma, along with lymphoma and other cancers. Researchers hope someday genetic testing can be a tool for developing better treatment plans for people with refractory cancers.

Understanding Later-Line Therapies

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.

Immunomodulatory Drugs

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

Proteasome Inhibitors

In cases where first-line PIs like bortezomib fail, there are a few other options. Ninlaro (a formulation of ixazomib) 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 (Kyprolis) 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 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.

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 to 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.

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 two different combination therapies to treat refractory myeloma. The first is with dexamethasone and lenalidomide to treat people who have already received one to three lines of treatment. The second 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 those with 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 Sarclisa, a formulation of isatuximab-irfc, to treat refractory myeloma in people who previously received one to three lines of treatment. It’s combined with dexamethasone and carfilzomib to be as effective as possible.

Histone Deacetylase Inhibitors

Outside of the main drug classes used to treat multiple myeloma, panobinostat (Farydak) is another option. This histone deacetylase inhibitor is combined with dexamethasone and bortezomib to treat myeloma in people who were previously treated with an immunomodulatory drug and bortezomib.

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.

Currently, several clinical trials are investigating refractory myeloma treatments. Existing drugs like selinexor, dexamethasone, and carfilzomib are being studied in combination, as well as new drugs like ABBV-453.

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 stages of myeloma, including refractory myeloma.

Read more about new treatment options for relapsed or refractory myeloma.

Talk With Others Who Understand

MyMyelomaTeam is the social network for people with myeloma and their loved ones. More than 16,000 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 on MyMyelomaTeam.

References
  1. What Is Multiple Myeloma? — American Cancer Society
  2. Frontline Treatment Options — International Myeloma Foundation
  3. Relapsed/Refractory Multiple Myeloma in 2020/2021 and Beyond — Cancers
  4. Induction Therapy for Newly Diagnosed Multiple Myeloma — American Society of Clinical Oncology Educational Book
  5. Bone Marrow Transplant — Mayo Clinic
  6. Choosing the Right Therapy for Patients With Relapsed/Refractory Multiple Myeloma (RRMM) in Consideration of Patient-, Disease-, and Treatment-Related Factors — Cancers
  7. Minimal Residual Disease (MRD) — Leukemia & Lymphoma Society
  8. Refractory Cancer — National Cancer Institute
  9. Approaches and Challenges in the Management of Multiple Myeloma in the Very Old: Future Treatment Prospects — Frontiers In Medicine
  10. Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial) — National Cancer Institute
  11. Pomalidomide Plus Low-Dose Dexamethasone in Relapsed Refractory Multiple Myeloma After Lenalidomide Treatment Failure — British Journal of Haematology
  12. Multiple Myeloma: Diagnosis and Treatment Options — The American Journal of Managed Care
  13. CAR T-Cell Therapy and Its Side Effects — American Cancer Society
  14. FDA Approves Idecabtagene Vicleucel for Multiple Myeloma — U.S. Food and Drug Administration
  15. Monoclonal Antibodies — National Cancer Institute
  16. FDA Drug Approval: Elotuzumab in Combination With Lenalidomide and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma — Clinical Cancer Research
  17. FDA Approves Isatuximab-irfc for Multiple Myeloma — U.S. Food and Drug Administration
  18. Selinexor, Carfilzomib, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma (SINE) — ClinicalTrials.gov
  19. A Study To Assess the Adverse Events and Change in Disease Activity in Adult Participants With Relapsed or Refractory Multiple Myeloma Receiving Oral ABBV-453 Tablets — ClinicalTrials.gov
  20. Find NCI-Supported Clinical Trials — National Cancer Institute
Posted on December 13, 2022
All updates must be accompanied by text or a picture.
Richard LoCicero, M.D. has a private practice specializing in hematology and medical oncology at the Longstreet Clinic Cancer Center, in Gainesville, Georgia. Review provided by VeriMed Healthcare Network. Learn more about him here.
Emily Wagner, M.S. holds a Master of Science in biomedical sciences with a focus in pharmacology. She is passionate about immunology, cancer biology, and molecular biology. Learn more about her here.

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