What Is Triple-Refractory Multiple Myeloma?

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A person's multiple myeloma is said to be triple-class refractory if it is resistant to all three classes of standard myeloma therapies, which include:

  • Proteasome inhibitors
  • Immunomodulatory agents
  • Monoclonal antibodies

The subset of people with triple-class refractory multiple myeloma has been characterized by poor survival outcomes. With this knowledge, a number of different strategies are being researched to try to overcome relapse and resistance to treatment to improve outcomes for individuals with multiple myeloma who have become resistant to the three standard myeloma therapies. 

woman with multiple myeloma

KatarzynaBialasiewicz / Getty Images

Triple-Refractory Multiple Myeloma Symptoms

New symptoms may be a clue that your multiple myeloma treatment isn’t working anymore and you have become resistant to treatment. They can include:

  • Bone pain, especially in the back or ribs
  • Bones that break easily
  • Fever for no known reason
  • Frequent infections
  • Easy bruising or bleeding
  • Trouble breathing
  • Weakness of the arms or legs
  • Feeling very tired

Be aware that even if you don’t have symptoms of myeloma, it could still be growing inside your body. That’s why it’s important to see your healthcare provider for regular checkups to monitor your condition.

Multiple myeloma common symptoms

Verywell / Nusha Ashjaee 


The reasons for people becoming resistant to multiple myeloma treatments are not fully understood. Despite the availability of new treatments, most people with multiple myeloma will become refractory to the therapies that currently comprise the standard of care for the malignancy, including:

  • Proteasome inhibitors
  • Immunomodulatory agents
  • Monoclonal antibodies

People with multiple myeloma can respond very differently to current treatment combinations. Some patients don’t respond well in the first place or they relapse quickly, despite having received the same treatment that, in other patients, leads to durable remissions, often many years long. 


The diagnosis of triple-refractory multiple myeloma depends on bone marrow tests and markers that can be detected in blood and sometimes in urine, all in addition to any signs and symptoms that may be present. Tests carried out include:

  • Specialized blood tests: These include immunoglobulin studies, complete blood count, and blood chemistry studies.
  • Urine tests: This is performed since the protein markers of interest in multiple myeloma can sometimes pass to the urine.
  • Bone marrow aspiration and biopsy: If you have multiple myeloma, there will be an excess of plasma cells in your bone marrow.
  • Imaging studies: These include X-ray of the bones, MRI, CT scan, and PET scan to determine whether bones have been damaged by multiple myeloma.


The current approaches to the treatment of triple-class refractory disease are limited and include:

Remember each patient may respond differently to treatment combinations. Drugs that may be used may include the following:

  • Targeted therapy with monoclonal antibodies (daratumumab or elotuzumab)
  • Targeted therapy with proteasome inhibitors (bortezomib, carfilzomib, or ixazomib)
  • Immunotherapy (pomalidomide, lenalidomide, or thalidomide)
  • Histone deacetylase inhibitor therapy with panobinostat
  • Antibody-drug conjugate therapy with belantamab mafodotin
  • Corticosteroid therapy

Drug research is also focused on further understanding the clonal evolution of myeloma cells, which is responsible for the progression of myeloma.

New technologies are allowing scientists to study the genetic changes in myeloma cells between when the disease is first diagnosed and when it relapses. This should allow the design of new drugs to prevent relapse and maintain long-term remissions.

Melflufen (melphalan flufenamide)

There are promising results coming from clinical trials of medications to treat triple-class refractory multiple myeloma.

The drug melflufen (melphalan flufenamide) kills myeloma cells through the use of peptidases (enzymes that break down peptides) that are often found in higher numbers in myeloma cells than in healthy cells.

When melflufen enters myeloma cells, the peptidases within the cell break the bond holding the melphalan and the peptidase together. This releases active melphalan within the myeloma cell. The melphalan then causes irreversible DNA damage, leading to cell death.

In the phase II HORIZON clinical trial, melflufen and dexamethasone were given to a total of 154 patients who had received an average of five previous treatment lines.

About three in every 10 patients (29%) responded to the treatment, and the average time before the myeloma started to come back was four months. These results indicated that melflufen may be beneficial for patients who have had multiple lines of treatment previously.

Clinical Trials

The National Cancer Institute has a clinical trial search to find cancer clinical trials that are accepting patients. You can search for trials based on the:

  • Type of cancer
  • Age of the patient
  • Where the trials are being done

General information about clinical trials is also available.


When multiple myeloma becomes refractory to three or more therapeutic agents, this can leave clinicians unsure of how to proceed. This is because fewer therapeutic options will remain for heavily pretreated people who have developed a more aggressive disease, resulting in poorer outcomes for this population.

A multicenter study enrolled 543 patients with triple-class-exposed refractory multiple myeloma, who had also been treated with an alkylating agent. The median overall survival was 13 months.

In a 2016 retrospective analysis investigating the outcomes in a similar patient population, the overall survival was poor despite the availability of newer agents, with a median overall survival of about 8 months.

The identification of more effective therapeutic interventions for this population has emerged as a key priority for multiple myeloma research.


Having multiple myeloma usually requires making some adjustments in life. Some of these changes may be transitory, while others are long-term. It’s important to seek out a support network both in-person and online, where you can find other patients with the same condition. 

You may reach a point when you decide not to have any more treatment for your multiple myeloma, or a time is reached when the cancer has progressed to a point where nothing more can be done to keep it under control. Making the decision to stop treatment is never an easy one. Planning ahead by having early discussions with your family and healthcare providers can help ease the process.

End-Of-Life Care

While it's understandable that most people do not want to focus on the fatality of any disease, learning to be proactive in managing advanced directives, living wills, and other end-of-life care issues can be very empowering.

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10 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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