What Is Triple-Refractory Multiple Myeloma?

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Multiple myeloma is a rare, incurable cancer of plasma cells that affects 1 in every 132 Americans. It can lead to multi-organ failure, causing a variety of symptoms that range from weakness and fatigue to bone pain and renal failure

The prevalence of relapse and drug resistance in people with multiple myeloma is rising. Experts are unsure why, especially since the advent of new, more effective, and less toxic therapies.

People with triple-refractory multiple myeloma have worse overall outcomes than those with multiple myeloma and experience more frequent and persistent symptoms—even after treatment. This underscores the importance of finding new, more effective treatment options. 

This article discusses the symptoms, diagnosis, causes, and treatment for triple multiple myeloma.

HCP and patient

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Triple-Refractory Multiple Myeloma Symptoms

Multiple myeloma may present with the generalized symptoms of fatigue, weakness, and unexplained weight loss. The symptoms that you experience will depend on the organ system that is affected.

Common symptoms of multiple myeloma include:

  • Anemia: This is a lack of healthy red blood cells, which can result in fatigue, weakness, or confusion.
  • Bone pain: Pain usually in the ribs, back, and hips.
  • Abnormal bleeding: This includes excessive nose bleeding or bleeding of the gums.
  • Recurrent infections: Repeat infections are due to a weakened immune system.
  • Kidney failure: This is due to a buildup of abnormal cells clogging the kidneys.
  • Hypercalcemia: This is caused by the destruction of the bones.
  • Hyperviscosity: This is commonly observed in Waldenstrom macroglobulinemia (WM). Hyperviscosity syndrome usually presents as neurological changes like seizure, headache, vertigo, stroke, vision changes, and mucosal bleeding (blood in the mucus).


The exact cause of multiple myeloma remains a mystery. Some research has pointed to radiation exposure or contact with chemical solvents such as benzene as a possible trigger. Other studies have cited the role of DNA mutations—mistakes or defects in the instructions that give rise to plasma cells—in the development of multiple myeloma.

Recent studies have found that abnormalities of oncogenes like MYC and RAS and tumor suppressor genes like TP53 have been found in myeloma cells in the bone marrow after treatment.

Multidrug resistance (MDR) is the phenomenon whereby cancer cells become resistant to (unable to be affected by) a wide variety of structurally and functionally unrelated drugs.

There are multiple causes of drug resistance in triple-resistant multiple myeloma, including:

  • Genetic alterations that can allow cells to replicate (multiply) uncontrollably or lead to the development of different resistance mechanisms in the mutated cells
  • Epigenetic alterations that can affect the patterns of DNA methylation and histone modifications of genes associated with tumor suppression
  • Abnormal drug transport and metabolism that decrease the intracellular drug levels
  • Dysregulation of programmed cell death (apoptosis) or other intracellular signaling pathways associated with autophagy
  • Persistence of cancer stem cells
  • Dysfunctional tumor microenvironment
  • Recruitment of surrounding healthy cells

Despite the introduction of new drugs into treatment regimens, most people with multiple myeloma eventually demonstrate multidrug resistance. This is why it's so important for science to determine what is causing the resistance.

Finding ways to enhance current therapies while also designing more effective ones is of the utmost importance in cancer research. 


Multiple myeloma is a clinical diagnosis that is suspected usually after an adult of about 60 years old or older reports symptoms such as bone pain, fatigue, and kidney problems.

Sometimes a diagnosis of multiple myeloma is made incidentally and only discovered after performing a blood test for another condition. Multiple myeloma will be indicated by a rise in certain antibodies in the blood and urine. A bone marrow biopsy and a bone marrow aspirate (a procedure in which a small sample of bone marrow is removed) are performed to look at the nature of the cells and confirm the diagnosis.


The standard treatment protocol for multiple myeloma is what's known as induction therapy. This includes the combination of an injectable drug called a proteasome inhibitor that blocks the action of cellular complexes that can degrade proteins, an oral immunomodulatory agent that uses the immune system to fight cancer, and a corticosteroid called Decadron (dexamethasone). Treatment is followed by a bone marrow transplant known as autologous hematopoietic stem cell transplantation, as well as maintenance therapy with Revlimid (lenalidomide) for eligible patients.

Induction therapy has been shown to slow the progression of multiple myeloma for about 41 months compared to 8.5 months without therapy.

Still, despite the advent of new, more effective, and less toxic therapies, experts have identified  people with multiple myeloma who have stopped responding to traditional therapies. This new subset of people with multiple myeloma experience more frequent symptoms—negatively impacting their quality of life—and have poor survival outcomes.

Salvage autologous stem cell transplantation and retrying previous regimens have proven to be effective for a short period of time, but it is clear that the search for new, more effective treatment options is a top research priority. 


Your overall outlook depends on the stage of your diagnosis, how your body responds to treatment, and your overall health.

Generally, healthy people who are diagnosed early have a five-year survival rate that is over 75%. The more advanced your stage—that is, the more your cancer has spread—the lower your general prognosis is with those with distant metastases displaying a five-year survival rate of 55%.

The advent of new drugs and the combination of multiple treatment regimens—like conventional chemotherapy and the use of proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies—usually are less effective over time.

Generally, the more resistant you are to conventional therapies, the worse your prognosis. Some research has shown median survival ranges as low as six to nine months for those who relapse or display resistance to two or more treatments.


Triple refractory multiple myeloma refers to a rare, incurable cancer of plasma cells. It has become more and more resistant to conventional cancer treatments (proteasome inhibitors, immunomodulatory agents, monoclonal antibodies) over time. This has resulted in a lower quality of life and poor survival outcomes for most patients. 

A Word From Verywell

The need for newer treatments for multiple myeloma cannot be understated. Clinical trials are vital in helping healthcare professionals and scientists better understand the disease and use this knowledge to develop new treatments.

If you have multiple myeloma, participating in a clinical trial may be a good option for you. If you are interested in such a trial, be sure to speak with a healthcare professional about which clinical trials are available and whether one of them may be right for you.

9 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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By Shamard Charles, MD, MPH
Shamard Charles, MD, MPH is a public health physician and journalist. He has held positions with major news networks like NBC reporting on health policy, public health initiatives, diversity in medicine, and new developments in health care research and medical treatments.