Risk Factors of Triple Refractory Multiple Myeloma

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Multiple myeloma is a cancer of the plasma cell, a type of white blood cell that produces antibodies that fight viral and bacterial infections. The causes of multiple myeloma are unknown. There are also no known environmental risk factors associated with the development of multiple myeloma. Additionally, it is unclear why some people develop resistance to treatment while others do not.

Triple refractory multiple myeloma refers to someone who has not responded to all three of the major class treatments for multiple myeloma.

This article discusses the risk factors for developing triple refractory multiple myeloma.

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Risk Factors for Triple Refractory Multiple Myeloma

The following factors may increase your risk of developing multiple myeloma:

  • Age: Being 65 years or older.
  • Gender: Assigned male gender at birth.
  • Race: Black Americans are twice as likely as White Americans to develop myeloma
  • Family history. If you have a parent, brother, or sister who has multiple myeloma, your risk is four times higher. Treatment response may differ for each affected family member. 
  • Obesity: As diagnosed by a healthcare provider.
  • History of monoclonal gammopathy of undetermined significance (MGUS): This is a precancerous condition associated with an increased risk of malignant transformation.
  • History of plasma cell disorder: Multiple myeloma risk may be heightened if you have a history of other plasma cell disorders such as solitary plasmacytoma or smoldering myeloma.

Common Causes

The exact cause of multiple myeloma remains a mystery, but it is likely that both environmental factors and underlying genetic factors play a role in increasing your risk of multiple myeloma.

Some research has pointed to exposure to radiation, farming pesticides, or chemical solvents like benzene as possible triggers. Other studies have also highlighted the role of DNA mutations—mistakes of defects in the instructions that give rise to plasma cells—in the development of multiple myeloma. Abnormalities of oncogenes—like MYC and RAS—and tumor suppressor genes—like TP53—have been found in myeloma cells in the bone marrow.

Multi-drug resistance (MDR) is the phenomenon whereby cancer cells become resistant to 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 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 multiple drug resistance, underscoring the urgent and unmet need to define the molecular mechanisms responsible for resistance.

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

Lifestyle Risk Factors

Currently, there are no lifestyle risk factors that are definitively associated with triple refractory multiple myeloma.

Still, avoiding toxic chemicals and radiation is always a good idea, as it may decrease your risk of developing other forms of cancer.

Even more, leading a healthy lifestyle that includes eating a diet low in processed foods, sodium, and sugar, as well as never smoking and exercising on a regular basis, is not only heart healthy but also reduces your overall cancer risk. 


There are no known causes or risk factors of multiple myeloma, but some research points to DNA changes as a result of long-term exposure to radiation, farming pesticides, or chemical solvents like benzene as possible causes. Additionally, it is unclear why some people develop resistance to treatment while others do not.

A Word From Verywell

Finding the causes of multiple myeloma is vital in discovering new treatments for this form of cancer, especially in treatment-resistant cases, underscoring the need for more research. If you are interested in forwarding the research in any way, be sure to speak with a healthcare professional about which clinical trials are available and whether one of them may be right for you.

6 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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  2. Mateos MV, Landgren O. MGUS and smoldering multiple myeloma: diagnosis and epidemiology. Cancer Treat Res. 2016;169:3-12. doi:10.1007/978-3-319-40320-5_1

  3. Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood. 2015;125(20):3069-3075. doi:10.1182/blood-2014-09-568899

  4. American Cancer Society. What causes multiple myeloma?

  5. Pinto V, Bergantim R, Caires HR, Seca H, Guimarães JE, Vasconcelos MH. Multiple myeloma: available therapies and causes of drug resistance. Cancers (Basel). 2020;12(2):407. Published 2020 Feb 10. doi:10.3390/cancers12020407

  6. Robak P, Drozdz I, Szemraj J, Robak T. Drug resistance in multiple myeloma. Cancer Treat Rev. 2018;70:199-208. doi:10.1016/j.ctrv.2018.09.001

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.