How Triple-Refractory Multiple Myeloma Is Treated

Medically reviewed by Gagandeep Brar, MD

Triple refractory multiple myeloma usually requires the use of two or more different kinds of drugs to improve survival outcomes and quality of life. Studies have shown that multiple myeloma at all stages responds better to combination therapy.

This article discusses treatment options for triple refractory multiple myeloma.

<p>Solskin / Getty Images</p>

Solskin / Getty Images

Conventional Treatment

The standard treatment protocol for multiple myeloma is induction therapy, which is a combination of an injectable proteasome inhibitor such as Velcade, an oral immunomodulatory agent such as REVLIMID (lenalidomide), and dexamethasone. This may be followed by autologous hematopoietic stem cell transplantation plus maintenance therapy with REVLIMID.

Induction therapy has been shown to slow the progression of multiple myeloma for a median of 41 months compared to eight and a half 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 recycling 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.

Stem Cell Transplantion

Stem cell transplant (SCT) is a commonly used treatment for multiple myeloma.

In SCT, high-dose chemotherapy and radiation kill harmful cells in the bone marrow and are replaced with new, healthy blood-forming stem cells from your own body (autologous) or someone else’s (allogenic) via a process known as infusion.

Currently, the combination of chemotherapy, radiation, and SCT provides the best chance of prolonging remission.


Below is an outline of prescriptive therapy treatments for multiple myeloma.


Chemotherapy drugs are used to destroy cancerous cells, and can be administered orally (taken by mouth) or intravenously (infused into the body at a medical facility). They may be combined with corticosteroid or immunomodulating drugs to increase effectiveness. Chemo drugs that can be used to treat multiple myeloma include:

  • Cytoxan (cyclophosphamide)

  • VP-16 (etoposide)

  • Adriamycin (doxorubicin)

  • Doxil (liposomal doxorubicin)

  • Alkeran (melphalan)

  • Treanda (Bendamustine)

Side effects of chemotherapy include hair loss, mouth sores, fatigue, nausea, and gastrointestinal issues.

Immunomodulating Drugs

Immunomodulating drugs stimulate or suppress the immune system. Although immunomodulating therapy has become a staple treatment for multiple myeloma, most people who use these drugs fall into one of three categories:

  • Responders

  • Non-responders

  • Initial responders to standard of care treatment who relapse (acquired resistance)

Therefore, if one immunomodulating drug does not work, another is used in combination with a corticosteroid until disease remission is achieved. The following immunomodulating drugs are used in the treatment of triple refractory multiple myeloma to target cancer cells in the body:

  • Thalomid (thalidomide): Thalomid has a high risk of blood clotting so it is often administered with aspirin or a blood thinner.

  • REVLIMID: REVLIMID is often used for long-term maintenance therapy.

  • Pomalyst (pomalidomide): Pomalyst may lower red and white blood cell levels leading to anemia and frequent infections.

Immunomodulators may affect your blood cell counts and all have been shown to increase your risk of nerve damage.


Corticosteroids work by limiting inflammation and the damage caused by cancer cells. They are a staple of multiple myeloma treatment in both acute and refractory settings.

Prednisone and dexamethasone are the most commonly used corticosteroid drugs, as they increase the effectiveness of chemotherapy agents and decrease symptoms of nausea and vomiting.

Generally, the rule of thumb is to use the lowest dose that provides therapeutic effectiveness, for the shortest period of time, as chronic steroid use can raise blood sugar levels and suppress your immune function, leading to more frequent infections.

Monoclonal Antibodies

Monoclonal antibodies are man-made versions of immunoprotective proteins designed to attack surface proteins on cells. The two most commonly targeted surface proteins on multiple myeloma cells are CD38 and SLAMF7.

Darzalex (daratumumab), Sarclisa (Isatuximab), and Tecvayli (teclistamab) all target CD38. Empliciti (elotuzumab) targets SLAMF7. These drugs are commonly used in the treatment of multiple myeloma. Monoclonal antibodies kill cancer cells directly while also stimulating the immune system to kill these foreign cells in the future. 

Nuclear Export Inhibitor

Proteins essential to the cell's function are made in the nucleus and then exported by carrier proteins to other parts of the cells. Nuclear export inhibitors (NEI), namely Xpovio (selinexor), preferentially stop this process from occurring in cancer cells.

NEIs are primarily introduced in refractory cases where five or more drugs have been used successfully. NEIs are used with the corticosteroid, dexamethasone. Side effects of NEIs include:

Proteasome Inhibitors

Proteasome inhibitors (PIs)—cytotoxic drugs that help destroy large protein complexes involved in cellular replication—have been the therapeutic backbone of myeloma treatment for refractory cases.

There are currently three proteasome inhibitors that are used for multiple myeloma treatment:

  • Velcade

  • Kyprolis (carfilzomib)

  • Ninlaro (Ixazomib)

Proteasome inhibitors may cause side effects like nausea, vomiting, and nerve damage that leads to numbness and tingling. Of note, Velcade can trigger shingles (herpes zoster) so you may be prescribed acyclovir, an antiviral medicine, to prevent this from occurring.


Malignant cells in multiple myeloma can cause cells to become weak and brittle by crowding out healthy cells. As a result, your bones can break down causing bone pain and hypercalcemia.

Bisphosphonates slow this process down, helping to keep your bones strong. The most common bisphosphonates used include:

  • Aredia (pamidronate)

  • Zometa (zoledronic acid)

  • Xgeva or Prolia (Drug denosumab)

Vaccines and Antibiotics

If you have triple refractory multiple myeloma you are likely to be more susceptible to infections due to bone marrow insufficiency, requiring the use of prophylactic broad-spectrum antibiotics for bacterial infections and immunization against influenza, pneumococcus, and Haemophilus influenzae B.

For active bacterial infections, the specific antibiotic that you will be prescribed will depend on the bacterial agent in question, its sensitivity to the antibiotic, your allergy history, and potential drug-drug interactions.


Over-the-counter (OTC) drugs are commonly combined with traditional therapies for symptomatic relief. Pain medicines, such as nonsteroidal anti-inflammatory drugs (NSAIDs), may be taken with bisphosphonates to help control or lessen bone pain. More chronic pain may result in a need for narcotics or stronger pain medication.

Zofran (ondansetron) may be used to prevent and treat nausea and vomiting caused by chemotherapy and radiation therapy.


Currently, no lifestyle risk factors are definitively associated with triple refractory multiple myeloma. Reducing environmental exposure to ionizing radiation or contact with chemical solvents—such as benzene—may decrease your risk. Still, research has hardly shown a definitive correlation between cell phone use, occupational radiation exposure, and the toxic chemicals associated with the two.

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 never smoking, eating a diet low in processed foods, sodium, and sugar, and exercising regularly reduces your overall cancer risk.


Triple refractory multiple myeloma is treated with a combination of drugs including proteasome inhibitors, immunomodulators, and nuclear export inhibitors. While combination therapy is standard to care for triple refractory multiple myeloma, your candidacy for these medications is based on multiple factors including perceived effectiveness, your overall health status, potential side effects, and possible drug-drug interactions.

A Word From Verywell

Novel agents such as immunomodulating agents and nuclear export inhibitors are becoming the staples of drug therapy for treatment-resistant multiple myeloma. These therapies are usually combined with dexamethasone to increase their effectiveness.

There is no one-size-fits-all combination of medication and a team of healthcare professionals will likely help you come up with the best combination that meets your treatment goals based on potential side effects, drug-drug interactions, and overall health status.

Read the original article on Verywell Health.