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Multiple myeloma is considered to be relapsed if symptoms of the disease appear after a time of improvement. It’s considered to be refractory when it gets worse even though it’s being treated.

To create the best treatment plan for relapsed/refractory multiple myeloma (RRMM), health care providers look at the big picture. They carefully think about several important things. Some relate to your general health, including age, ability to be able to take certain drugs, and other conditions such as heart or kidney diseases. They also must look at what type of initial treatment you got and how long your MM was in remission (not growing or gone).

What Is Relapsed/Refractory Multiple Myeloma?

There are three kinds of relapsed/refractory multiple myeloma:

  • Relapsed but not refractory
  • Relapsed and refractory
  • Primary refractory RRMM

Multiple myeloma is considered to be relapsed if it responds positively when you first get treatment, but then starts growing again. Or there might be other signs your initial treatment’s effectiveness has gone down. It’s said to be relapsed and refractory if your treatment works at least a little, at first, and then no longer works at all. Multiple myeloma that has never responded to initial treatment of any kind is considered to be primary refractory.


What Considerations Affect Treatment Plans?

In order to create the best treatment plan for your RRMM, your doctors will look at several aspects of your health.

Age and frailty

Since older and weak (frail) people don’t respond as well when new treatments are introduced, your doctor may give you a frailty assessment. If you are too frail, you may need to get lower drug doses or take the drugs or treatments less often. The goal of your treatment may focus more on symptom relief and stopping new symptoms from happening. 

Other health issues (comorbidities)

Some treatments for RRMM can make other health issues worse, like heart diseases, kidney problems, diabetes, nerve damage, and blood clots. If your treatment plan includes certain drugs, your doctor will have to keep a close eye on your other conditions.

Cancer (MM) aggressiveness

Your doctor may find signs that some treatments may not be effective, such as certain elevated proteins or a lack of response after a stem cell transplant. If the MM spreads to a location outside of the bone marrow -- which happens in around 14% of RRMM cases -- that may limit the effectiveness of treatment. If your MM is considered to be “aggressive,” that’s reflected in your treatment plan.


Cytogenetic testing should be done (on samples of tissue, blood, or bone marrow) to find gene differences related to specific types of cancer. People with high-risk MM are more likely to relapse early. If testing shows that you have high-risk MM, it can help your team create the best treatment plan.

What Are the Second- and Third-Line Treatments for RRMM?

Both second- and third-line treatments for RRMM depend on several factors. Your health care team will carefully examine your previous treatment and response. For example, if the MM is refractory to a specific drug or drugs included in the first-line treatment, it likely won’t be included in your new treatment plan. Because of the growing number of first-line treatments for MM, especially combination approaches, most people are refractory to one or more drugs when they first relapse.

Your doctor also will consider things like:

  • How long the first-line treatment worked
  • What the MM looks like (its characteristics, where it’s located)
  • Overall treatment goals like qualify of life
  • Potential side effects

Triplet regimens

In general, RRMM is treated with triplet regimens, which include at least:

  • Two drug classes (other than steroids) that were used previously, and
  • At least one drug from a class that hasn’t been used

The drugs included in a triplet regimen vary depending on your first-line treatment and response. For example, since most first-line MM treatment now includes lenalidomide, many people are resistant to it when they first relapse. Also, people who are older and frail or who have other health conditions may benefit from doublet regimens (two drugs instead of three).

Third-line treatments are especially challenging. That’s because after a second relapse the MM likely is refractory to one or all of these: bortezomib, carfilzomib, lenalidomide, and monoclonal antibodies. The best combination regimen may include any treatments that have not been tried. Clinical trials may also be a good option.

What Treatments Are Available and How Are They Given?

Most people get RRMM treatment as an outpatient. Treatment can be given as tablets or capsules, injections, or as an intravenous (IV) drip into a vein. Each treatment cycle is 21-35 days. You may have some drugs daily and others weekly during each cycle. Most people will have four to six cycles, but some treatments will keep on until they stop working.

Drugs and treatments approved to treat RRMM include:

Proteasome inhibitors (PIs) -- like bortezomib, carfilzomib, and ixazomib -- that stop cancer cells from destroying “garbage” proteins, allowing them to pile up and kill the cancer cells

Immunomodulatory agents (IMiDs) -- including lenalidomide, pomalidomide, and thalidomide – that build up the immune system to fight the cancer

Alkylators -- like melflufen, a peptide-drug conjugate (PDC) that targets

tumor cells and has been shown to be effective in MM that’s resistant to bortezomib

Histone deacetylase (HDAC)inhibitors -- like panobinostat and vorinostat -- a relatively new cancer agent that stops the cell’s life cycle

Monoclonal antibodies (mAbs) -- laboratory-produced molecules that change or act like your immune system to attack cancer cells

Antibody drug conjugates (ADC) -- immunotherapy drugs that combine a chemotherapy agent with a monoclonal antibody that targets myeloma cells

Selective inhibitor of nuclear export (SINE) -- like selinexor -- drugs that keep tumor-fighting proteins in the cell nucleus

CAR T-cell therapy -- a type of immunotherapy in which T cells are reengineered with new receptors that target proteins produced by cancer cells. CAR T-cell therapy is more effective when cells from healthy donors are used instead of patient cells. The cells are healthier and can be frozen for treatment on-demand.

Autologous stem cell transplantation (ASCT) -- in which your own healthy blood stem cells are transplanted into bone marrow to replace diseased cells. ASCT should be considered in RRMM patients who haven’t yet had a stem-cell transplant.

Combination therapies

Newly approved treatments and treatment combinations for RRMM include:

  • Pomalidomide and dexamethasone -- shown to kill cancer cells and stop them from multiplying
  • Bortezomib and pegylated doxorubicin -- significantly reduces risk of disease progression by 45%. (Peripheral neuropathy related to bortezomib happens in almost half of cases.)
  • Carfilzomib alone or with dexamethasone or lenalidomide-low-dose dexamethasone -- improves survival and is most beneficial at first relapse (second-line treatment)
  • Panobinostat and bortezomib-dexamethasone -- benefited almost 69% of those receiving treatment. (Side effects include diarrhea and low blood-platelet count.)
  • Elotuzumab and lenalidomide-low-dose dexamethasone -- has encouraging response rates and is generally well-tolerated
  • Ixazomib and lenalidomide-low-dose dexamethasone -- significantly improves survival rates. (Side effects include diarrhea and rash.)
  • Daratumamab -- good response rates when used alone, with few side effects

People with certain health conditions may need to be watched more closely if second- or third-line treatment for RRMM includes:

  • Anthracyclines and carfilzomib – may cause heart damage
  • Lenalidomide and ixazomib – doses may be lowered if you have poor kidney function
  • Thalidomide, bortezomib, vincristine – may affect peripheral neuropathy (nerve damage)
  • Corticosteroids – may affect glucose intolerance (diabetes)
  • IMiDs – may affect thrombosis (blood clots)

If your MM is high risk, your doctor may give you the most effective RRMM treatments early, rather than saving them for later. Treatment options include three-drug combinations with proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. You could also get conventional cytotoxics, anti-BCMA antibody-drug conjugates, and XPO1 inhibitors. Newer CAR T-cell therapies, bispecific antibodies, and novel small molecules look promising. More clinical trials are needed in order to come up with more effective treatments of high-risk RRMM. 

Show Sources

Photo Credit: MicroStockHub / Getty Images


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