How Multiple Myeloma Is Treated

Treatment for multiple myeloma depends not only on the characteristics of the disease, but also on who you are as an individual and where you are in your life. Physicians who treat multiple myeloma are not yet using the word "cure," and even when multiple myeloma is well controlled, it almost always returns at some point. However, today there are more options than ever for keeping the disease at bay, and people are living longer and longer with multiple myeloma.

First-Line Treatment

Many different treatment options are now available for multiple myeloma. If you are relatively young and otherwise healthy, you might choose a more aggressive treatment regimen. If you are older or have multiple health conditions, you might try to control the disease as best as possible with a slightly less aggressive approach while prioritizing your quality of life. 

Although statistics can help a person come to grips with the disease and their future, no individual is a statistic. Plus, currently-published statistics may not reflect advances, as they are expected to vastly improve in 2021—five years since the 2016 introduction of several effective new drugs.

Chemo Plus Stem Cell Transplant 

For younger or healthier people with multiple myeloma, the standard treatment has, up to this point, been high-dose chemotherapy plus autologous stem-cell transplantation (ASCT). Today, however, some are questioning the optimal timing of ASCT, now that newer, less toxic options are available. 

In autologous transplant, or ASCT, your own stem cells are removed from your bone marrow or peripheral blood before the transplant and stored until they are needed for the transplant. Then, you get high-dose chemotherapy to kill multiple myeloma cells. After that, the stored stem cells are given back to you through a vein.

ASCT is still a potential tool in the toolbox, and may be an important option for some individuals with multiple myeloma. But it is also true that combination drug therapy (for example, with lenalidomide-bortezomib-dexamethasone) can be the upfront treatment, regardless of whether or not you plan to have a stem cell transplant at some point in the future. 

For those who are planning to go on to ASCT, there are a variety of three-drug regimens that are currently recommended upfront, prior to the transplant, including:

  • Bortezomib-lenalidomide-dexamethasone
  • Bortezomib-doxorubicin-dexamethasone
  • Bortezomib-cyclophosphamide-dexamethasone 

Combination Drug Therapy

Regardless of whether or not you may at some point receive a transplant, when your multiple myeloma requires treatment, this first-line of treatment is referred to as “induction therapy.” This refers to the induction of remission. There are many different drug regimens that can be used for first-line treatment, or induction therapy.

Combination drug therapy is believed to have at least two major benefits: it can impact more of the cancerous myeloma cells, and it can also lower the likelihood that the myeloma cells will become drug-resistant.

That is, if the cancer becomes resistant to one of the agents, the other two agents can help to keep it under control. 

Common Forms of Triplet Therapy

Most of the time, a three-drug combination regimen is recommended for induction, referred to as "triplet therapy." This kind of approach is preferred because individual drugs in the regimen work in different ways, and combining them helps to target the disease in multiple ways. 

Currently, the most widely-used upfront regimen for the primary treatment of multiple myeloma in the United States is lenalidomide-bortezomib-dexamethasone, a drug combination also known as “RVD.”

This is a prototype drug combination or “backbone” triplet regimen, consisting of three drugs that represent three different classes of medicine, each doing a different thing, together. Those classes are immunomodulators, proteasome inhibitors, and steroids. Lenalidomide is an immunomodulator, bortezomib is a proteasome inhibitor, and dexamethasone is the steroid:

  • Bortezomib-lenalidomide-dexamethasone (RVD)

Sometimes, cyclophosphamide, a chemotherapy agent, is used instead of the lenalidomide, especially initially in a person whose kidneys are not functioning well:

  • Bortezomib-cyclophosphamide-dexamethasone (VCD)

Multiple myeloma can affect how well your kidneys function, so initial treatment may actually help the kidneys as well. In such cases, a person might begin with VCD and switch to RVD.

Triplet Therapy With or Without Transplant to Follow

In a recent study among adults with multiple myeloma, treatment with RVD (alone) was compared to treatment with RVD followed by autologous transplant, or ASCT. Those who received RVD followed by ASCT did not live any longer than those who received the RVD alone. However, it took longer for the disease to progress in those who received the transplant. It is not known why people who receive ASCT have the benefit of delayed disease (longer progression-free survival) without the benefit of living longer (overall survival) compared with those who receive RVD alone.

Lower-Dose Triplets and Doublets

Another consideration for first-line treatment of multiple myeloma is that not everyone who requires treatment can or should have the full triplet therapy. Sometimes a person will have trouble tolerating the combination and should pursue other options, including reduced-dose triplets or doublet regimens. Lenalidomide and dexamethasone are examples of a doublet. Lenalidomide-bortezomib-dexamethasone "lite" or “RVD lite” is an example of a reduced dose regimen.

Maintenance Treatment

When you and your doctors have succeeded in beating down the disease for the very first time, it is cause for celebration, but you may not be done with treatment.

Clinical trials offer evidence that people who continue taking a maintenance drug to keep multiple myeloma down end up having a longer period of time without disease progression.

While it is not certain, maintenance treatment may also increase lifespan.

Currently, the most widely used and recommended maintenance medication is lenalidomide. Sometimes, instead of lenalidomide, a different agent will be used, such as bortezomib.

As with any treatment, maintenance therapy is not without risks and side effects, so you should discuss your options for this part of your treatment with your health care provider.

Monitoring Your Response to Treatment

When you have symptoms from multiple myeloma and receive a treatment that is working, you generally start to feel better within about four to six weeks.

Before and after each cycle of treatment, you will be evaluated to see how your disease is responding to therapy, how you are handling the treatment, and to look for any new disease-related complications.

Typically, the markers that doctors look for are the same ones that were used when you were diagnosed to evaluate your disease. These include measurements of myeloma protein in your blood and urine, measurements of the different types of antibodies in your blood, measurements that help show how well your bone marrow and kidneys are working, and measurements that let your doctor know about your bone metabolism (serum calcium). In addition, imaging studies such as PET/CT, MRI, or whole-body low-dose CT may be needed. A bone marrow aspiration and biopsy might be done, especially in cases where your doctor believes there may be a turning point in your disease, or the disease may be breaking through treatment, but this is not always necessary.

Disease Progression

There is still no cure for multiple myeloma, and it almost always returns, at which point you are said to have “relapsed or refractory” disease. Fortunately, there are multiple lines of therapy that can be used when the first line of treatment fails.

Your health care team will monitor markers and scans to see if your multiple myeloma is responding to treatment, is stable, or is progressing.

Different doctors might use different cut-offs for deciding when your disease has relapsed and is in need of an additional line of therapy. In clinical trials, there is a more formal classification system based on seeing a rise in those markers, scans, and tests (International Myeloma Working Group, or IMWG criteria). Generally, a 25 percent increase in protein markers from your lowest point is considered progression using these IMWG criteria. If your myeloma isn’t producing good protein markers for doctors to monitor, other measurements are relied upon, such as the percent of plasma cells in your bone marrow increasing above 10 percent of the total marrow cells.

Your myeloma can progress in other ways, such as a substantial increase in size or development of new spots in the bone. Your calcium rising, hemoglobin falling, or creatinine rising past thresholds due to your myeloma also qualifies as progression. Finally, the development of stickiness of your blood due to excess myeloma protein (hyperviscosity) is also considered relapsed disease.

Second and Subsequent Lines of Treatment

Most of the time, you will continue on a maintenance treatment such as lenalidomide until you need a change in therapy or additional therapy. If the disease is not responding to a particular agent or regimen, then the goal is to use two new drugs in the triplet. That is, it is preferable to use a combination of drugs that has at least two new drugs that the myeloma cells won’t already be resistant to.

People who relapse after regimens containing bortezomib may respond to a newer proteasome inhibitor such as carfilzomib or ixazomib. Likewise, people who relapse on lenalidomide-containing regimens may respond to a regimen containing the newer agent in the same group of drugs, pomalidomide. 

A variety of triplet regimens are approved for relapsed/refractory multiple myeloma. For example, there are three triplets using the antibody daratumumab, all referred to as daratumumab-based triplet therapy:

  • Daratumumab-lenalidomide-dexamethasone
  • Daratumumab-pomalidomide-dexamethasone
  • Daratumumab-bortezomib-dexamethasone

Daratumumab is an antibody that targets CD38 (a marker on the outside of myeloma cells and other immune cells) and can be very effective. Pomalidomide is a next-generation version of lenalidomide and can be a good option if your doctor suspects you are lenalidomide-refractory.

Studies show that triplet therapy is most effective for relapsed multiple myeloma. Some of them are only approved in certain circumstances, such as when you have already been through two lines of therapy containing certain agents. That said, sometimes a drug that has already been used in the past can be used again, because cancer evolves and may have lost its resistance to a formerly used agent. 

Additionally, other novel agents are continuously being introduced. Some relatively recent additions that may be used in multiple myeloma treatment include:

  • Carfilzomib, ixazomib (same class as bortezomib)
  • Elotuzumab (an antibody that directly activates natural killer cells by targeting a protein known as SLAMF7)
  • Panobinostat (selectively inhibits histone deacetylase enzyme)

There are also many ongoing clinical trials for relapsed and refractory multiple myeloma in which newer combinations are being investigated, so that may be an option to discuss with your doctor.

As you get further along in the disease course, there might not be brand new agents to use in a triplet, or you may not be physically able to tolerate as many agents in combination. That is ok, and you and your doctor should talk about what you can tolerate and what you cannot. Sometimes, doses can be adjusted without sacrificing effectiveness. It’s a balance between keeping the disease down and living the rest of your life, and you are obviously a key part of that equation.

The use of genetic markers to help target your cancer cells has been advancing in a variety of cancers, and multiple myeloma is no exception. Right now, for multiple myeloma, there is a genetic marker known as a translocation that seems to predict whether or not you might respond to an agent called Venetoclax. There are studies in progress involving people with relapsed/refractory multiple myeloma carrying a t(11;14) translocation—essentially a switch in genetic information between chromosomes 11 and 14. This trial began based on some in vitro findings showing that Venetoclax could kill myeloma cells, so it is still investigational at this time.

Other Treatments

Along with the treatments that are keeping your multiple myeloma away, other supportive treatments are very important. These are medications to manage the symptoms of the myeloma or the side effects of myeloma treatment. These may include:

  • Bisphosphonates or denosumab for bone health
  • Treatment for bone pain (drugs, radiation, or surgery)
  • Treatment for blood calcium that gets too high
  • Erythropoietin to boost your red blood cells
  • Special care and hydration to keep your kidneys functioning well
  • Vaccines and careful monitoring and treatment for infections
  • Blood thinners to prevent blood clots

Common Side Effects of Treatment

Each drug has its own side effect profile, and your doctor will take these into consideration when recommending a particular regimen. It’s also important for you to be alerted to these possibilities so that you can recognize them quickly and report them back to your doctor. Listing all potential side effects is beyond the scope here, but a simplified overview of some of the commonly described concerns follows.

Almost all multiple myeloma drugs are "myelosuppressive," which means they can result in low blood cell counts. This is good in the sense that your cancer cells are in the blood cell family and it is good to kill cancer cells, but you want your healthy blood cells (red, white, and platelet-generating cells), in good numbers to carry oxygen and fight infection and keep the balance between bleeding/easy bruising and blood clots. Most regimens are also associated with some degree of gastrointestinal upset (nausea/vomiting) and fatigue as a possibility, though every individual is different in the extent to which they will experience these things.

Cardiovascular complications from multiple myeloma treatment, which may include things like worsening heart disease and blood clots, are also relatively common. It's important for your doctor to match your treatment to your risk profile, for instance, if you already have heart disease.

Bortezomib, the proteasome inhibitor in many triplets, seems to be uniquely beneficial to the kidneys. Conversely, a side effect includes peripheral neuropathy (decreased sensation and numbness and tingling of the hands and feet).

Lenalidomide is teratogenic (it may disturb the development of unborn children) and also carries black box warnings for hematologic toxicity (low blood counts), venous/arterial thromboembolisms (serious potential side effects including blood clots in the body, and harm to the liver.

Daratumumab, an antibody that targets CD38 (a marker on the outside of myeloma cells and other immune cells), may lead to serious infusion reactions. These reactions are more common with the first administration and less common thereafter, but can be severe. There are protocols set up with pre-medication to minimize these risks.

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