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MULTIPLE MYELOMA OVERVIEW — Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Plasma cells are a type of white blood cell that make antibodies to help fight infections. In multiple myeloma, the plasma cells are abnormal and grow out of control. The uncontrolled growth of these cells can lead to bone pain and fractures and an inadequate number of normal, healthy blood cells (white blood cells and red blood cells). These cancer cells also produce large amounts of abnormal proteins, which can cause kidney damage.
The treatment of multiple myeloma is complex because of rapid advances in stem cell transplantation, medications, and better supportive care, which have led to improved survival over the past 30 years. The main options for treatment include non-chemotherapy drugs that target the cancer cells, standard chemotherapy drugs, corticosteroids, and stem cell (bone marrow) transplant.
Each option needs to be weighed carefully. Because current therapy rarely cures the disease completely, most people go through many treatment regimens during the course of their illness. Stem cell transplantation may not be an option for many people because of advanced age, presence of other serious illness, or other physical limitations. (See 'Stem cell transplantation' below.)
This topic review discusses the treatment of multiple myeloma. The symptoms, diagnosis, and staging of multiple myeloma are discussed separately. (See "Patient education: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics)".)
More detailed information about multiple myeloma, written for healthcare providers, is available by subscription. (See 'Professional level information' below.)
CANCER CARE DURING THE COVID-19 PANDEMIC — COVID-19 stands for "coronavirus disease 2019." It is an infection caused by a virus called SARS-CoV-2. The virus first appeared in late 2019 and has since spread throughout the world. Getting vaccinated lowers the risk of severe illness; experts recommend COVID-19 vaccination for anyone with cancer or a history of cancer.
In some cases, if you live in an area with a lot of cases of COVID-19, your doctor might suggest rescheduling or delaying medical appointments. But this decision must be balanced against the importance of getting care to screen for, monitor, and treat cancer. Your doctor can talk to you about whether to make any changes to your appointment schedule. They can also advise you on what to do if you test positive or were exposed to the virus.
TREATMENT ISSUES
When should treatment start? — Multiple myeloma can remain stable for prolonged periods of time. Some people with early myeloma who have no symptoms (often called smoldering myeloma) may be advised to wait months to years before considering treatment. In contrast, people who are considered at higher risk for disease progression may be advised to start treatment right away. Your doctor will talk with you about your options and help you determine when to start treatment.
People with a related condition, called monoclonal gammopathy of undetermined significance (MGUS), do not require treatment, although long-term follow-up is needed; a small percentage of people with MGUS will eventually develop full-blown multiple myeloma.
Once symptoms of multiple myeloma develop, treatment with one or more of the options discussed below is recommended for almost all people.
Types of treatment — There are six main types of treatment for multiple myeloma. The options will depend on whether a person has been newly diagnosed or has relapsed disease, as well as their age, overall health, and preferences:
●Newer drugs – There are several types of non-chemotherapy drugs that have emerged in the past decade as important options for the treatment of multiple myeloma. These drugs may be options both for people who have been newly diagnosed and at the time of relapse. In most cases, these drugs are used in combination with dexamethasone (a steroid medication), with each other, or with standard chemotherapy agents (see below). Most of these fall into a few general categories:
•Immunomodulatory drugs – These drugs use the body's immune system to fight myeloma cells. They include lenalidomide (brand name: Revlimid), pomalidomide (brand name: Pomalyst), and thalidomide (brand name: Thalomid). They all have the potential to cause severe birth defects and are absolutely unsafe (contraindicated) for pregnant women. When given with steroids they also increase the chance of developing blood clots; aspirin or another blood thinner is usually recommended to reduce this risk. They are all available as pills.
•Proteasome inhibitors – The proteasome breaks down proteins in cells and is especially active in multiple myeloma cells since they have a lot of excess protein being made. Proteasome inhibitors block this action so that the proteins build up and the cells die. They include bortezomib (brand name: Velcade), carfilzomib (brand name: Kyprolis), and ixazomib (brand name: Ninlaro). Usually, bortezomib is given under the skin (subcutaneously), carfilzomib is given by vein (IV), and ixazomib is taken as a pill. They can all cause nerve damage and increase the risk for certain infections. While bortezomib can be given by IV, this results in a higher rate of nerve damage and so is not preferred.
•Monoclonal antibodies – Monoclonal antibodies are purified proteins that target specific groups of cells. They treat multiple myeloma by attacking specific substances (antigens) on the surface of the cancer cells. There are several monoclonal antibodies available for the treatment of multiple myeloma. They include daratumumab (brand name: Darzalex), elotuzumab (brand name: Empliciti), and isatuximab (brand name: Sarclisa). All can be given by IV (intravenously, meaning into a vein). Daratumumab may be given under the skin (subcutaneously).
•Nuclear export inhibitor – The nuclear export machinery in a cell is responsible for transferring proteins out of the nucleus. Selinexor (brand name: Xpovio) is a pill that blocks this action so that the proteins build up and the cells die. Selinexor can be used for the treatment of multiply relapsed multiple myeloma in selected cases. More data are needed to determine the safety and efficacy of selinexor.
●Chemotherapy – Chemotherapy refers to the use of medicines to stop or slow the growth and longevity of cancer cells. In most people, chemotherapy partially controls multiple myeloma; in some cases, chemotherapy may lead to complete remission. Chemotherapy drugs used in multiple myeloma include melphalan (brand name: Alkeran), cyclophosphamide (brand name: Cytoxan), doxorubicin (brand name: Adriamycin), and liposomal doxorubicin (brand name: Doxil).
●Corticosteroids – Corticosteroids include dexamethasone and prednisone.
●Stem cell transplantation – Stem cell (bone marrow) transplantation can be done using one's own stem cells (autologous transplantation) or stem cells from a close relative or matched unrelated donor (allogeneic transplantation). In multiple myeloma, most transplants performed are of the autologous kind. Such transplants, although not curative, have been shown to prolong life in some people. They can be done as part of the initial therapy in people who have been newly diagnosed, or at the time of relapse. In some cases, more than one transplant may be recommended to adequately control the disease. Autologous transplants for multiple myeloma are very safe in centers with experience in the procedure. (See 'Stem cell transplantation' below.)
●"CAR-T" therapy – CAR-T therapy is a newer form of immunotherapy that may be effective in relapsed or refractory multiple myeloma (see 'Treatment of relapsed or refractory multiple myeloma' below). CAR-T therapy involves genetically modifying specific cells from a person’s immune system; this enables the cells to directly target the cancer cells.
Is stem cell transplantation an option? — Because of the risk of toxic and even fatal complications related to stem cell transplantation, not everyone with multiple myeloma is a candidate for stem cell transplantation. Eligibility varies across countries and across institutions. In most European countries, stem cell transplantation for multiple myeloma is offered primarily to people less than 65 years of age. In the United States, a strict age limit is not used. Instead, decisions are made on a case-by-case basis based on a person's age, health, and other factors, and vary across institutions.
The decision regarding transplant eligibility should be made by the person and their physician after discussing the potential risks, benefits, and the needs and wishes of the individual.
INITIAL TREATMENT OF MULTIPLE MYELOMA — The initial choice of therapy depends upon the person's health, age, ability to undergo stem cell transplantation in the future, and the aggressiveness of the cancer (whether the disease is considered high risk or standard risk). More detail about the different risk categories is available separately. (See "Patient education: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics)", section on 'Risk stratification'.)
Most people will be treated with a three-drug regimen that includes a proteasome inhibitor such as bortezomib (brand name: Velcade), an immunomodulatory drug such as lenalidomide (brand name: Revlimid), and a corticosteroid such as dexamethasone. One popular regimen is bortezomib, lenalidomide, dexamethasone ("VRd"). Some people will be treated with a regimen that includes the monoclonal antibody daratumumab (brand name: Darzalex).
High-risk multiple myeloma treatment options — The best treatment option for people with high-risk multiple myeloma is not clear. Most experts recommend enrolling in a clinical trial (see 'Clinical trials' below).
For people who are not willing or able to participate in a clinical trial, incorporation of a proteasome inhibitor such as bortezomib (brand name: Velcade) is recommended.
●People who are candidates for stem cell transplantation are usually treated with a three-drug regimen such as bortezomib, lenalidomide, dexamethasone ("VRd"). After this initial therapy (usually about four months), most clinicians prefer to proceed directly with stem cell transplantation rather than to delay this procedure until the time of disease progression.
●People who are not candidates for stem cell transplantation (because of underlying medical problems, age, or poor health) are also treated with a three-drug regimen, such as "VRd." Following initial combination therapy, the proteasome inhibitor is usually continued for an extended time.
The goal of therapy in high-risk multiple myeloma is to achieve and maintain a complete response as much as possible. A complete response means that there is no monoclonal (M) protein in the serum or urine, no large collections of plasma cells outside of the bone marrow, and that the number of plasma cells in the bone marrow is not elevated.
Standard-risk multiple myeloma treatment options — The treatment of standard-risk multiple myeloma depends partially on whether the person is a candidate for transplant:
●People who are candidates for stem cell transplantation are usually treated with a three-drug regimen such as bortezomib, lenalidomide, dexamethasone ("VRd"). After this initial therapy (usually about four months), stem cells are collected and the person can either proceed directly to transplantation or postpone transplantation until the time of relapse. Those who postpone transplantation receive additional cycles of VRd then continue lenalidomide plus dexamethasone ("Rd") until progression.
●People who are not candidates for stem cell transplantation (because of underlying medical problems, age, or poor health) are usually treated with a three-drug regimen such as VRd or daratumumab, lenalidomide, dexamethasone ("DRd"). Some three-drug regimens have been shown to improve survival when compared with two-drug regimens, but they are also associated with more side effects. As such, the two-drug regimen Rd is an acceptable option for people who are older or in poor health. With any of these regimens, if treatment is effective, lenalidomide may be continued by itself (and the other drugs stopped) until disease progression, unless there are significant side effects.
STEM CELL TRANSPLANTATION — Stem cell (bone marrow) transplantation is a treatment option for some people with multiple myeloma. There are three general types of transplantation, based on the source of the stem cells:
●Autologous transplantation – The stem cells are obtained from your own blood or bone marrow. This is the type of transplantation that is most commonly recommended for treating multiple myeloma.
●Allogeneic transplantation – The stem cells or bone marrow are obtained from a donor with a tissue type matching yours. This type of transplantation carries very high risks and is not recommended for most people with multiple myeloma.
●Syngeneic transplantation – The stem cells or bone marrow are obtained from an identical twin. This is the optimal form of transplantation, although few people with multiple myeloma have an identical twin who can serve as a donor.
Transplantation, when successful, leads to a remission and prolongs survival; rarely, allogeneic transplantation cures multiple myeloma. However, transplantation has several limitations. The high-dose chemotherapy given before transplantation usually fails to kill all of the plasma cells, allowing the condition to relapse after transplantation. Such treatment also increases your risk of serious infections and bleeding, which can be fatal. (See "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)".)
Autologous stem cell transplantation — Autologous stem cell transplantation refers to transplantation with your own stem cells. During this procedure, stem cells are collected and frozen for later use. High-dose chemotherapy is then given to kill as many plasma cells as possible, and the stem cells are thawed and returned to your body. Stem cells can be obtained from the blood or the bone marrow; in this case, obtaining them from the blood is preferred, because blood stem cells take up residence in tissues more quickly and are less likely to be contaminated with cancerous plasma cells.
At present, autologous stem cell transplantation is appropriate for up to 50 percent of people with multiple myeloma. Autologous stem cell transplantation is not recommended for people with smoldering multiple myeloma (people with multiple myeloma who do not have any symptoms).
Procedure — After initial therapy with a regimen such as bortezomib, lenalidomide, dexamethasone ("VRd") for three to four months, you are given granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) to stimulate the production of stem cells and encourage their release into your bloodstream. If there are not sufficient numbers of stem cells in your blood after G-CSF or GM-CSF, another agent, called Plerixafor, may be added to help with collection. Stem cells are then collected from the blood, frozen, and stored for later use.
After you recover from the stem cell collection, you are given high-dose chemotherapy with melphalan (or similar drugs) to kill as many of the cancer cells as possible; then the previously collected stem cells are thawed and returned to your body. In about one-half of people, this procedure can be done on an outpatient basis (ie, without a hospital stay).
Alternatively, the high-dose chemotherapy and transplant may be saved until the time of relapse. With this option, after stem cell collection, you may be given additional cycles of the treatment regimen you received before collection. Later, at the time of relapse, high doses of melphalan (or similar drugs) are given, and the previously collected stem cells are returned to your body. This is called delayed transplantation.
Single versus double autologous transplantation — Double autologous transplantation (sometimes called "tandem transplant") involves two consecutive autologous transplantations done within 6 to 12 months of each other. Double transplant does not appear to offer additional benefit to most people with multiple myeloma. Although the evidence for this approach is weak, it is sometimes offered to people with high-risk multiple myeloma since this group has worse outcomes with standard therapy.
Role of age and stage of multiple myeloma — Because autologous stem cell transplantation has serious side effects, it is generally not recommended for people over the age of 70. However, this procedure may be an option for some people over age 70 who are otherwise healthy. The likelihood of a good response to transplantation is somewhat lower for older adults than for younger adults, although the effects of age on survival after transplantation are not completely clear.
Importance of prior treatment — Autologous transplantation is not recommended for people who have already received prolonged chemotherapy with alkylating drugs (such as melphalan). This is because it is often difficult to collect a sufficient number of healthy stem cells for transplantation. Other treatments commonly used for multiple myeloma, including bortezomib, lenalidomide, and thalidomide, are safe to take before stem cell transplantation.
Effectiveness — About 1 percent of people die from complications related to autologous transplantation. However, compared with chemotherapy alone, autologous stem cell transplantation is more likely to produce a response and is associated with longer survival compared to chemotherapy alone.
Allogeneic stem cell transplantation — Allogeneic transplantation requires stem cells from a donor with a matching tissue type. Unfortunately, approximately 25 percent of people who undergo allogeneic transplantation die from transplant-related complications, such as infection, lung inflammation, and graft-versus-host disease (a condition in which the donor's transplanted stem cells attack your body). Primarily because of this as well as the lack of clear benefit, allogeneic transplantation is seldom used for the treatment of multiple myeloma.
Syngeneic transplantation — A syngeneic transplantation refers to a transplantation between identical twins. For people who have an identical twin, this treatment option is more effective than either autologous or allogeneic transplantation.
Remission after transplantation — The strict definition of remission requires that there are no signs or symptoms of multiple myeloma and that highly sensitive tests cannot detect any abnormal plasma cells. This type of remission occurs in about 50 to 60 percent of people after autologous transplantation.
TREATMENT OF MULTIPLE MYELOMA COMPLICATIONS — Multiple myeloma can cause a variety of complications, some of which are life-threatening.
High blood calcium levels — High blood calcium levels develop as bone is lost. People with multiple myeloma should remain as active as possible because physical activity helps counter bone loss.
The treatment of high blood calcium levels usually includes the use of intravenous (IV) fluids and prednisone. If this treatment is not effective, treatment with drugs that act against bone loss, such as zoledronic acid (sample brand name: Zometa) or pamidronate (sample brand name: Aredia), a class of drugs called bisphosphonates, may be recommended.
Impaired kidney function — Kidney function becomes impaired in about one-half of people with multiple myeloma. The treatment of impaired kidney function is aimed at the specific underlying cause.
Treatment usually includes IV fluids; it may also include dialysis (a type of blood filtration used for kidney failure), prednisone (a steroid that can indirectly lower blood calcium levels), and allopurinol, a drug that can lower blood levels of uric acid, a waste product from the increased turnover of the cancer cells, which can damage the kidneys.
It's important to stay well hydrated and drink enough fluid to produce three liters of urine daily if you have an excess of light chain proteins in the urine (called "Bence Jones proteinuria"). You should also avoid using any nonsteroidal anti-inflammatory drugs (NSAIDs, such as Advil, Motrin, or Aleve), because these drugs might worsen kidney function.
If impaired kidney function has progressed to kidney failure, the treatment options include hemodialysis or peritoneal dialysis. Advanced degrees of kidney failure are usually not reversible even if the multiple myeloma later responds to treatment. (See "Patient education: Dialysis or kidney transplantation — which is right for me? (Beyond the Basics)".)
Infection — Bacterial infections, often indicated by the presence of fever, require prompt treatment with antibiotics. Daily use of the antibiotic trimethoprim-sulfamethoxazole (sample brand names: Bactrim, Septra) can help prevent infections. If you get frequent infections, your doctor may have you take penicillin daily; rarely, people need periodic IV infusions of gamma globulin (normal antibodies collected from plasma donors).
Anyone with multiple myeloma should receive the pneumococcal vaccine (which reduces the likelihood of pneumonia) and the influenza vaccine (which reduces the likelihood of flu). (See "Patient education: Pneumonia prevention in adults (Beyond the Basics)" and "Patient education: Influenza prevention (Beyond the Basics)".)
Bone pain and fractures — Physical activity, with careful avoidance of injury, can promote bone strength in people with multiple myeloma. The bone pain associated with multiple myeloma can be controlled with chemotherapy, analgesics (pain relieving drugs), radiation, and bone strengthening drugs such as zoledronic acid (sample brand name: Zometa) or pamidronate (sample brand name: Aredia). These bone strengthening drugs are commonly referred to as "bisphosphonates." Denosumab is a different kind of bone strengthening drug that may be used to help prevent bone damage in certain people with multiple myeloma.
In people who have early signs of bone erosion, these bone strengthening drugs both reduce bone pain and reduce the risk of fractures. Therefore, bone strengthening drugs are recommended for all people who have early signs of bone erosions on X-rays. Bisphosphonates are usually given by IV infusion every four weeks; this treatment is continued for approximately two years. Bisphosphonates may affect kidney function, which should be monitored on a regular basis to avoid this complication.
Dental procedures, such as root canal or extraction of teeth, may be associated with infection or destruction of the jaw (osteonecrosis) in people treated with IV bisphosphonates. Accordingly, people should avoid such procedures, if possible, while taking these agents; any needed dental procedures should be performed before these agents are started.
Spinal cord compression — Spinal cord compression is a medical emergency that requires prompt treatment to prevent irreversible damage, such as paralysis. Initial treatment may consist of radiation and dexamethasone (a steroid) to reduce swelling around the spinal cord; if these measures are not effective, surgery is needed to relieve pressure on the spinal cord. People should call their doctor immediately if they have severe back pain; weakness, numbness, or tingling in the legs; or new problems with bladder or bowel control (incontinence).
Anemia — Anemia (low red blood cell count) that is causing symptoms may require blood transfusions or treatment with erythropoietin (EPO), a substance that stimulates the production of red blood cells. Erythropoietin is usually given by injection one to three times per week. This treatment effectively increases levels of hemoglobin (the protein in red blood cells that helps carry oxygen to the tissues), improves symptoms, and reduces the need for blood transfusion.
Thickening of the blood — Thickening of the blood (called hyperviscosity syndrome) rarely occurs in people with multiple myeloma. This complication is treated with plasmapheresis, a type of blood filtration that removes the excess monoclonal proteins that cause the thickening.
TREATMENT OF RELAPSED OR REFRACTORY MULTIPLE MYELOMA — Almost all people with multiple myeloma eventually relapse, and a modest percentage are resistant to initial treatment.
Multiple myeloma that responds poorly or not at all to initial therapy is called refractory multiple myeloma. This condition can occur during the administration of initial chemotherapy or during chemotherapy given after a relapse. Refractory multiple myeloma is more difficult to treat.
Relapsed or refractory myeloma is usually treated with combinations of drugs from two or three general classes. The main classes of drugs used to treated relapsed or refractory myeloma are:
●Immunomodulatory drugs (lenalidomide, pomalidomide, thalidomide)
●Proteasome inhibitors (bortezomib, carfilzomib, ixazomib)
●Steroids (dexamethasone)
●Antibodies that target myeloma cells (daratumumab, elotuzumab, isatuximab)
●Nuclear export inhibitor (selinexor)
●Chemotherapy drugs (melphalan, cyclophosphamide)
These can be used in various combinations depending on the person's situation; all of these drugs can have side effects. With each relapse, a new regimen may provide meaningful clinical benefit. Thus, the various regimens available are considered sequentially with each relapse. Most people will receive each available drug at some point during the disease course.
Relapses occurring more than one year after completing treatment can also be treated by repeating the initial chemotherapy regimen. Most people will again have a response to chemotherapy when it is given a second time, although the response is usually not as good as the original response.
If a person does not respond to an initial round of chemotherapy, they may still respond to autologous stem cell transplantation. A transplant may be considered in this case if the person is eligible. Some people may also be candidates for "CAR-T" therapy.
CLINICAL TRIALS — Progress in treating multiple myeloma requires that better treatments be identified through clinical trials. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies; clinical trials are conducted all over the world. Ask for more information about clinical trials, or read about clinical trials at:
●https://www.cancer.gov/about-cancer/treatment/clinical-trials
Videos addressing common questions about clinical trials are available from the American Society of Clinical Oncology (https://www.cancer.net/research-and-advocacy/clinical-trials/welcome-pre-act).
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem.
This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.
Patient level information — UpToDate offers two types of patient education materials.
The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.
Patient education: Multiple myeloma (The Basics)
Patient education: Monoclonal gammopathy of undetermined significance (The Basics)
Patient education: Neutropenia and fever in people being treated for cancer (The Basics)
Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.
Patient education: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics)
Patient education: Vaccines for adults (Beyond the Basics)
Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)
Patient education: Dialysis or kidney transplantation — which is right for me? (Beyond the Basics)
Patient education: Influenza symptoms and treatment (Beyond the Basics)
Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.
Multiple myeloma: Use of allogeneic hematopoietic cell transplantation
Multiple myeloma: Use of autologous hematopoietic cell transplantation
Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis
Multiple myeloma: Overview of management
Diagnosis and management of solitary extramedullary plasmacytoma
Diagnosis and management of solitary plasmacytoma of bone
Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis
Multiple myeloma: Evaluating response to treatment
Multiple myeloma: Initial treatment
Multiple myeloma: Management in resource-limited settings
Diagnosis of monoclonal gammopathy of undetermined significance
Multiple myeloma: Pathobiology
Monoclonal immunoglobulin deposition disease
Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis
Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation
Multiple myeloma: The use of osteoclast inhibitors
Multiple myeloma: Treatment of first or second relapse
The following organizations also provide reliable health information.
●National Library of Medicine
(medlineplus.gov/healthtopics.html)
●National Cancer Institute
●American Cancer Society
●The Leukemia & Lymphoma Society
●National Marrow Donor Program
●The American Society of Clinical Oncology
