Version May 2024
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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. The main options include medications that target the cancer cells, autologous stem cell (bone marrow) transplantation, and chimeric antigen receptor (CAR)-T cell therapy.
Each option needs to be weighed carefully, and not all people are candidates for all of these options. Because current therapy rarely cures the disease completely, most people go through many treatment regimens during the course of their illness.
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 health care providers, is available by subscription. (See 'Professional level information' below.)
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 or even years before considering treatment. In contrast, people who are considered at higher risk for disease progression (from smoldering to "active" myeloma) may be advised to start treatment right away. When a person is diagnosed with active multiple myeloma, their doctor will explain the different options and offer guidance on when to start treatment.
People with a related condition called "monoclonal gammopathy of undetermined significance" (MGUS) do not require treatment. However, they do need long-term follow-up, as a small percentage of people with MGUS will eventually develop multiple myeloma.
Once symptoms of multiple myeloma develop, treatment with one or more of the options below is recommended for almost all people.
Types of treatment — Major treatment options for multiple myeloma include:
●Medications – Medications for multiple myeloma are often combined into treatment regimens that include several medications. The medications work in different and complementary ways.
●Autologous stem cell (bone marrow) transplant – This approach allows for the use of high doses of chemotherapy that would otherwise destroy the bone marrow stem cells. "Autologous" means the transplanted stem cells come from the person's own body rather than a donor. Stem cells are collected before having chemotherapy, then returned to the body afterwards to repopulate the bone marrow.
While it does not cure the disease, autologous stem cell transplant can lead to significant and prolonged responses in multiple myeloma. Transplant can be done immediately following initial therapy in people who have newly diagnosed disease, an approach known as "consolidation," or at the time of relapse. Autologous transplant for multiple myeloma is very safe in centers with experience in the procedure; however, not everyone is a candidate for this treatment. (See 'Autologous stem cell transplantation' below.)
●"CAR-T" therapy – CAR-T therapy is a form of immunotherapy. It uses the person's own immune system to target a specific antigen (a type of protein) found on the surface of the cancer cells. The person's immune cells (T cells) are collected, genetically modified, and returned to the body. The modified T cells then directly target the cancer cells.
CAR-T therapy is used for the treatment of relapsed or refractory multiple myeloma (see 'Treatment of relapsed or refractory multiple myeloma' below). Decisions regarding eligibility for CAR-T therapy are made on a case-by-case basis, considering an individual’s age, health, functional status, and preferences regarding the type of therapy they are to receive.
Medications used in multiple myeloma — Medications used for the treatment of multiple myeloma can be loosely categorized by how they work. Common medication categories include:
●Immunomodulatory drugs – These medications fight cancer in several different ways, including using the body's immune system to target myeloma cells. They include lenalidomide (brand name: Revlimid), pomalidomide (brand name: Pomalyst), and thalidomide (brand name: Thalomid). They are all available as pills.
●Proteasome inhibitors – The proteasome is an intracellular complex that breaks down proteins that are no longer necessary within the cell. It is particularly active in neoplastic (abnormal) plasma cells, as found in myeloma and related conditions, since these cells generate a large amount of protein in the form of excess immunoglobulins in particular. Proteasome inhibitors block this action so that the proteins build up and in doing so lead to death of the cancer cells. The proteasome inhibitors include bortezomib (brand name: Velcade), carfilzomib (brand name: Kyprolis), and ixazomib (brand name: Ninlaro). Bortezomib is usually given as a shot under the skin (subcutaneously), carfilzomib is given into a vein (IV), and ixazomib is taken as a pill.
●Corticosteroids – Corticosteroids include dexamethasone (sample brand name: Decadron) and prednisone (sample brand name: Deltasone). They can be taken as a pill or given into a vein (IV).
●Monoclonal antibodies – Monoclonal antibodies treat multiple myeloma by targeting 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), isatuximab (brand name: Sarclisa), and elotuzumab (brand name: Empliciti). All can be given by vein (IV). Daratumumab may be given as a shot under the skin (subcutaneously).
●Bispecific antibodies – Bispecific antibodies (also known T cell engagers) are monoclonal antibodies that target an antigen on the tumor (cancer) cell and a different antigen on the person's T cells. This brings the immune cells and tumor cells closer together and aids in immune cell killing of the tumor cells. Bispecific antibodies used for multiple myeloma include teclistamab (brand name: Tecvayli), elranatamab (brand name: Elrexfio), and talquetamab (brand name: Talvey). They are all given as a shot under the skin (subcutaneously).
●Nuclear export inhibitor – The nuclear export machinery in a cell is responsible for transferring certain proteins out of the cell nucleus. Selinexor (brand name: Xpovio) is a pill that blocks this action, leading to death of the tumor cells. Selinexor can be used for the treatment of multiply relapsed multiple myeloma in selected cases. (See 'Treatment of relapsed or refractory multiple myeloma' below.)
●Cytotoxic chemotherapy agents – Traditional chemotherapy agents used in multiple myeloma include melphalan (brand name: Alkeran), cyclophosphamide (brand name: Cytoxan), doxorubicin (brand name: Adriamycin), and liposomal doxorubicin (brand name: Doxil).
INITIAL TREATMENT OF MULTIPLE MYELOMA — The initial choice of therapy depends on the person's health, age, frailty, eligibility for stem cell transplantation, 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:
●An immunomodulatory drug such as lenalidomide (brand name: Revlimid),
●A corticosteroid such as dexamethasone, and
●Either a proteasome inhibitor such as bortezomib (brand name: Velcade) or the monoclonal antibody daratumumab (brand name: Darzalex)
Two popular regimens are bortezomib, lenalidomide, dexamethasone ("VRd") and daratumumab, lenalidomide, dexamethasone ("DRd"). Some people will be treated with a four-drug regimen that includes all of these drug types, for example, daratumumab, bortezomib, lenalidomide, and dexamethasone ("DVRd") or daratumumab, bortezomib, thalidomide, and dexamethasone ("DVTd").
High-risk multiple myeloma treatment options — The best treatment option for people with high-risk multiple myeloma is not clear. Participation in a clinical trial is recommended when this is feasible and the trial under consideration matches the needs of the individual (see 'Clinical trials' below).
For people who cannot or choose not to participate in a clinical trial, treatment depends on eligibility for autologous stem cell transplantation:
●People who are candidates for stem cell transplantation are often treated with a four-drug regimen such as DVRd or DVTd. 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 their disease progresses. Following transplant, two drugs are usually given for an extended time as "maintenance therapy," typically lenalidomide in combination with a proteasome inhibitor, or in some instances daratumumab.
●People who are not candidates for stem cell transplantation (because of age, health, or preference) are treated with a three-drug regimen, such as VRd or DRd. Following initial combination therapy, two drugs are usually given for an extended time as "maintenance therapy," typically lenalidomide in combination with a proteasome inhibitor or daratumumab.
For all people with multiple myeloma, the goal of therapy is to achieve a lasting response and prevent damage to the body related to myeloma. Ideally, treatment will result in a "complete response." This means that there is no monoclonal (M) protein found in the blood serum or urine; there are no large collections of plasma cells outside of the bone marrow; and that the percentage of plasma cells in the bone marrow is not higher than normal.
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 VRd or DRd. 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 typically receive additional cycles of VRd or DRd before transitioning to maintenance therapy with lenalidomide alone or lenalidomide plus dexamethasone until their disease progresses.
●People who are not candidates for stem cell transplantation (because of age, health, or preference) are also usually treated with a three-drug regimen such as DRd or VRd. Although three-drug regimens are strongly preferred to two-drug regimens for initial therapy, a two-drug regimen such as lenalidomide plus dexamethasone ("Rd") can be considered in certain situations, for example, a person who is very frail and may be less able to tolerate the greater toxicity associated with the three-drug combination. After initial treatment, the person is transitioned to maintenance with lenalidomide and dexamethasone or lenalidomide alone until their disease progresses.
For all people with multiple myeloma, the goal of therapy is to achieve a durable response and prevent damage to the body related to myeloma.
AUTOLOGOUS STEM CELL TRANSPLANTATION — Autologous stem cell (bone marrow) transplantation is a treatment option for some people with multiple myeloma. (see "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)").
Autologous stem cell transplantation refers to transplantation with the person's own stem cells. It is the most common type of transplantation recommended for treating multiple myeloma. After several cycles of chemotherapy are given to control the disease, stem cells are collected using a procedure called "pheresis" and frozen for later use. High-dose chemotherapy, most often with a drug called melphalan, is then given to kill as many cancer cells as possible, and the stem cells are thawed and returned to the body. This type of transplantation is very safe in centers with experience in the procedure. In contrast, "allogeneic" stem cell transplantation uses stem cells obtained from another person (a donor). This type of transplantation carries very high risks and is not recommended for most people with multiple myeloma.
Autologous stem cell transplantation is an option for people who are healthy enough to undergo intensive therapy. Compared with chemotherapy alone, autologous stem cell transplantation is more likely to produce a significant and prolonged response. However, it is very intensive and there is potential for serious side effects. With appropriate candidate selection, less than 1 percent of people die from complications related to autologous transplantation.
Experts at a transplant center can offer detailed guidance regarding candidacy, the role of transplant for a specific person, and preferred timing. The decision to proceed with transplant should be made by the person and their physician after discussing the potential risks, benefits, and the needs and wishes of the individual.
Stem cell collection occurs after several cycles of chemotherapy have been given to control the disease. At that point:
●A treatment called "granulocyte colony-stimulating factor" (G-CSF) or "granulocyte-macrophage colony-stimulating factor" (GM-CSF) is given, either alone or with other drugs. This stimulates the production of stem cells and encourage their release into the bloodstream.
●Stem cells are collected from the blood, frozen, and stored.
●After the person recovers from the stem cell collection, high-dose chemotherapy with melphalan (or similar drugs) is used to kill as many of the cancer cells as possible.
●The previously collected stem cells are then thawed and returned to the body through a vein. Depending on the person's needs and condition, this may be done in the hospital or as an outpatient (ie, without a hospital stay).
●Alternatively, the stem cells may be stored and saved for a later time point in the person's treatment, most often at the time of a first relapse. This is called delayed transplantation.
TREATMENT OF MULTIPLE MYELOMA COMPLICATIONS — Multiple myeloma can cause a variety of complications, some of which are life-threatening. Complications may be present at the time multiple myeloma is diagnosed and/or occur at relapse.
High blood calcium levels — High blood calcium levels in individuals with multiple myeloma develop as bone is lost, or resorbed, as a result of the disease.
The treatment of high blood calcium levels usually includes the use of intravenous (IV) fluids plus a drug that act against bone loss such as zoledronic acid (sample brand name: Zometa), pamidronate (sample brand name: Aredia), or denosumab (brand name: Xgeva).
In addition, the underlying cancer should be controlled as quickly as possible by starting or adjusting therapy directed at the multiple myeloma.
Impaired kidney function — Kidney function is impaired in about one-half of people with multiple myeloma. The treatment of impaired kidney function (ie, kidney dysfunction) is aimed at the specific underlying cause.
Treatment of kidney dysfunction involves:
●Chemotherapy – This is used to try to control the disease and prevent disease-related damage to the kidney.
●Fluids – It is important for people with myeloma to drink plenty of fluids, as dehydration can lead to kidney impairment as well. In some cases, intravenous (IV) fluids are needed.
●Treatments to lower blood calcium levels – High levels of either calcium or uric acid can occur in association with multiple myeloma, both of which can damage the kidney. Thus, treatments to lower calcium concentration (eg, zoledronic acid or denosumab) and uric acid (eg, allopurinol or rasburicase) are used when necessary.
People with impaired kidney function should avoid using nonsteroidal anti-inflammatory drugs (NSAIDs); these include ibuprofen (sample brand names: Advil, Motrin) and naproxen (sample brand name: Aleve). They should also avoid frequent use of diuretics such as furosemide (sample brand name: Lasix). These drugs might worsen kidney function.
If impaired kidney function progresses to the point of kidney failure, treatment options include hemodialysis or peritoneal dialysis in addition to the treatments described above. Dialysis is a treatment to take over the job of the kidneys by removing waste and excess fluid from the blood. Advanced kidney failure may be reversible, but in some instances kidney function doesn’t recover, and long-term dialysis is necessary. (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. It is common for people with multiple myeloma to take medications to help prevent infections, including the antibiotic trimethoprim-sulfamethoxazole (sample brand names: Bactrim, Septra) and an antiviral drug. Rarely, people who get frequent infections need periodic IV infusions of gamma globulin (normal antibodies collected from plasma donors).
All people with multiple myeloma should receive the pneumococcal (pneumonia) vaccine, the influenza (flu) vaccine, and the COVID-19 vaccine. (See "Patient education: Pneumonia prevention in adults (Beyond the Basics)" and "Patient education: Influenza prevention (Beyond the Basics)".)
Bone pain and fractures — Physical activity, while taking care to avoid injury, can promote bone strength in people with multiple myeloma. The bone pain associated with multiple myeloma can be controlled with chemotherapy, pain-relieving medication, radiation, and bone strengthening drugs such as zoledronic acid (sample brand name: Zometa), pamidronate (sample brand name: Aredia), or denosumab (brand name: Xgeva).
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 with myeloma. Bisphosphonates (ie, zoledronic acid and pamidronate) are usually given by IV every one to three months, and denosumab is given as a shot under the skin (subcutaneously); this treatment is continued for approximately two years. Bisphosphonates and denosumab 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 or denosumab. Accordingly, people should avoid such procedures, if possible, while taking these agents; any needed dental procedures should be performed before these medications are started.
Spinal cord compression — In some patients, the multiple myeloma tumor cells extend from the bone marrow and bone structures into the spinal canal; this can lead to compression of the spinal cord. 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 is the medical term for a low red blood cell count. Anemia that is causing symptoms may require blood transfusions or treatment with medications that stimulate the production of red blood cells, called erythropoietin and darbepoetin. Erythropoietin and darbepoetin can increase levels of hemoglobin (the protein in red blood cells that helps carry oxygen to the tissues), improve symptoms, and reduce 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 initially treated with plasmapheresis, a type of blood filtration that removes the excess monoclonal proteins that cause the thickening. The underlying cancer must be treated with effective chemotherapy to suppress tumor growth and reduce the production of the monoclonal protein.
TREATMENT OF RELAPSED OR REFRACTORY MULTIPLE MYELOMA — Almost all people with multiple myeloma eventually relapse, and a small 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.
The main treatments used for relapsed or refractory multiple myeloma are:
●Immunomodulatory drugs (lenalidomide, pomalidomide, thalidomide)
●Proteasome inhibitors (bortezomib, carfilzomib, ixazomib)
●Steroids (dexamethasone)
●Antibodies that target myeloma cells (daratumumab, elotuzumab, isatuximab)
●Bispecific antibodies (teclistamab, elranatamab, talquetamab)
●Nuclear export inhibitor (selinexor)
●Cytotoxic chemotherapy drugs (melphalan, cyclophosphamide)
●Chimeric antigen receptor (CAR) T cells
●Autologous stem cell transplantation
These can be used in various combinations depending on the situation; all of these treatments 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 medication at some point during the disease course.
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 or bispecific antibodies.
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 health care 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 health care 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: Clinical features, laboratory manifestations, and diagnosis
Multiple myeloma: Overview of management
Multiple myeloma: Initial treatment
Multiple myeloma: Use of hematopoietic cell transplantation
Multiple myeloma: Evaluating response to treatment
Multiple myeloma: Treatment of first or second relapse
Multiple myeloma: Treatment of third or later relapse
Multiple myeloma: Administration considerations for common therapies
Multiple myeloma: The use of osteoclast inhibitors
Multiple myeloma: Prevention of venous thromboembolism
Multiple myeloma: Management in resource-limited settings
Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis
Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation
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
(www.cancer.net/cancer-types/multiple-myeloma)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Robert A Kyle, MD to earlier versions of this topic review.
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