Multiple myeloma treatment

Multiple myeloma treatment

Author
S Vincent Rajkumar, MD
Section Editor
Robert A Kyle, MD
Deputy Editor
Rebecca F Connor, MD

Disclosures

MULTIPLE MYELOMA OVERVIEW — The treatment of multiple myeloma (MM) is complex because of rapid advances in stem cell transplantation, medications, and better supportive care, which have led to improved survival for patients with multiple myeloma over the past thirty years [1]. The main options for therapy include:

Standard chemotherapy drugs such as melphalan (Alkeran®), cyclophosphamide (Cytoxan®), Doxorubicin (Adriamycin®) and liposomal doxorubicin (Doxil®)
Newer drugs such as thalidomide (Thalomid®), lenalidomide (Revlimid®), and bortezomib (Velcade®)
Corticosteroids such as prednisone or dexamethasone (Decadron®)
Stem cell (bone marrow) transplantation
Each option needs to be weighed carefully. Because current therapy is rarely curative, 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 information: Multiple myeloma symptoms, diagnosis, and staging”.)

TREATMENT ISSUES

Types of treatment — There are four main types of treatment:

Chemotherapy — In most people, chemotherapy partially controls multiple myeloma; rarely, chemotherapy leads to complete remission.
Corticosteroids — Corticosteroids include dexamethasone (Decadron) or prednisone.
Newer Drugs — Drugs such as thalidomide (Thalomid®), lenalidomide (Revlimid®), and bortezomib (Velcade®) have emerged as important options for treatment of myeloma, both in newly diagnosed patients and in patients with advanced disease who have failed chemotherapy or transplantation. In most cases, these agents are used in combination with standard chemotherapy agents.
Stem cell transplantation — Stem cell transplantation can be done using one’s own stem cells (autologous) or using cells from a close relative or matched unrelated donor (allogeneic). In multiple myeloma, most transplants performed are of the autologous kind. Such transplants, although not curative, have been shown to prolong life in selected patients. They can be done as initial therapy in newly diagnosed patients or at the time of relapse. Sometimes, in selected patients 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.
When to start treatment? — Multiple myeloma can remain stable for prolonged periods of time. Individuals with early myeloma who have no symptoms (often called smoldering myeloma) may be advised to wait months to years before considering chemotherapy.

Individuals 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 patients with MGUS will eventually develop full-blown myeloma.

However, once symptoms develop, treatment with one or more of the options discussed above is recommended for almost all patients.

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 patients 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 upon a person’s health and vary across institutions.

In most centers in the United States, patients with multiple myeloma who have one or more of the following factors are NOT considered eligible for transplantation:

Age >77 years
Direct bilirubin >2.0 mg/dL (an elevated bilirubin level indicates that the liver may not tolerate the high dose chemotherapy required before transplantation)
Serum creatinine >2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis (creatinine is a reflection of kidney function; those with poor kidney function may not tolerate high dose chemotherapy)
Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain (table 1)
New York Heart Association functional status Class III or IV (table 2)
However, these factors are guidelines; the decision regarding transplant eligibility should be made by the patient and physician after discussing the potential risks, benefits, and the needs and wishes of the patient.

TREATMENT OF NEWLY DIAGNOSED MULTIPLE MYELOMA — The initial choice of chemotherapy depends upon the patient’s health, age, ability to undergo stem cell transplantation in the future and disease characteristics that denote high or standard risk multiple myeloma [2]. High versus standard risk multiple myeloma is discussed separately. (See “Patient information: Multiple myeloma symptoms, diagnosis, and staging”, section on ‘Standard versus high-risk MM’.)

High risk multiple myeloma treatment options — The best treatment option for patients with high risk multiple myeloma is not clear. Most experts recommend enrolling in a clinical trial (see ‘Clinical trials’ below).

For patients who are not willing or able to participate in a clinical trial:

If a person is a candidate for stem cell transplantation, a treatment regimen that includes bortezomib (Velcade®) such a bortezomib, cyclophosphamide, dexamethasone (VCD) or bortezomib, thalidomide, dexamethasone (VTD) is recommended as initial therapy; several studies have suggested that using a regimen that includes bortezomib can improve survival in people with high risk multiple myeloma. After initial therapy (usually about four months), stem cell transplantation either early or later in the treatment course should be considered.
If a person is not a candidate for stem cell transplantation (because of underlying medical problems, age, or poor health), a regimen that includes bortezomib, such as melphalan, prednisone, and bortezomib (VMP) or bortezomib, cyclophosphamide, dexamethasone (VCD), chemotherapy is usually recommended as initial therapy.
The goal of therapy in high risk myeloma is to achieve and maintain a complete response as much as possible.
Standard risk multiple myeloma treatment options — People who have standard risk multiple myeloma and who develop symptoms are usually treated with one of the following regimens:

If a person is a candidate for stem cell transplantation, treatment usually consists of a regimen that does not contain melphalan, such as lenalidomide plus dexamethasone (Rd) or bortezomib, cyclophosphamide, dexamethasone (VCD). These treatments are less likely to interfere with later collection of stem cells compared with melphalan. (See ‘Lenalidomide’ below.)
If a person is not a candidate for stem cell transplantation (because of underlying medical problems, age, or poor health), treatment usually consists of regimens such as melphalan prednisone thalidomide (MPT), bortezomib melphalan prednisone (VMP), or lenalidomide plus low dose dexamethasone (Rd). If later stem cell transplantation is a possibility, stem cells should be collected before melphalan is given because this drug can cause long-lasting damage to stem cells.
Melphalan is not usually recommended for people who have kidney failure. In such situations, thalidomide/dexamethasone, bortezomib/dexamethasone, or bortezomib, thalidomide, dexamethasone (VTD) is preferred.

Melphalan prednisone thalidomide (MPT) chemotherapy — The combination of melphalan, prednisone, and thalidomide has been shown to be one of the most effective treatments of multiple myeloma for people who are not planning to undergo stem cell transplantation.

Melphalan is a chemotherapy drug that functions to kill tumor cells
Prednisone is a steroid that functions to kill tumor cells
Thalidomide may work to slow the growth of new blood vessels to a tumor and may slow or stop the growth of tumor cells. Thalidomide is absolutely UNSAFE (contraindicated) for pregnant women.
Melphalan and prednisone are taken by mouth, usually on days one through four every six weeks. Each 6 week interval is called a cycle; a total of 12 cycles is usually recommended. Thalidomide is taken every day until the 12 cycles are completed. It may take 6 to 12 months or even longer for blood tests to reflect the full effects of this chemotherapy on multiple myeloma. The average survival among individuals treated with MPT is four years.

During MPT chemotherapy, periodic blood tests are needed to ensure that an individual has adequate levels of white blood cells (cells that fight infection) and platelets (cells important for clotting). The dose of melphalan must be adjusted based on these findings.

Lenalidomide — Lenalidomide (Revlimid®) is an immune-modulating drug that is effective in the initial treatment of multiple myeloma, usually in combination with dexamethasone. This combination is one of the preferred initial treatment for people with multiple myeloma who are planning to have stem cell transplantation. Both medications are taken as a pill; lenalidomide is taken for 21 of 28 days, along with dexamethasone, which is taken once per week.

The combination of lenalidomide with dexamethasone increases the chance of developing blood clots; an anticoagulant (eg, aspirin or warfarin) is usually recommended to reduce this risk. Lenalidomide has the potential to cause severe birth defects; it is absolutely unsafe (contraindicated) for pregnant women.

Thalidomide (Thalomid®) plus dexamethasone is an alternative to lenalidomide plus dexamethasone, although it may not be as effective and may have more toxic side effects. The risks of thalidomide are similar to those of lenalidomide.

Bortezomib — Bortezomib (Velcade®) is a medication that is effective in treating patients with multiple myeloma and other tumors. It may be especially useful in people with kidney failure and those with high-risk multiple myeloma. Bortezomib is given intravenously or subcutaneously, and its main side effects are low blood counts and nerve damage.

Treatment-related infections — There is an increased risk of infection during the first two months of chemotherapy or immune modulating therapy. As many as one-third of these infections are fatal and, in many cases, they limit the ability to administer chemotherapy. In some centers, daily antibiotics are given during the first two months of chemotherapy to reduce the risk or severity of infections. However, other centers do not routinely recommend preventive antibiotics.

In all cases, vaccination against influenza and pneumonia is strongly recommended before starting chemotherapy. (See “Patient information: Adult vaccines”.)

Plateau phase — Chemotherapy is usually continued until multiple myeloma enters a stable (plateau) phase. The plateau phase is reached when the myeloma becomes stable and shows no signs of progressing. Although this phase is usually temporary, it typically lasts six months or longer. The plateau phase occurs in about one half of individuals after chemotherapy.

Achieving this phase usually requires at least six cycles of treatment, although some people require additional cycles to reach the plateau phase. People with standard risk multiple myeloma do not usually require additional chemotherapy during the plateau phase. However, some physicians recommend maintenance chemotherapy for people with high risk multiple myeloma (see ‘High risk multiple myeloma treatment options’ above).

A “response” to chemotherapy is defined as a 50 percent reduction in blood and urine levels of the abnormal M protein and an improvement of symptoms.

STEM CELL TRANSPLANTATION — Stem cell transplantation is a treatment option for some individuals with multiple myeloma. There are three types of transplantation, based on the source of the stem cells:

Autologous transplantation: the stem cells are obtained from the individual with multiple myeloma. This is the type of transplantation that is most commonly recommended.
Allogeneic transplantation: the stem cells or bone marrow are obtained from a donor with a tissue type matching that of the patient. This type of transplantation carries very high risks and is not recommended for most individuals with multiple myeloma.
Syngeneic transplantation: the stem cells or bone marrow are obtained from an identical twin of the individual. 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, prolongs survival, leads to a remission, and, infrequently, 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 puts the patient at risk for serious infections and bleeding, which can be fatal. (See “Patient information: Bone marrow transplantation (stem cell transplantation)”.)

Autologous stem cell transplantation — Autologous stem cell transplantation refers to transplantation with a person’s 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 the patient. Stem cells obtained from the blood are preferred to stem cells from the bone marrow 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 individuals with smoldering myeloma.

Procedure — After initial therapy with a regimen such as lenalidomide/dexamethasone or bortezomib, cyclophosphamide, dexamethasone (VCD) for three to four months, an individual is given granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) to stimulate the production of stem cells. If there are not sufficient numbers of stem cells in the 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 an individual recovers from the stem cell collection, he or she is given high-dose chemotherapy with melphalan (or similar drugs) to kill as many of the malignant plasma cells as possible; then the previously collected stem cells are thawed and returned to the patient. In about one-half of patients, this procedure can be done on an outpatient basis.

Alternatively, after stem cell collection, an individual may be given standard chemotherapy to achieve a plateau phase. At the time of relapse, high doses of melphalan (or similar drugs) are given, and the previously collected stem cells are returned to the patient; this is called delayed transplantation.

Single versus double autologous transplantation — Double autologous transplantation (two consecutive autologous transplantations) may be more effective than single autologous transplantation if the first transplant has not produced a complete or near complete response. The second transplantation is usually performed within six months of the first.

Among individuals undergoing double transplantation, 51 percent have a complete response, lasting, on average, 50 months. One study has shown that double transplantation improves long-term survival relative to single transplantation with the greatest benefit seen in patients who have not achieved an excellent response with the first transplant.

Role of age and stage of myeloma — Because autologous stem cell transplantation has serious side effects, it is generally not recommended for individuals 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 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 thalidomide, bortezomib, and lenalidomide, are safe to take before stem cell transplantation.

Effectiveness — About 1 percent of individuals die from complications related to transplantation. However, compared with chemotherapy alone, autologous stem cell transplantation is more likely to produce a response, and is associated with 12-month longer survival compared to chemotherapy alone (approximately 57 versus 44 months) [3].

Allogeneic bone marrow transplantation — Allogeneic transplantation requires bone marrow or stem cells from a donor with a matching tissue type. Unfortunately, approximately 25 percent of individuals who undergo allogeneic transplantation die from transplant-related complications, such as infection, lung inflammation, and graft-versus-host disease. Primarily because of this toxicity and the lack of clear benefit, allogeneic transplantation is seldom used for the treatment of myeloma.

Syngeneic transplantation — A syngeneic transplantation refers to a transplantation between identical twins. For individuals 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 4 percent of individuals 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. Individuals with MM 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 fluids and prednisone. If this treatment is not effective, treatment with drugs that act against bone loss, such as zoledronic acid (Zometa™) or pamidronate (Aredia™), a class of drugs called bisphosphonates, may be recommended.

Impaired kidney function — Kidney function becomes impaired in about one half of individuals with multiple myeloma. The treatment of impaired kidney function is aimed at the specific underlying cause.

Treatment usually includes intravenous 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 malignant plasma cells, which can damage the kidneys.

Patients are advised to stay well-hydrated and should drink enough fluid to produce three liters of urine daily if they have Bence Jones proteinuria (increased light chains in the urine). They should also avoid using any nonsteroidal anti-inflammatory drugs (NSAIDs, such as Advil®, Motrin®, 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 information: Dialysis or kidney transplantation — which is right for me?”.)

Infection — Bacterial infections, often indicated by the presence of fever, require prompt treatment with antibiotics. Daily use of the antibiotic trimethoprim-sulfamethoxazole (Bactrim) can help prevent infections. Individuals who get frequent infections may be advised to take penicillin daily or rarely to have periodic intravenous infusions of gamma globulin.

All individuals 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 information: Influenza symptoms and treatment”.)

Bone pain and fractures — Physical activity, with careful avoidance of injury, can promote bone strength in individuals 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 (Zometa™) or pamidronate (Aredia™) (commonly referred to as bisphosphonates) that can also reduce the likelihood of fractures.

In individuals who have early signs of bone erosion, bisphosphonates reduce the risk of fractures and reduce bone pain. Therefore, bisphosphonates are recommended for all individuals who have early signs of bone erosions on x-rays. Bisphosphonates are usually given by intravenous infusion every four weeks; this treatment is continued for approximately two years. These medications 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 patients treated with intravenous bisphosphonates. Accordingly, patients 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. Patients should call their doctor immediately if they have severe back pain; weakness, numbness, or tingling in the legs; or new problems with control over their bladder or bowel (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 individuals with multiple myeloma. This complication is treated with plasmapheresis, a type of blood filtration that removes the excess monoclonal proteins responsible for the increased viscosity.

TREATMENT OF RELAPSED OR REFRACTORY MULTIPLE MYELOMA — Almost all patients with multiple myeloma eventually relapse, and a modest percentage are resistant to initial treatment.

Multiple myeloma that responds poorly or not at all to melphalan-prednisone thalidomide or other therapy is called refractory multiple myeloma. This condition can occur during initial chemotherapy or during chemotherapy given after a relapse. Refractory multiple myeloma is more difficult to treat.

Thalidomide, bortezomib, or lenalidomide, given with steroids, and/or standard chemotherapy drugs such as melphalan or cyclophosphamide, form the major treatment options for relapsed or resistant disease.

Relapses occurring more than six months after completing chemotherapy are often treated by resuming the initial chemotherapy. Most individuals will again have a response to chemotherapy when it is given a second time, although the response is usually shorter and smaller than the original response. Selected patients can consider autologous stem cell transplantation.
The lack of response to initial induction chemotherapy does not always mean that the person will not have a good response to autologous stem cell transplantation. Said another way, if a person does not respond to induction chemotherapy, he or she may still respond to autologous stem cell transplantation.
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:

www.cancer.gov/clinicaltrials/learning/

www.cancer.gov/clinicaltrials/

file://clinicaltrials.gov/

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem.

 

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:

Patient information: Multiple myeloma symptoms, diagnosis, and staging
Patient information: Adult vaccines
Patient information: Bone marrow transplantation (stem cell transplantation)
Patient information: Dialysis or kidney transplantation — which is right for me?
Patient information: Influenza symptoms and treatment

Professional Level Information:

Allogeneic hematopoietic cell transplantation in multiple myeloma
Autologous hematopoietic cell transplantation in multiple myeloma
Clinical features, laboratory manifestations, and diagnosis of multiple myeloma
Determination of initial therapy in patients with multiple myeloma
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 (primary amyloidosis)
Evaluating response to treatment of multiple myeloma
Initial chemotherapy for symptomatic multiple myeloma in patients who are candidates for transplantation
Initial chemotherapy for symptomatic multiple myeloma in patients who are NOT candidates for transplantation
Diagnosis of monoclonal gammopathy of undetermined significance
Pathobiology of multiple myeloma
Pathogenesis of immunoglobulin light chain (AL) amyloidosis and light and heavy chain deposition diseases
Pathogenesis and diagnosis of myeloma cast nephropathy (myeloma kidney)
Treatment of relapsed or refractory multiple myeloma
Treatment of kidney disease in multiple myeloma
Treatment of the complications of multiple myeloma
Types of renal disease in multiple myeloma
The use of bisphosphonates in patients with multiple myeloma

The following organizations also provide reliable health information.

National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)

National Cancer Institute
(www.cancer.gov)

American Cancer Society
(www.cancer.org)

The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)

National Marrow Donor Program
(www.marrow.org)

The American Society of Clinical Oncology
(www.cancer.net/portal/site/patient)

REFERENCES
UK myeloma forum. British Committee for Standards in Haematology. Diagnosis and management of multiple myeloma. Br J Haematol 2001; 115:522.
Rajkumar SV. Treatment of multiple myeloma. Nat Rev Clin Oncol 2011; 8:479.
Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348:1875.
Kyle RA. Multiple myeloma: an odyssey of discovery. Br J Haematol 2000; 111:1035.
Riedel DA, Pottern LM. The epidemiology of multiple myeloma. Hematol Oncol Clin North Am 1992; 6:225.
Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004; 351:1860.
Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc 2005; 80:1371.