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Multiple Myeloma: An Overview

Eric Shinohara, MD, MSCI and Elizabeth N. Kuhn, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 11, 2013

What is Bone Marrow?

The bone marrow is a spongy material found primarily in the center of long bones and it is where blood cells are produced. Bone marrow is comprised of a variety of cells, which gradually mature to form:

  • Red blood cells (also known as erythrocytes), which carry inhaled oxygen from the lungs to other organs and carry carbon dioxide from the organs to the lungs to be exhaled.
  • Platelets (also known as thrombocytes), which help form clots.
  • White blood cells (also known as leukocytes) come in several varieties: granulocytes, lymphocytes, and monocytes, each of which has a different role in the immune system. Lymphocytes are designated as either B or T lymphocytes.
  • Plasma cells are a mature form of B-lymphocytes, which produce antibodies, and make up less than 5% of the cells in bone marrow.

There are a large number of different pathogens, such as bacteria or viruses, which can attack your body. When your immune system fights an infection, it needs to make an antibody that specifically targets the pathogen causing that infection. Each plasma cell can only produce one specific kind of antibody. Individual plasma cells can then divide repeatedly to form copies of themselves, known as clones. This group of clonal plasma cells can produce large amounts of a single kind of antibody to fight a specific infection. There are several thousand different populations of plasma cell clones, which then allow the immune system to make a wide variety of antibodies to target many different kinds of pathogens. Antibodies coat the pathogen that they are built to attack, and thus make it easier for other immune cells to also attack the pathogen.

What is multiple myeloma?

Multiple myeloma is a cancer of the blood (hematologic cancer) in which one population of clonal (identical) plasma cells starts to reproduce uncontrollably. These cells are known as malignant plasma cells, or myeloma cells. Myeloma cells produce large amounts of one type of antibody, which is known as the monoclonal protein or M-protein. As the number of myeloma cells grows, they begin to overcrowd the bone marrow and prevent normal production of the other blood cell types (red blood cells, platelets, and other white blood cells) in the bone marrow. This also negatively affects the immune system because the bone marrow now predominantly produces only one type of antibody, and can no longer effectively target all pathogens. Thus there is increased risk of infection in patients with multiple myeloma. Anemia results when multiple myeloma prevents the bone marrow from producing enough red blood cells. As the plasma cells continue to multiply, they can invade and damage other organs. The monoclonal protein produced by plasma cells can also damage organs, specifically the kidneys. The acronym "CRAB" is often used to describe symptoms associate with organ damage by multiple myeloma: hyperCalcemia (High levels of calcium in the blood), Renal insufficiency (kidney failure), Anemia (low red blood cell counts), and Bone lesions.

Precursors to multiple myeloma

Almost all patients with multiple myeloma evolve from an asymptomatic condition called Monoclonal Gammopathy of Unknown Significance (MGUS). However, since MGUS does not cause any symptoms (asymptomatic), they may not know they have it. People with MGUS have an increased number of clonal plasma cells, but not to the degree seen in multiple myeloma nor do these patients have other symptoms associated with multiple myeloma. However, people with MGUS do have a 1-2% annual risk of developing multiple myeloma or a related blood cancer, such as leukemia or lymphoma. In light of this risk, when someone is first diagnosed with MGUS, it is recommended that blood tests be performed to check for elevated monoclonal protein levels every three months initially.

Some patients may be diagnosed with "smoldering multiple myeloma", which is an early stage of multiple myeloma. Smoldering multiple myeloma meets all the diagnostic criteria for multiple myeloma, but lacks any of the "CRAB" features listed above. The risk of developing symptomatic multiple myeloma is 10% per year for the first 5 years, 3% per year for the next 5 years, and 1.5% per year thereafter. Patients with smoldering myeloma typically do not receive treatment, but are monitored closely for any progression to active myeloma.

Am I at risk for multiple myeloma?

Approximately 22,350 people are diagnosed with multiple myeloma a year in the United States. Multiple myeloma comprises approximately 1% of all cancers and comprises about 10% of all "blood cancers", which includes leukemia. The rate of multiple myeloma in blacks is twice that seen in white Americans. Rates appear to be lower in Asians. This disease occurs more commonly in men than in women. The average age at diagnosis is 60 and people under age 40 rarely develop this disease.

At this time, the cause of multiple myeloma is not well established. However, there appear to be several factors which increase the risk of developing multiple myeloma, such as extensive exposure to radiation, chemical resins, organic solvents, pesticides, and herbicides. There is also a herpes virus, Human Herpes Virus 8 (HHV-8), which is thought to be related to the development of multiple myeloma. People with first-degree relatives, such as a mother or brother, who have multiple myeloma, may also be at increased risk for developing the disease. However, a clear genetic mutation related to multiple myeloma has not been discovered.

How can I prevent multiple myeloma?

Unfortunately, because the exact cause of multiple myeloma is unknown, there are no specific guidelines for the prevention of multiple myeloma. Limiting exposure to radiation, chemical resins, organic solvents, pesticides, and herbicides may decrease the risk for developing multiple myeloma.

If you have MGUS or smoldering multiple myeloma, you should see your physician regularly to check for progression to multiple myeloma.

What screening tests are available?

Multiple myeloma is very rare, accounting for only 1% of all cancers diagnosed in the United States, and thus there are no effective screening tests available. However, there are some basic tests which can help with the diagnosis of multiple myeloma. Almost all people with multiple myeloma have monoclonal proteins in their blood or urine, and there are effective tests available to check for them. Other blood tests to check for kidney disease, high calcium levels, and low red blood cell counts (anemia) can also be used to test for the disease. X-rays can be used to detect erosions in bones caused by multiple myeloma.

What are the signs and symptoms of multiple myeloma?

The increased number of myeloma cells, as well as the high levels of monoclonal protein that they produce, can cause several symptoms in people with multiple myeloma. The symptoms are related either to infiltration of the bone marrow by plasma cells or end-organ damage. Because of advances in routine blood work over the last 20 years, patients are more frequently being diagnosed with asymptomatic disease.

Bone Pain

Multiple myeloma increases bone breakdown and decreases formation of new bone, leading to "lytic lesions," or areas where the bone has been "punched out" and looks like holes on the x-ray. Bone pain is the most common presenting symptom, with up to two-thirds of patients having bone pain at diagnosis. The pain is typically in the back or chest, but can occur in the leg or arm bones. It is usually associated with movement and is not commonly present at night, unless the person moves. Multiple myeloma can cause osteoporosis, or generalized weakening of the bone, and weakness at the location of the "punched out" bony lesions. This makes people with multiple myeloma more vulnerable to fractures (broken bones). Often fractures can occur with little or no trauma due to the weakening of the bone. Very commonly, the vertebral bodies (the bones that make up the spine) are affected, leading to "compression fractures." A compression fracture is one where some of the height of the vertebral body is lost and can cause pain or numbness if nerve roots exiting the spinal cord are injured. Multiple myeloma can also cause bone erosions, which occur when small areas of bone are eaten away. On x-ray, erosions can make the bone appear patchy with the areas of bone loss appearing darker. At diagnosis, about 75% of people with multiple myeloma will have evidence of fractures, bone erosions, or osteoporosis on x-ray. Bisphosphonates, a class of medication which strengthens bone, can be used to help improve bone weakness.

High Calcium Levels

Bones have high calcium content and as they are broken down, a large amount of calcium is released into the blood. This condition is also known as hypercalcemia and can occur in up to 30% of people with multiple myeloma. High level of calcium in the blood can cause GI symptoms, such as nausea, vomiting, and constipation. It can affect the urinary system and cause increased urination as well as kidney stones due to the higher calcium concentration in the urine. It can also affect how you feel or act by causing nausea/vomiting, decreased appetite, increased thirst and urination, restlessness and confusion.

Low Red Blood Cell Count (Anemia)

About 70% of people with multiple myeloma will have anemia at the time of diagnosis. As the bone marrow becomes overcrowded with myeloma cells, red blood cells cannot be produced in adequate numbers. There are not enough red blood cells in the blood, and this decreases the body's ability to transport oxygen to the tissues and to transport carbon dioxide to the lungs for elimination. Due to this, people with anemia often appear pale and have weakness, fatigue and shortness of breath.

Increased Blood Thickness (Hyperviscosity syndrome)

The myeloma cells produce a large amount of monoclonal protein, which can thicken the blood to the point where the blood has problems circulating properly in smaller blood vessels. In general, hyperviscosity is uncommon in multiple myeloma. The most common symptom associated with hyperviscosity syndrome is an increased risk of bleeding. People may have spontaneous bleeding of their gums, nose, or bowel during bowel movements. People may also notice continued bleeding after minor procedures, such as dental work. People may also notice that they bruise easier than they do normally. Symptoms related to the neurological system are also frequently seen in hyperviscosity syndrome. These include changes in vision, such as blurriness or loss of vision, hearing loss, numbness, difficulty with balance, headache, tingling, sleepiness, and even seizures. The thicker blood can also affect the heart and cause symptoms of heart failure, where the heart cannot pump blood well. People with heart failure often have fatigue and difficulty breathing.

Neurologic Impairment

The spinal cord communicates with the body through a network of nerves. Nerve roots are large bundles of nerves which conduct signals into and out of the spinal cord. Multiple myeloma can weaken the vertebral bones surrounding the spine, leading to fractures, which in turn can compress the nerve roots. Compression can lead to irritation and inflammation of the nerve roots, which is also known as radiculopathy. These nerves control body movement as well as sensation, thus symptoms of radiculopathy are numbness, tingling, shooting pains, and weakness. The spinal cord, which is protected by the surrounding vertebral bodies, can be compressed by collapsing bone or by the growth of a tumor into the spinal canal. This can occur in 5-10% of patients with multiple myeloma. Compression of the spinal cord is a medical emergency, and immediate medical care is necessary to decompress the cord and prevent permanent damage. Cord compression typically causes severe back pain, leg weakness, urinary retention and/or loss of sensation to the genitals.

Excess proteins can build up and cause irritation to nerves, which can result in a condition called peripheral neuropathy. Peripheral neuropathy typically begins with a tingling and/or numbness in the fingers and toes and can progress to painful sensations and extend into the hands and feet.

Increased Risk of Infection

Myeloma cell overgrowth in the bone marrow prevents normal plasma cells from producing antibodies. It also prevents adequate numbers of other white blood cells from being formed in the bone marrow. Due to this, people with multiple myeloma are more susceptible to infections, often caused by bacteria such as Streptococcus pneumoniae, which can cause pneumonia, meningitis, and bloodstream infections. Treatments, including steroids and chemotherapy, can further increase one's susceptibility to infection. Infection is one of the most important causes of illness and death in multiple myeloma and should be diagnosed and treated promptly.

Plasmacytoma

A plasmacytoma is a collection of myeloma cells that builds up either in the bone or other tissues. Plasmacytomas can develop in the skin anywhere on the body and may appear as purplish lumps. Reports have shown that about 12% of people can develop plasmacytomas in the ribs. Very rarely, plasmacytomas can develop in the brain.

Kidney Failure

Kidney failure is a frequent and serious complication of multiple myeloma. Kidney function can be measured by checking the level of a compound called creatinine in the blood. Normally, the kidneys remove creatinine from the body, so high levels of creatinine (detected in a blood test) indicate that the kidneys are not functioning well. About 25-50% of people with multiple myeloma have an increased level of creatinine in their blood, indicating kidney failure. There are many factors that contribute to kidney failure in multiple myeloma. However, the most common is deposition of monoclonal protein (produced by myeloma cells) in the kidney's filtration apparatus. This results in an inability of the kidney to filter appropriately, leading to kidney failure. High blood levels of calcium caused by bone breakdown, use of NSAIDs, certain chemotherapy agents, and bisphosphonates can also cause kidney failure. Caution should be taken when having CT scans, as the "contrast" used in these tests can cause or worsen renal failure in patients with multiple myeloma.

How is multiple myeloma diagnosed?

Tests Used in Diagnosing Myeloma

Multiple myeloma cannot be diagnosed with any single test result and your healthcare providers may order a combination of laboratory tests to confirm a diagnosis of myeloma, monitor MGUS or smoldering myeloma, or to monitor the disease's response to treatment. While blood count and chemistry levels are used, there are a few tests that are less common, but often used in myeloma diagnosis and management:

  • SPEP (serum protein electropheresis): test that is used to find the M protein (also called monoclonal immunoglobulin or that abnormal protein that is growing out of control). This can be a first step in diagnosing myeloma.
  • Immunoelectropheresis: a blood test used to determine the type of abnormal immunoglobulin (i.e. IgA, IgE) that was found to be elevated by SPEP.
  • Quantitative Immunoglobulins: your immune system makes different types of antibodies in the blood (called IgA, IgD, IgE, IgG, and IgM). This blood test measures the levels of these different antibodies. In myeloma, one type may be particularly high, with the others being normal or low.
  • UPEP (Urine protein electropheresis): a 24-hour collection of urine is tested to find M protein or Bence-Jones proteins in the urine. Bence-Jones proteins are also called immunoglobulin light chains, which are a part of normal antibodies. When too much is produced, it is filtered by the kidneys and can be detected in the urine.
  • Free Light Chains: in some myelomas, M proteins cannot be detected by SPEP. SPEP can only measure intact immunoglobulins. However, immunoglobulins can break down into the parts that make them up: 2 heavy chains and 2 light chains. These light chains may be detected in the blood, which can be helpful in myeloma where SPEP cannot detect M proteins.
  • Beta-2 microglobulin: a blood test to measure the amount of this protein in the blood. High levels can be indicative of more advanced disease.
  • Plasma Cell Labeling Index (PCLI): a blood test to determine the percentage of the abnormal plasma cells that are actively reproducing.
  • Bone Marrow Biopsy: used to determine the percent of abnormal plasma cells in the bone marrow.
  • Immunohistochemistry and Flow Cytometry: tests used to evaluate the bone marrow sample and detect myeloma cells.
  • Cytogenetics and FISH (fluorescent in situ hybridization): tests used to detect chromosomal abnormalities, which can be used to determine prognosis and guide treatment decisions. For instance, abnormalities associated with a better prognosis include trisomies, t(11;14), t(6;14); those associated with a worse prognosis include 17p deletion, t(14;16), t(14;20).
  • Skeletal Survey: x-rays of the entire skeleton that can identify lytic lesions or fractures.
  • Radiology tests, including MRI, CT Scan and PET Scan.

Diagnosis of Myeloma

There are a specific set of criteria for the diagnosis of multiple myeloma, to help distinguish it from other blood disorders that have similar characteristics to multiple myeloma, such as MGUS, smoldering myeloma, primary amyloidosis, and metastatic carcinoma. A combination of the tests discussed above may be necessary to make a diagnosis.

For a diagnosis of active (symptomatic) multiple myeloma to be made, all of the following criteria must be met:

  • Bone marrow biopsy shows that at least 10% of the bone marrow cells are clonal (identical) plasma cells. Alternatively, a biopsy-proven plasmacytoma may satisfy this criterion.
  • Evidence of organ damage due to excessive plasma cells, demonstrated by at least one of the following:
    • Elevated calcium: serum calcium > 11.5 mg/dL; or
    • Kidney damage: serum creatinine > 2 m/dL, or estimated creatinine clearance < 40 mL/min; or
    • Anemia: hemoglobin value at least 2 g/dL less than the lower limit of normal (or Hb<10 g/dL); or
    • Bone lesions: lytic lesions or osteoporosis with pathologic fracture.
  • In the absence of organ damage, the diagnosis can be made if >60% of the bone marrow is comprised of clonal plasma cells.

If these criteria are not met, a diagnosis of MGUS or smoldering myeloma is considered.

  • Smoldering (asymptomatic) myeloma is diagnosed if there are no signs/symptoms of organ damage, but clonal bone marrow plasma cells comprise 10-60% of the bone marrow and/or serum monoclonal protein ?3 g/dL.
  • Monoclonal gammopathy of undetermined significance (MGUS) is diagnosed if there are no signs or symptoms of organ damage, clonal bone marrow plasma cells <10%, and serum monoclonal protein <3 g/dL.

How is multiple myeloma staged?

Multiple myeloma is disease that can behave very differently in different individuals. It is critically important to identify those patients at high-risk versus low-risk, and tailor treatment accordingly. There are several factors that can predict how aggressive the multiple myeloma will behave and these are incorporated into staging of the disease.

Staging is a way to give a cancer a sort of "rating" that reflects prognosis and helps guide treatment decisions. Staging for myeloma is different than staging for solid tumors (i.e. breast, lung and colon cancer), which typically uses an I-IV stage rating. There are two staging systems used in multiple myeloma; The Durie-Salmon Criteria and The International Staging System (ISS).

The Durie-Salmon Criteria were initially described in 1975 and incorporate levels of M protein, number of bone lesions, hemoglobin and calcium levels and kidney function. The ISS is a simpler system that incorporates beta-2 microglobulin and albumin levels. The ISS is more commonly used today.

Stage

International Staging System (ISS)

Durie-Salmon Criteria

I

Serum beta2-microglobulin <3.5 mg/L and albumin >3.5 g/dL

All of the following:

  • Hemoglobin >10 g/dL
  • Serum calcium: normal or <12 mg/dL
  • Normal bone xrays or single bone plasmacytoma
  • Low production rate of monoclonal (M) protein:
    • IgG < 5 g/dL
    • IgA < 3 g/dL
    • Bence Jones protein <4 g/24 hours

II

Not stage I or III

Not stage I or III

III

Serum beta2-microglobulin ?5.5 mg/L

One or more of the following:

  • Hemoglobin <8.5 g/dL
  • Serum calcium >12 mg/dL
  • 3 or more lytic bone lesions
  • High production rate of monoclonal (M) protein:
    • IgG >7 g/dL
    • IgA > 5 g/dL
    • Bence Jones protein >12 g/24 hours
 

**Durie-Salmon also classifies the stage as A if the kidney function is normal, or B if there is abnormal kidney function (elevated creatinine).

In addition to the stage, many of the tests discussed above are used to determine prognosis, which is also used to make treatment decisions.

What is the treatment for multiple myeloma?

MGUS & Smoldering Myeloma

Treatment is not recommended for MGUS, and no intervention (treatment) has been found to delay or prevent MGUS from progressing to myeloma. Patients with asymptomatic or smoldering myeloma (stage I) should be followed closely, without treatment, because research studies have found that treating asymptomatic myeloma does not improve survival. The past decade has seen unprecedented advances in the treatment of symptomatic myeloma, with most patients responding to initial therapy, though curative treatment is still lacking.

Treatment for Stages II & III

There are a number of treatment options for myeloma, including chemotherapy, steroids, targeted therapy and high dose chemotherapy with stem cell transplant. Your oncology team will work with you to determine the best treatment or combination of treatments for your cancer. Below you will find an introduction to the available treatments. Research on the treatment of multiple myeloma has made great strides in recent years. Just 10-15 years ago treatment options for myeloma were limited and now there are several options that can be used to fit each person's unique case. These advances occur because patients participate in clinical trials that help find better treatments. Talk with your oncology team about available clinical trials.

High Dose Chemotherapy with Stem Cell Transplant

Several clinical trials have shown that in patients who are young (age <65 years) and fit enough, high dose chemotherapy and autologous stem cell transplant (using the patient's own stem cells) is a very good treatment option. This may be used as the first line therapy or after the disease has progressed on other therapies. This treatment is not considered a good option for certain high-risk patients with particular DNA abnormalities (chromosome 13 deletion, chromosome 17 translocation), as this may lead to poorer survival.

There are three phases to stem cell transplant therapy: induction therapy, stem cell transplant and maintenance therapy. In transplant candidates, the goal of the initial chemotherapy – called "induction chemotherapy" - is to kill as many myeloma cells as possible without damaging the stem cells. Patients are given several "rounds" of chemotherapy that typically contains bortezomib combined with dexamethasone and a third agent (thalidomide, lenalidomide, doxorubicine or cyclophosphamide), or lenalidomide and dexamethasone alone.

Following this "induction chemotherapy", patients will undergo a stem cell collection. Stem cells used to be collected from bone marrow, in the operating room. Due to the advances in stem cell collection, they can be taken from the blood, which is done in a photopheresis unit at a hospital using a procedure similar to dialysis. The patient sits in a recliner chair and, using a catheter in the chest or arm, blood is pulled out and passed through a machine that takes out the stem cells and returns the rest of the blood to the patient. These cells are then frozen until the patient is ready to receive them.

The next part of the transplant is typically done in the hospital. The patient is given high doses of chemotherapy to kill as much of the myeloma as possible. This treatment also damages or kills the stem cells in the patient's body. A day or two after completing the chemotherapy, the stem cells are thawed and given back to the patient through a catheter. These cells replace the stem cells that were damaged during the high dose chemotherapy, allowing your body to recover from this chemotherapy. In some institutions, the patient will remain in the hospital during the recovery, while others have an apartment or hotel nearby where patients stay and come to the clinic to be checked every day. Talk to the oncology team about their specific procedure.

After transplant, if remission is achieved, patients may require treatment with "maintenance" chemotherapy. It is not currently clear whether maintenance therapy is needed in all patients and your physician may elect instead for observation without maintenance chemotherapy. This is usually a less intense chemotherapy regimen and its goal is to prolong the period of remission. Preferred maintenance therapy is bortezomib, lenalidomide, or thalidomide.

Some studies are looking at the benefit of a second transplant (called tandem transplant) for patients who do not achieve a full remission after the first transplant. With this therapy, a second transplant is done within six months of the first. Up to half of patients treated with tandem transplants may have a complete response, however this is still being studied. In some cases, allogeneic transplant (stem cells from a donor) may be a treatment option. Allogeneic transplant has significant side effects and the risks and benefits of this therapy need to be discussed with each potential patient (see more below).

Chemotherapy & Targeted Therapy Treatments

Patients older than 65 years or with many multiple other medical problems may not be candidates for stem cell transplant. In other patients, stem cell transplant may be reserved for a future treatment. In those patients, chemotherapy and targeted therapies may be used. There are several regimen options that may include a combination of two or more of these medications:

Some clinicians feel that melphalan therapy should be avoided because it destroys the bone marrow stem cells and carries an increased risk of developing leukemia or other bone marrow disorders, such as myelodysplastic syndrome. After achieving remission, maintenance chemotherapy may be recommended with bortezomib, lenalidomide, or thalidomide.

Treatment of relapse

Almost all patients with multiple myeloma eventually relapse, many within 36 months. Management of relapsed myeloma depends on the initial treatment, length of remission, and persisting toxicities and other medical problems. If the initial therapy resulted in a remission >12 months in duration, that therapy will often be used again to treat the relapse. In general, first relapse is treated with regimens containing bortezomib, while subsequent relapses are treated with lenalidomide-containing regimens. Other agents, which have been recently shown effective in treating relapsed myeloma, include liposomal doxorubicin, carfilzomib, and pomalidomide. In relatively healthy patients who had remission longer than 18 months after transplant, a second stem cell transplant may be considered. Overall, patients who do not respond to initial therapy (especially regimens containing bortezomib) have poor overall prognosis. These patients are excellent candidates for clinical trials to investigate novel therapies, such as vorinostat, panabinostat, daratumumab, and elotuzumab.

Other treatment considerations

Patients with kidney failure at presentation require urgent treatment to improve chances of restoring kidney function. Both bortezomib and lenalidomide have been reported to be effective in reversing kidney damage. Plasmapheresis, a process which separates myeloma cells from the blood, has not been shown to be beneficial.

When there is evidence or suspicion of spinal cord compression, dexamethasone should be started immediately followed by urgent imaging of the spine. A neurosurgeon and/or radiation oncologist should be consulted to consider surgical decompression of the spine or radiation therapy to the spine.

Patients experiencing bone pain due to involvement of myeloma may be treated with low-dose radiation (10-30 Gy) to the bones to relieve pain, improving quality of life. If myeloma involves the bones in the spine (the vertebrae) and a vertebral compression fracture occurs, vertebroplasty or kyphoplasty is recommended. Both procedures involve injecting bone cement into the vertebral body; kyphoplasty also uses a balloon to restore normal height of the bone.

Bisphosphonates are commonly used in patients with myeloma to strengthen bones, prevent fractures and lower calcium levels. Bisphosphonates (pamidronate, zoledronate) inhibit bone breakdown and promote formation of new bone, thus opposing the effects of multiple myeloma on bones. Common side effects of oral bisphosphonates include nausea and esophageal inflammation and erosion, which can be prevented by remaining upright for 30-60 minutes after taking the medication. Intravenous (IV) bisphosphonates often cause a flu-like syndrome the first time the medication is received. Long-term use of bisphosphonates is associated with a small risk of osteonecrosis of the jaw (death of the jaw bone), atrial fibrillation, unusual fractures, and esophageal cancer. Usually the benefits of bisphosphonates outweigh the risks, but it is important to discuss risks and benefits as they pertain specifically to you. In addition, bone health can be improved using the medication denosumab, which prevents further bone damage from cancer cells.

Patients with a solitary plasmacytoma (a solid tumor made of myeloma cells) are best treated with radiation therapy as initial (and potentially curative) treatment. Sometimes, surgery is needed after radiation therapy.

Important side effects of multiple myeloma & the treatments

Myeloma increases one's risk of developing a blood clot in the legs, known as a deep vein thrombosis (DVT). The risk of developing a DVT is even further increased when taking thalidomide or lenalidomide. Fortunately, DVT only happens in 1-3% of people on thalidomide. However, when used in combination with dexamethasone, this can increase to 10-15%, and if used in combination with dexamethasone and doxorubicin, (another chemotherapeutic drug), this number can increase to 25%. DVT in the leg is concerning because the blood clot in the leg can travel to the lungs, causing a serious condition called pulmonary embolus. A pulmonary embolus can cause cough, chest pain, shortness of breath, and even death. Due to the risk of DVT and pulmonary embolism, all patients taking lenalidomide with dexamethasone or any thalidomide-containing therapy should receive anticoagulation (blood thinners) to prevent formation of a blood clot. Thalidomide and lenalidomide also cause severe life-threatening birth defects. You should not become pregnant or father a child while taking these medications. Bortezomib can increase one's risk of developing herpes zoster (shingles), so a shingles vaccine is recommended prior to bortezomib therapy. Other side effects of chemotherapy agents include low blood counts, fatigue, constipation, diarrhea and neuropathy (nerve damage, usually manifesting as numbness in the fingers and toes).

Allogeneic stem cell transplant

There are two types of transplants: autologous transplants, where the stem cells to be transplanted come from the person with multiple myeloma, and allogeneic transplants, where stem cells are harvested from a donor who has been matched with the person with multiple myeloma. The role of allogeneic transplant in myeloma is controversial and still being studied.

One theoretical advantage of allogeneic over autologous transplant is that even after induction chemotherapy, there are often still malignant cells in the blood. Inevitably, during harvesting of stem cells, some of the remaining malignant cells are accidentally collected. Allogeneic cells come from a donor with no malignant cells; hence the collected stem cells contain no cancer cells.

Allogeneic cells also cause graft versus host phenomenon, which can be good and bad. The grafted stem cells form the new immune system for the person receiving the transplant. Unfortunately, this new immune system may perceive the host tissues (the organs of the patient who received the transplant) as foreign and attack them. Typically, the liver, gastrointestinal tract, and skin are most severely affected. However, the new immune system can be used for good since it recognizes the myeloma cells as foreign and can attack any myeloma cells that are left. Graft versus host disease can cause organ failure, and immunosuppression to control graft versus host disease can increase the risk of infection. Hence, there has to be a careful balance when suppressing the new immune system to protect organs, but also allowing the new immune system to destroy any left over myeloma cells.

Another complication of allogeneic transplants is that the donor tissue must be matched to the recipient. Sometimes family members can be donors, but in the event that is not possible, the national registry of bone marrow donors can be searched for a match. Mortality from allogeneic transplant can be as high as 10-20%. Currently, allogeneic transplant as initial therapy should only be considered in the context of a clinical trial.

There is continued investigation of nonmyeloablative transplants ("mini-transplants"), where low doses of chemotherapy are used after stem cell harvest to kill myeloma cells prior to allogeneic transplant. In nonmyeloablative transplants, the goal is to decrease toxicity, but preserve the beneficial graft-versus-myeloma effect. Like other allogeneic transplants, mini-transplants are only recommended when used in the setting of a clinical trial.

Follow-up testing

Follow up appointments to monitor for recurrence are very important in people with multiple myeloma given the high rate of relapse. Generally, after completion of treatment your doctor may ask you to follow up every one to three months. The follow up visit usually entails a physical exam, x-rays, blood tests and urine tests. X-rays are used to check for bone disease and blood and urine tests are used to check for the level of monoclonal proteins. Blood tests to check kidney function, calcium levels, and cell counts are also done routinely. Repeated bone marrow biopsies may also be needed to check for myeloma cells in the bone marrow.

Clinical trials

Multiple myeloma is an area of active research and numerous clinical trials. Currently, clinical trials are investigating new therapeutic agents, new combinations of existing treatments, and different sequencing or timing of treatments. Many promising agents are in the pipeline, some with completely novel mechanisms of action. Some agents under investigation include vorinostat and panabinostat (histone deacetylase inhibitors), daratumumab (a human anti-CD38 monoclonal antibody), anti-cyclin dependent kinase inihibitors, and elotuzumab (an anti-CS1 monoclonal antibody), aplidin, marizomib, and ixazomib. You can learn more about ongoing clinical trials and find those that may be right for you using the OncoLink Clinical Trials Matching Service or online at clinicaltrials.gov.

References & Further Reading

  • Multiple Myeloma Research Foundation
  • Abeloff M., Armitage J., Niederhuber J., et al. (Eds): Clinical Oncology 4th Edition. (2008). Elsevier Churchill Livingstone, Philadelphia, Pennsylvania.
  • The American Cancer Society: Multiple Myeloma.
  • Anderson KC. Therapeutic advances in relapsed or refractory multiple myeloma. JNCCN 2013; 11: 676-679.
  • Hoffman: Hematology: Basic Principles and Practice, 6th ed. Chapter 85. Plasma Cell Neoplasms (2013).
  • Kyle R., Rajkumar S. (2004) Multiple Myeloma. The New England Journal of Medicine, 351:1860-1873.
  • National Cancer Institute: What you need to know about multiple myeloma and Multiple Myeloma sections.
  • The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Multiple Myeloma Version 1.2014. www.nccn.org.
  • Rajkumar S., Gertz M., Kyle, R. et al. (2002) Current Therapy for Multiple Myeloma. Mayo Clinic Proceedings, 77:813-822.
  • Rajkumar S., Kyle R. (2005) Multiple Myeloma: Diagnosis and Treatment. Mayo Clinic Proceedings, 80:1371.
  • Rajkumar SV (2013). Multiple myeloma: 2013 update on diagnosis, risk-stratification, and management. American Journal of Hematology, 88(3): 226-235.
  • Smith D and Yong K (2013). Multiple myeloma. BMJ, 346: f3863.