Multiple Myeloma

What is Multiple Myeloma

Multiple myeloma is a form of cancer. It develops when abnormal plasma cells grow out of control.

Plasma cells are a type of white blood cell that is made in the soft tissue inside the bones (bone marrow). They are part of the body’s disease-fighting system (immune system).

Multiple myeloma damages bones and causes other health problems because of its effect on blood cells.

Abnormal plasma cells produce monoclonal proteins (M proteins) and interfere with many important functions that normal cells perform in the body. The disease gets worse over time (progresses) and reduces the body’s ability to fight infections.

10 Interesting Facts of Multiple myeloma

  1. Multiple myeloma is a malignancy of plasma cells characterized by bone marrow infiltration and extensive skeletal destruction resulting in anemia, bone pain, and fractures
  2. Patient may come to clinical attention because of abnormal laboratory test results or because of symptoms resulting from renal insufficiency, anemia, hypercalcemia, or bone lesions
  3. Multiple myeloma is defined by presence of 10% or more clonal plasma cells (ie, percentage of all nucleated cells) on bone marrow examination (or extramedullary plasmacytoma) and evidence of 1 or more myeloma-defining events 
  4. Multiple myeloma is preceded by a stage of monoclonal gammopathy of undetermined significance characterized by presence of a lower serum level of M protein but absence of myeloma-defining events, macroglobulinemia, amyloidosis, or other related disorders
  5. Patients with monoclonal gammopathy of undetermined significance or asymptomatic, smoldering myeloma do not require immediate treatment but must receive careful follow-up for signs of disease progression 
  6. Diagnosis requires a combination of laboratory tests, imaging, procedures, and demonstration of selected clinical factors
    • Initial step in diagnosis is identification of M protein in serum and urine
    • Bone marrow biopsy shows clonal marrow plasma cells at 10% or more or biopsy-proven bony or extramedullary plasmacytoma
    • Myeloma-defining events include evidence of end-organ damage such as hypercalcemia, anemia, renal insufficiency, and lytic bone lesions
  7. Treatment options include stem cell transplant, chemotherapy, and radiotherapy
  8. Supportive care elements include vaccinations, other prophylaxis of infections, erythropoiesis-stimulating agents, and thromboprophylaxis
  9. Complications include fractures, osteoporosis, renal failure, and recurrent infections
  10. Multiple myeloma cannot be cured, but treatment with either primary chemotherapy or stem cell transplant can prolong survival

Multiple myeloma is an uncommon cause of back pain that is frequently initially misdiagnosed. It is a unique disease in that it may cause pain via several mechanisms that can act alone or in concert. These mechanisms include invasion or compression of pain-sensitive structures (1) by the tumor itself, (2) by the products that the tumor produces, and (3) by the host response to the tumor and its products.

Although the exact cause of multiple myeloma is unknown, the following facts have been elucidated. There seems to be a genetic predisposition to the development of myeloma. It also is known that exposure to radiation increases the incidence of the disease, as witnessed in survivors of the nuclear bombs used in World War II. RNA viruses also have been implicated in the evolution of multiple myeloma. There also appear to be abnormalities in signaling pathways. The disease is rare in individuals younger than 40 years, with a median age of diagnosis of 60 years. A male gender predilection is seen, and blacks have twice the incidence of multiple myeloma compared with whites. Worldwide, the incidence of multiple myeloma is 3 per 100,000 people.

The most common clinical presentation of multiple myeloma is back and rib pain. It occurs in more than 70% of patients ultimately diagnosed with the disease. These bone lesions are osteolytic and are best diagnosed with plain radiography rather than with radionucleotide bone scanning. Pain with movement is common, and hypercalcemia occurs with sufficient frequency to be the presenting symptom in many patients with multiple myeloma. Life-threatening infection, anemia, bleeding, and renal failure are often present in conjunction with the symptoms of pain. Hyperviscosity of the serum that is the result of the products of tumor production may lead to cerebrovascular accidents.

What are the causes?

The cause of multiple myeloma is not known.

What increases the risk?

You are more likely to develop this condition if you:

  • Are older than age 65.
  • Are male.
  • Are African American.
  • Have a family history of multiple myeloma.
  • Have a history of monoclonal gammopathy of undetermined significance (MGUS).
  • Have a history of radiation exposure.
  • Have been exposed to certain chemicals, such as benzene or pesticides.

What are the symptoms?

Signs and symptoms of multiple myeloma may include:

  • Bone pain, especially in the back, ribs, and hips.
  • Broken bones (fractures).
  • Having a low level of red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia). Platelets are cells that help blood to clot so a wound does not keep bleeding.
  • Fatigue.
  • Weakness.
  • Infections.
  • Unusual bleeding, such as:
    • Bleeding from the nose or gums.
    • Bleeding a lot from a small scrape or cut.
  • High blood calcium levels.
  • Increased urination.
  • Confusion.
  • Shortness of breath.
  • Weakness or numbness in your legs.
  • Sudden, severe back pain.

Pain is the most common clinical symptom that ultimately leads the clinician to the diagnosis of multiple myeloma. Seemingly minor trauma may cause pathological vertebral compression or rib fractures.

Pain on movement of the affected bones is a common finding on physical examination, as is the finding of tumor mass on palpation of the skull and other affected bones. Neurological findings, either based on neural compression secondary to tumor or fracture or as a result of cerebrovascular accident, are often present.

Positive Trousseau and Chvostek signs secondary to hypercalcemia also may be elicited. Anasarca resulting from renal failure, if present, is an ominous prognostic sign.

How is this diagnosed?

This condition is diagnosed based on your symptoms, your medical history, and a physical exam. You will have blood and urine tests to confirm that M proteins are present.

You may also have other tests, including:

  • Additional blood tests.
  • X-rays.
  • MRI.
  • CT scan.
  • PET scan.
  • Tests to check the function of your kidneys.
  • Heart tests, such as an echocardiogram. An echocardiogram uses sound waves to produce an image of the heart.
  • A procedure to remove a sample of bone marrow (bone marrow biopsy). The sample is examined for abnormal plasma cells.

The presence of Bence Jones protein in the urine, anemia, and increased M protein on serum protein electrophoresis point strongly to the diagnosis of multiple myeloma.

Peripheral blood smears will often reveal erythrocyte rouleaux formation. Classic punched-out bone lesions in the skull and spine on plain radiographs are pathognomonic for the disease. Because little osteoclastic activity is present in patients with multiple myeloma, radionucleotide bone scanning can be negative in the face of diffuse bony destruction.

Magnetic resonance imaging (MRI) is indicated in any patient thought to have multiple myeloma who exhibits signs of spinal cord compression. Serum creatine testing and automated blood chemistries that include serum calcium determinations are indicated in all patients with multiple myeloma.

Differential Diagnosis

A variety of other abnormalities of the bone marrow, including the heavy chain diseases and Waldenström macroglobulinemia, can mimic the clinical presentation of multiple myeloma. Amyloidosis also shares many common clinical signs and symptoms.

Metastatic disease from prostate and breast cancer can produce pathological fractures of the spine and ribs and calvarial metastases that may be mistaken for multiple myeloma. A small group of patients have benign monoclonal gammopathy, which in most patients requires no therapy but can mimic the laboratory findings of multiple myeloma.

How is this treated?

There is no cure for multiple myeloma. However, treatments can manage symptoms and slow the progression of the disease. Treatment options may vary depending on how much the disease has advanced. Possible treatment options may include:

  • Medicines that kill cancer cells (chemotherapy).
  • Radiation therapy. This is the use of high-energy rays to kill cancer cells.
  • A bone marrow transplant. This procedure replaces diseased bone marrow with healthy bone marrow (stem cell transplant).
  • Medicines that block the growth and spread of cancer cells (targeted drug therapy).
  • Medicines that strengthen your immune system’s ability to fight cancer cells (immunotherapy or biologic therapy).
  • Participating in clinical trials to find out if new (experimental) treatments are effective.
  • Medicines that help to prevent bone damage (bisphosphonates).
  • Medicines that reduce swelling (corticosteroids).
  • Surgery to repair bone damage.
  • A procedure to remove plasma cells from your blood (plasmapheresis).
  • Other medicines to treat problems such as infections or pain.

Management of multiple myeloma is aimed at the treatment of progressive bone lesions and reduction in serum myeloma proteins. These goals are accomplished with radiation therapy and chemotherapy, alone or in combination.

High-dose pulsed steroids have been shown to provide symptomatic relief and to extend life expectancy in patients with multiple myeloma.

Initial treatment of the pain associated with multiple myeloma should include either nonsteroidal antiinflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors. It may be necessary to add opioid analgesics to control the more severe pain of pathological fractures.

Orthotic devices such as the Cash brace and rib belts may help stabilize the spine and ribs and should be considered in the presence of pathological fractures. Local application of heat and cold may be beneficial.

The repetitive movements that incite the syndrome should be avoided. For patients who do not respond to these treatment modalities, injection of the affected areas with a local anesthetic and steroid using either intercostal or epidural nerve blocks is a reasonable next step.

Spinal administration of opioids may be beneficial in selected cases. Ultimately, radiation therapy is often required to provide adequate pain control if significant bony involvement occurs. Stem cell transplant and gene therapy are emerging as exciting new options in the treatment of this disease.

Follow these instructions at home:

Eating and drinking

  • Drink enough fluid to keep your urine pale yellow.
  • Try to eat healthy meals on a regular basis. Some of your treatments might affect your appetite. If you are having problems eating or if you do not have an appetite, meet with a diet and nutrition specialist (dietitian).
  • Take vitamins or supplements only as told by your health care provider or dietitian. Some vitamins and supplements may interfere with how well your treatment works.

General instructions

  • Take over-the-counter and prescription medicines only as told by your health care provider.
  • Stay active. Talk with your health care provider about what types of exercises and activities are safe for you.
    • Avoid activities that cause increased pain.
    • Do not lift anything that is heavier than 10 lb (4.5 kg), or the limit that you are told, until your health care provider says that it is safe.
  • Consider joining a support group or getting counseling to help you cope with the stress of having multiple myeloma.
  • Keep all follow-up visits as told by your health care provider. This is important.

Seek Additional Information

Contact a health care provider if you:

  • Have pain that gets worse or does not get better with medicine.
  • Have a fever.
  • Have swollen legs.
  • Have weakness or dizziness.
  • Have unexplained weight loss.
  • Have unexplained bleeding or bruising.
  • Have a cough or symptoms of the common cold.
  • Feel depressed.
  • Have changes in urination or bowel movements.

Get help right away if you:

  • Have sudden severe pain, especially back pain.
  • Have numbness or weakness in your arms, hands, legs, or feet.
  • Become very confused.
  • Have weakness on one side of your body.
  • Have slurred speech.
  • Have trouble staying awake.
  • Have shortness of breath.
  • Have blood in your stool (feces) or urine.
  • Vomit blood or cough up blood.

Pitfalls

  • Bone marrow biopsy is usually diagnostic for multiple myeloma
    • However, in 4% of patients, bone marrow examination shows fewer than 10% plasma cells, even though the patient otherwise meets the criteria for myeloma 
    • Repeated bone marrow examinations or biopsy of a discrete bone or extramedullary lesion may be required because bone marrow involvement in myeloma may be focal rather than diffuse
  • Deep vein thrombosis can occur during therapy with immunomodulators (such as lenalidomide); in all patients taking immunomodulators, provide prophylactic aspirin or an anticoagulant 
  • Renal failure caused by light chain cast nephropathy is regarded as a myeloma-defining event, but other renal disease is not. Evaluation of other causes of acute kidney injury and chronic kidney disease is required (Related: Acute kidney injury)

Multiple myeloma is a malignancy of plasma cells characterized by bone marrow infiltration and extensive skeletal destruction resulting in anemia, bone pain, and fractures 

Malignant plasma cells secrete M proteins (ie, monoclonal proteins—intact or incomplete immunoglobulin molecules that are electrophoretically and immunologically homogeneous) 

In most clonal plasma cell disorders, intact immunoglobulin molecules are secreted as M proteins 

In some patients, heavy chain expression is completely lost and only monoclonal free light chains (often called Bence Jones proteins) are secreted 

Multiple myeloma is also commonly called myeloma

Classification

  • Diagnostic criteria for selected plasma cell neoplasms 
    • Solitary plasmacytoma 
      • Solitary lesion of bone or soft tissue involving clonal plasma cells
      • Clonal bone marrow plasma cells less than 10%
      • Absence of end-organ damage
      • Normal skeletal survey and MRI or CT (apart from solitary lesion)
    • Smoldering myeloma (asymptomatic) 
      • Serum monoclonal protein (IgG or IgA) level of 30 g/L or more or urinary monoclonal protein measurement of 500 mg or more per 24 hours and/or clonal bone marrow plasma cells 10% to 59%
      • Absence of myeloma-defining events or amyloidosis
    • Multiple myeloma (active, symptomatic)
      • Clonal bone marrow plasma cells (ie, percentage of all nucleated cells) more than 10% (or extramedullary plasmacytoma) 
      • Evidence of 1 or more of the following myeloma-defining events:
        • Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
          • Hypercalcemia: serum calcium level more than 1 mg/dL higher than upper reference limit or more than 11 mg/dL
          • Renal insufficiency: creatinine clearance less than 40 mL/minute or serum creatinine level more than 2 mg/dL
          • Anemia: hemoglobin level more than 2 g/dL below lower reference limit or less than 10 g/dL
          • Bone lesions: 1 or more osteolytic lesions on skeletal radiography, CT, or PET-CT
        • Clonal bone marrow plasma cells more than 60%
        • Involved to uninvolved serum free light chain ratio of 100 or more
        • MRI identification of more than 1 focal bone lesion measuring 5 mm or more
  • Staging for multiple myeloma
    • Revised International Staging System 
      • Stage I
        • Serum albumin level more than 3.5 g/dL, serum β₂-microglobulin level less than 3.5 mg/L, no high-risk cytogenetics, and normal serum lactate dehydrogenase level
      • Stage II
        • Neither stage I nor stage III
      • Stage III
        • Serum β₂-microglobulin level more than 5.5 mg/L and either high-risk cytogenetics [t(4;14), t(14;16), or del(17p)] or elevated serum lactate dehydrogenase level

Clinical Presentation

History

  • Patient may come to clinical attention because of abnormal laboratory test results or because of symptoms resulting from renal insufficiency, anemia, hypercalcemia, or bone lesions
  • General 
    • Weakness and fatigue (associated with anemia)
    • Weight loss
  • Skeletal 
    • Bone pain, particularly in the back or chest and less often in the extremities
      • Present at time of diagnosis in more than two-thirds of patients 
  • Neurologic
    • Paresthesias (associated with radiculopathy)
    • Weakness of legs or bowel/bladder incontinence or retention (can signify spinal cord compression)
  • Symptoms related to hypercalcemia
    • Mental status changes (eg, obtundation, delirium)
    • Polyuria
  • Infection
    • Fever
    • Cough (pneumococcal pneumonia is a common complication)

Physical examination

  • Pallor (most frequent physical finding) 
  • Palpable liver edge in about 5% of patients 
  • Palpable spleen in 1% of patients 
  • Tenderness may be noted at sites of bone involvement 
  • Extramedullary plasmacytomas are palpable on rare occasions 
  • Patient’s height may be reduced by several centimeters because of vertebral collapse 

Causes

  • Cause of multiple myeloma is unknown 
    • Exposure to radiation, benzene, other organic solvents, herbicides, or insecticides may play a role 
  • Almost all cases of multiple myeloma evolve from a premalignant monoclonal gammopathy phase, but the precise mechanisms of progression are unknown
    • 2 main molecular events associated with progression of monoclonal gammopathy of undetermined significance to multiple myeloma appear to be mutations in the RAS family (rat sarcoma family) and abnormalities in MYC (v-myc avian myelocytomatosis viral oncogene homologue) 
    • Annual risk of progression of monoclonal gammopathy of undetermined significance to a lymphoid or plasma cell malignancy ranges from 0.5% to 1% in population-based cohorts, but risk ranges from 2% to 20% in higher-risk patients 
  • Changes in the bone marrow microenvironment likely play a major role in pathogenesis, including induction of angiogenesis and abnormal paracrine loops involving cytokines such as interleukin-6, which serves as a major growth factor for plasma cells 
  • Cytogenetic abnormalities are common
    • Primary translocations involving the IgH loci (14q32) are seen in up to 40% of patients with multiple myeloma [eg, t(4;14), t(14;16)] 
    • 40% of patients do not have IgH translocations but have evidence of trisomies (hyperdiploid myeloma), 15% have both IgH translocations and trisomies, and 5% have other abnormalities 
    • Secondary cytogenetic abnormalities occur as late events during the course of symptomatic myeloma; these include deletion of 17p13, deletion of 1p, and amplification of 1q21 

Risk factors and/or associations

Age
  • Risk increases with age
    • Most frequently diagnosed among people aged 65 to 74 years 
    • Third most common blood cancer in adults
  • Median age at diagnosis is about 69 years 
  • Only 2% of patients are younger than 40 years 
Sex
  • Slightly more common in men than in women 
Genetics
  • Multiple myeloma has been reported in familial clusters of 2 or more first-degree relatives and in identical twins 
Ethnicity/race
  • Incidence of multiple myeloma in black people is approximately twice that in white people 
Other risk factors/associations
  • Environmental exposures
    • Exposure to radiation, benzene, other organic solvents, herbicides, or insecticides is associated with increased risk
  • Diagnosis requires a combination of laboratory tests, imaging, procedures, and demonstration of selected clinical factors
  • First step involves identification of M protein (monoclonal protein) in serum and urine
    • Obtain serum studies: 
      • Serum protein electrophoresis
      • Serum immunofixation electrophoresis
      • Quantitative immunoglobulin tests
    • Obtain 24-hour urine collection: 
      • 24-hour urine total protein measurement
      • Use aliquot for urine protein electrophoresis
      • Use aliquot for urine immunofixation electrophoresis
  • Further evaluation of patients found to have M protein in serum and/or urine
    • Obtain quantitative serum free light chain assay
      • Free light chain assay is also required if M protein is not apparent but diagnosis is still suspected 
    • Obtain serum M protein level from serum electrophoresis
    • Measure the amount of M protein excreted in urine over 24 hours
  • Obtain radiologic imaging in all patients with suspected multiple myeloma
    • For initial work-up, full radiographic survey, whole body low-dose CT scan, or whole body fludeoxyglucose F 18 PET with CT is recommended to evaluate for lytic bone lesions 
      • Whole body low-dose CT scan and whole body fludeoxyglucose F 18 PET with CT are favored by many experts because they have a superior detection rate for lytic bone lesions compared with conventional radiography/skeletal survey 
    • Skeletal survey is less sensitive, but it may be used initially owing to its availability and low cost 
      • Obtain radiographs of skull, ribs, vertebrae, pelvis, shoulder girdle, and long bones
      • If skeletal survey result is negative, perform whole body or skeletal MRI or whole body fludeoxyglucose F 18 PET with CT 
    • Whole body MRI scan may be useful if low-dose CT or PET-CT scans are negative 
  • Bone marrow biopsy is necessary to make a formal diagnosis
    • Determine the percentage of marrow plasma cells in bone marrow specimen
      • Be aware that marrow plasma cell distribution may vary in different sites
    • Bone marrow studies at initial diagnosis should include chromosome analysis by metaphase cytogenetics and fluorescence in situ hybridization testing using plasma cells obtained from bone marrow aspirate (for genetic markers of high-risk disease)
  • Obtain the following basic laboratory studies:
    • CBC (hemoglobin, leukocyte, platelet, and differential counts) and examination of peripheral smear (in all patients)
    • Comprehensive serum chemistry panel, including measurement of serum levels of calcium, creatinine, alkaline phosphatase, lactic dehydrogenase, and uric acid (in all patients)
    • Measure serum albumin and β₂-microglobulin levels as independent prognostic factors
    • Obtain serum viscosity when M protein levels are high
    • HLA typing 
  • Obtain biopsy for suspicion of solitary osseous or extraosseous plasmacytoma 
    • If clinically warranted, take needle aspirates of a solitary lytic bone lesion, extramedullary tumor, or enlarged lymph node to determine whether these are plasmacytomas
    • If amyloidosis is suspected, perform needle aspiration of subcutaneous abdominal fat and stain both the fat and the bone marrow specimen for amyloid as the easiest and safest way to confirm the diagnosis
  • Criteria for diagnosis of active myeloma 
    • Clonal marrow plasma cells at 10% or more or biopsy-proven bony or extramedullary plasmacytoma plus the following:
    • Any 1 or more of the following myeloma-defining events:
      • Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
        • Hypercalcemia: serum calcium level more than 1 mg/dL higher than upper reference limit or more than 11 mg/dL
        • Renal insufficiency: creatinine clearance less than 40 mL/minute or serum creatinine level more than 2 mg/dL
        • Anemia: hemoglobin level more than 2 g/dL below lower reference limit or less than 10 g/dL
        • Bone lesions: 1 or more osteolytic lesions on skeletal radiography, CT, or PET-CT
      • Clonal marrow plasma cell percentage of 60% or more
      • Involved to uninvolved serum free light chain ratio of 100 or more (provided that the involved free light chain level is 100 mg/L or more)
      • 1 or more focal marrow lesions on MRI (at least 5 mm in diameter)
  • Criteria for diagnosis of smoldering myeloma (both must be met): 
    • Serum monoclonal protein (IgG or IgA) level of 30 g/L or more or urinary monoclonal protein measurement of 500 mg or more per 24 hours and/or clonal bone marrow plasma cells 10% to 59%
    • Absence of myeloma-defining events or amyloidosis

Laboratory

  • Serum protein electrophoresis 
    • Identifies and quantifies M protein (test is sensitive in 80% of patients with multiple myeloma) 
    • Monoclonal proteins must be distinguished from an excess of polyclonal immunoglobulins (1 or more heavy chain types and both κ and λ light chains, usually limited to the γ region) 
      • M protein appears as a narrow peak/spike on the densitometer tracing or as a dense, discrete band on agarose gel
      • Polyclonal immunoglobulins produce a broad-based peak or broad band, and this finding is associated with chronic infectious or inflammatory states 
    • Does not detect monoclonal free light chains (Bence Jones proteins)
  • Serum immunofixation electrophoresis
    • Performed when a peak or band is seen on protein electrophoresis to determine clonality and to identify the type of heavy and light chains in the M protein 
      • Immunofixation alone cannot quantify M protein
    • Immunofixation electrophoresis is more sensitive than protein electrophoresis and should be done in conjunction with it when multiple myeloma is first suspected to detect small, unmeasurable M proteins that may be missed on protein electrophoresis 
    • With serum immunofixation, an M protein can be detected in 93% of patients with myeloma 
    • When the serum studies are combined with urine protein electrophoresis plus immunofixation, an M protein can be detected in 97% of patients with myeloma 
  • Urine protein collection for urine protein electrophoresis and urine immunofixation electrophoresis 
    • Similar to its appearance on serum protein electrophoresis, M protein on urine protein electrophoresis appears as a narrow peak/spike on the densitometer tracing or as a dense, discrete band on agarose gel
    • Urine tests detect monoclonal free light chains easily
    • Collect 24-hour urine specimen to measure total protein
      • From an aliquot of the 24-hour urine specimen, run urine protein electrophoresis and urine immunofixation electrophoresis
      • Measure the amount of M protein excreted in urine over 24 hours via the following steps:
        • Measure the total amount of protein excreted over 24 hours
        • Multiply 24-hour urine total protein measurement by percentage of urine protein that is M protein, as determined by electrophoresis of concentrated urine protein
    • Urine immunofixation electrophoresis must be performed in conjunction with urine protein electrophoresis in order to differentiate a monoclonal from a polyclonal increase in immunoglobulins and to determine the type of light chain involved
  • Quantitative immunoglobulin test
    • Increase in abnormal immunoglobulins (typically IgG and IgA) contributes to hypergammaglobulinemia
    • Decreased level of normal immunoglobulins often occurs in multiple myeloma
    • By itself, a quantitative immunoglobulin test cannot determine monoclonality; corresponding serum protein electrophoresis and serum immunofixation electrophoresis are required to show clonality
  • Quantitative serum free light chain assay
    • A small percentage of patients with myeloma have no M protein in serum or urine and have normal serum and urine immunofixation values
    • Serum free light chain assay measures monoclonal free light chains (κ and λ light chains unbound to heavy chains)
    • Normal free light chain κ to λ ratio is 0.26 to 1.65; ratios that fall outside this range are considered abnormal 
      • Ratio of 100 or more is a diagnostic criterion for multiple myeloma 
  • CBC
    • Normocytic, normochromic anemia is present initially in approximately 75% of patients, but it eventually occurs in nearly every patient with multiple myeloma 
    • Peripheral blood smear may show abnormal conglomeration of RBCs, such as rouleau formation
  • Serum chemistry panel
    • Creatinine level is more than 2 mg/dL in 20% of patients at time of diagnosis 
    • Serum calcium level is elevated in 15% to 20% of patients at time of diagnosis 
    • Serum levels of uric acid, lactate dehydrogenase, and β₂-microglobulin
      • Elevated levels reflect high tumor cell burden and increased cell turnover
    • Elevated serum total protein measurement is a clue to an underlying monoclonal gammopathy
  • Serum viscosity
    • Hyperviscosity can occur in patients with multiple myeloma when there are very high levels of monoclonal IgA or IgG
    • Hyperviscosity more commonly occurs in Waldenström macroglobulinemia (elevated IgM level) 
  • HLA typing

Imaging

  • Whole body low-dose CT scan
    • Low-dose CT scan, if available, is an ideal initial imaging modality for diagnosis owing to greater sensitivity in detecting most lytic bony lesions 
    • Whole body low-dose CT is particularly sensitive for detecting lesions located in spine, pelvis, or thoracic cage 
    • Low-dose CT scan can provide a comprehensive assessment of fracture risk and of the stability of any collapsed vertebrae 
  • Fludeoxyglucose F 18 PET with CT
    • Alternative initial imaging modality to detect bone abnormalities in multiple myeloma
      • PET-CT is more sensitive than plain radiographs and is indicated in initial staging if skeletal survey result is negative, or when symptomatic areas show no abnormality on routine radiographs 
    • Active myeloma is positive on fludeoxyglucose F 18 PET with CT; it has very high sensitivity and specificity for multiple myeloma and is especially effective at demonstrating extramedullary disease 
    • Fludeoxyglucose F 18 PET with CT can also be used to monitor for treatment response because the fludeoxyglucose F 18 uptake of osseous lesions decreases with successful treatment 
    • False-positive results in fludeoxyglucose F 18 PET can occur; they may result from metabolically active areas of inflammation or infection, brown fat, or other malignancies 
  • Skeletal survey: plain radiographs
    • Plain radiographs are not sensitive, and whole body low-dose CT or PET-CT is typically preferred 
    • Radiographic findings of multiple myeloma include focal or diffuse osteolysis 
      • Vertebrae, calvaria, thoracic cage, pelvis, and proximal portions of humeri and femora are the most frequent sites of involvement
    • Conventional radiography finds abnormalities (eg, punched-out lytic lesions, osteoporosis, fractures) in about 80% of patients 
    • Osteolytic lesions involving long bones tend to show signs of cortical erosion from the medullary side; this is known as endosteal cortical scalloping 
  • Bone scans are not indicated in evaluation of multiple myeloma because of the absence of osteoblastic activity; technetium 99m bone scan results are typically negative even in the presence of significant bone involvement

Procedures

Bone marrow biopsy (aspiration and core types)
General explanation
  • A cutting needle collects bone marrow from iliac crest or sternum for hematologic and cytogenetic analyses 
  • Aspiration and core biopsy are usually performed at same time 
    • Aspiration provides sample of marrow cells
    • Core biopsy provides marrow cells and cellular framework of marrow
    • Usually performed under conscious (moderate) sedation and/or local anesthesia
  • Analysis of specimen should include bone marrow immunohistochemistry and/or bone marrow flow cytometry
  • Analysis should also include metaphase cytogenetics on bone marrow
  • Staining of both bone marrow and subcutaneous abdominal fat specimens for amyloid is used in differentiating myeloma from amyloidosis 
Indication
  • Suspected multiple myeloma, for confirmation of diagnosis and characterization of cell type and cytogenetics
Contraindications
  • Uncorrected hemorrhagic disorder
  • Skin infection or recent radiation at or near puncture site
  • Anticoagulant therapy
Complications
  • Bleeding
  • Infection
  • Localized pain at biopsy site
Interpretation of results
  • Clonal plasma cells account for more than 10% of all nucleated cells in 96% of patients 
  • In 4% of patients, bone marrow examination shows less than 10% plasma cells, even though the patient otherwise meets the criteria for myeloma 
  • Be aware that marrow plasma cell distribution may vary at different sites
  • Repeated bone marrow examinations or biopsy of a discrete bone or extramedullary lesion may be required because bone marrow involvement in myeloma may be focal rather than diffuse
  • Flow cytometry results
    • Plasma cells in myeloma are cytoplasmic Ig⁺, CD38⁺, CD45⁻, CD138⁺, and CD56⁺
    • Clonality of the plasma cells is established using the κ/λ ratio by immunohistochemistry or flow cytometry
    • The κ/λ ratio is abnormal in myeloma (either more than 4:1, indicating a clonal κ population, or less than 1:2, indicating a clonal λ population) 

Other diagnostic tools

  • Risk stratification (based on cytogenetic abnormalities) 
    • High risk of multiple myeloma: patients with del(17p), t(14;16), and t(14;20)
    • Intermediate risk of multiple myeloma: patients with t(4;14) translocation and 1q+ gain
    • Standard risk of multiple myeloma: all others [eg, trisomies, t(11;14), t(6;14)]

Differential Diagnosis

Most common

Treatment Goals

  • Delay progression of disease 
  • Prolong disease-free survival 

Admission criteria

  • Admission may be required for complications, including severe hypercalcemia, symptomatic hyperviscosity, infections (particularly febrile neutropenia), or neurologic emergencies (eg, spinal cord compression)
  • Admission is usually required for hematopoietic stem cell transplant
  • Most other chemotherapy and/or radiotherapy can be done in an outpatient setting

Recommendations for specialist referral

  • Consult medical oncologist for diagnostic work-up, including bone marrow biopsy, and for coordinating all aspects of treatment
  • Consult radiation oncologist for design and implementation of radiotherapy
  • Consult orthopedic surgeon for impending or actual long-bone fractures or for evaluation of procedures to treat vertebral compression fractures
  • Consult neurosurgeon and orthopedic surgeon for spinal cord compression or for vertebral column instability
  • Consult nephrologist for renal biopsy or as needed to evaluate and manage renal insufficiency
  • Consult infectious disease specialist for guidance on prophylaxis and treatment of infections

Treatment Options

General overview

  • Treatment is complex and directed by medical oncologist, along with specialists to manage various aspects of the disease and its complications
  • Treatment options include stem cell transplant, chemotherapy, and radiotherapy
    • Early decision regarding stem cell transplant is necessary to avoid using a medication regimen that contains stem cell toxins, which could compromise stem cell reserve
  • Treatment is selected depending on whether patient is younger, fit, and transplant-eligible or older, with comorbidities, and not transplant eligible 
    • Patients younger than 65 years are usually transplant eligible, whereas patients older than 75 years are usually not transplant eligible
    • Consider comorbidities and performance status in all age groups, but especially between the ages of 65 and 75 years, to help decide about transplant eligibility
  • Important to identify high-risk cytogenetic abnormalities that are associated with aggressive disease and poorer outcomes and have implications for choice of therapy 
  • Stem cell transplant–eligible patients
    • Autologous stem cell transplant after high-dose chemotherapy 
      • Autologous transplant is not curative, but it prolongs event-free and overall survival 
      • Criteria for autologous stem cell transplant include good performance status, no or few comorbid conditions, and younger age (usually younger than 65 years; 65-75 years only if excellent organ function and performance status) 
      • Initial therapy typically consists of combination chemotherapy (bortezomib-based) for approximately 3 to 4 months followed by stem cell collection
        • VRd regimen (bortezomib-lenalidomide-dexamethasone) is considered the preferred option for primary treatment of transplant-eligible patients with multiple myeloma, based on significant improvements in progression-free and overall survival 
        • Second most preferred regimen is VCd (bortezomib-cyclophosphamide-dexamethasone), which is particularly suitable for patients with acute renal insufficiency 
        • Numerous other alternative induction regimens exist (several available options)
      • Maintenance therapy after autologous stem cell transplant with an immunomodulatory drug (usually with lenalidomide) is recommended 
        • Deep vein thrombosis can occur during therapy with immunomodulators (such as lenalidomide); in all patients taking immunomodulators, provide prophylactic aspirin or an anticoagulant 
      • Cryopreservation of stem cells is also an option for patients with newly diagnosed disease, for future use after initial therapy
    • Allogeneic bone marrow transplant
      • Most patients with multiple myeloma cannot undergo allogeneic bone marrow transplant because of their age, lack of an HLA-matched sibling donor, or inadequate renal, pulmonary, or cardiac function 
      • Allogeneic bone marrow transplant can be performed after prior myeloablative therapy or after nonmyeloablative therapy (with the latter often referred to as a mini-transplant)
      • Allogeneic bone marrow transplant is controversial and is mostly considered investigational 
        • Allogeneic transplant for myeloma is usually reserved for participants in clinical trials or for second line salvage therapy in selected high-risk patients who are willing to accept the high treatment-related mortality risk associated with the procedure 
        • It has been used after failed autologous transplant, and as the second phase of tandem procedures, but it is not considered routine practice
  • Non–transplant candidate patients
    • For patients who are not candidates for stem cell transplant, treatment consists of combination chemotherapy with 1 of 4 preferred regimens 
      • Initial therapy preferably consists of VRd regimen (bortezomib-lenalidomide-dexamethasone) for approximately 9 to 12 months followed by Rd regimen (lenalidomide-dexamethasone) 
      • In frail/elderly patients, lenalidomide plus low-dose dexamethasone alone may be given until disease progresses 
      • Another preferred regimen especially useful for patients with acute renal insufficiency is VCd (bortezomib-cyclophosphamide-dexamethasone) 
      • Daratumumab-lenalidomide-dexamethasone is another recommended regimen 
    • Maintenance therapy should continue with lenalidomide, or alternatively with bortezomib 
  • Progressive or relapsed multiple myeloma
    • Therapy for progressive or relapsed multiple myeloma is considered in the following situations: 
      • Relapse after autologous or allogeneic stem cell transplant
      • Progressive or relapsing disease after initial primary therapy
    • Choice of a treatment regimen at relapse is complicated and is affected by many factors including the type of prior regimen, number of prior lines of therapy, and aggressiveness of the relapse 
    • Options include systemic therapy, stem cell transplant, and clinical trial 
      • If relapse occurs more than 6 months after completion of initial primary systemic therapy, consider retreatment with the same primary regimen
      • The following regimens are preferred for relapsed multiple myeloma, according to the National Comprehensive Cancer Network:
        • VRd (bortezomib-lenalidomide-dexamethasone) 
        • Kd (carfilzomib-dexamethasone) 
        • DVd (daratumumab-bortezomib-dexamethasone) 
        • DRd (daratumumab-lenalidomide-dexamethasone) 
        • ERd (elotuzumab-lenalidomide-dexamethasone) 
        • IRd (ixazomib-lenalidomide-dexamethasone) 
      • Consider autologous stem cell transplant at first relapse for patients who have cryopreserved stem cells early in the disease course
      • For relapse after autologous stem cell transplant, consider second transplant, on or off clinical trial
  • Other supportive care for multiple myeloma
    • Treatment of bone disease 
      • Guidelines recommend treating all patients with active symptomatic multiple myeloma who are receiving primary myeloma therapy with bisphosphonates (zoledronic acid or pamidronate) or denosumab 
        • Denosumab is preferred in patients with renal insufficiency 
        • Zoledronic acid reduces the incidence of bone pain and pathologic fractures, and it may improve overall survival 
        • Denosumab is as effective as zoledronic acid for preventing skeletal-related events (spinal cord compression, pathologic fracture, or surgery or radiotherapy to affected bone); survival data are not available
        • Treatment with bone modifying agent should be continued to up to 2 years 
        • Treatment with bone modifying agents is not recommended for patients with solitary plasmacytoma or smoldering (asymptomatic, indolent) myeloma 
      • Consider vertebroplasty or kyphoplasty for symptomatic vertebral compression fractures 
      • Palliative radiotherapy is an option for patients with active myeloma and uncontrolled pain, impending pathologic fracture, or impending spinal cord compression
    • Anemia
      • Consider erythropoiesis-stimulating therapy to treat cancer- and chemotherapy-induced anemia 

Rationale

  • Multiple myeloma is incurable, but durable responses to treatment are feasible
    • Relapses are to be anticipated, necessitating retreatment, sometimes repeatedly
    • Treatment strategy involves maximizing response while minimizing adverse effects and preserving future treatment options
  • Supportive care is an important element in early management
    • Many patients already have complications of the disease
    • Many patients are at risk for disease-related complications that can limit treatment options but that can be avoided with preemptive measures
  • Patients with monoclonal gammopathy of undetermined significance or asymptomatic, smoldering myeloma do not require immediate treatment but must receive careful follow-up for signs of disease progression 

Outcomes

  • Stem cell transplant
    • Autologous stem cell transplant is associated with higher complete response rates, increased progression-free survival, and possibly increased overall survival, compared with conventional chemotherapy 
    • There are no clear data showing the benefit of either conventional myeloablative allogeneic transplant or nonmyeloablative allogeneic transplant compared with autologous stem cell transplant; results of randomized trials are conflicting 
  • Chemotherapy
    • In patients who can tolerate it, the 3-drug VRd regimen (bortezomib-lenalidomide-dexamethasone) achieves superior progression-free and overall survival, compared with the 2-drug Rd regimen (lenalidomide-dexamethasone) 
    • Dual-therapy Rd regimen (lenalidomide-dexamethasone) has been shown to improve progression-free and overall survival compared with older melphalan-based therapy in elderly patients 

Drug therapy

  • Immunomodulators
    • Thalidomide
    • Lenalidomide
    • Pomalidomide
  • Proteasome inhibitors
    • Bortezomib
    • Carfilzomib
    • Ixazomib
  • Monoclonal antibodies
    • Daratumumab
    • Elotuzumab
  • DNA alkylating agents
    • Cyclophosphamide
  • Chemotherapy combination regimens (preferred options only) 
    • VRd (bortezomib-lenalidomide-dexamethasone)
    • Rd (lenalidomide-dexamethasone)
    • VCd (bortezomib-cyclophosphamide-dexamethasone)
    • Kd (carfilzomib-dexamethasone)
    • DRd (daratumumab-lenalidomide-dexamethasone)
    • ERd (elotuzumab-lenalidomide-dexamethasone)
    • IRd (ixazomib-lenalidomide-dexamethasone)
    • DVd (daratumumab-bortezomib-dexamethasone)
  • Bone-modifying agents
    • Bisphosphonates
      • Zoledronic acid
      • Pamidronate
    • Denosumab
      • Preferred for patients with renal insufficiency
  • Erythropoiesis-stimulating agents 
    • Epoetin alfa
    • Darbepoetin
  • Anticoagulants 
    • Enoxaparin (preferred for most patients)
    • Aspirin (for patients with myeloma who have no risk factors or only 1 individual risk factor)
    • Dalteparin (preferred in setting of renal insufficiency when creatinine clearance is less than 30 mL/minute)
    • Fondaparinux
Drug classDrugToxicitiesKey commentsOther comments
Immunomodulators
ThalidomideNeurotoxicity, fatigue, constipationUseful agent for renal insufficiency or cytopeniasRequires thromboprophylaxis
LenalidomideCytopenias, fatigue, diarrheaMore potent than thalidomide and generally has a better safety profileRequires thromboprophylaxis
PomalidomideCytopeniasInduces responses even in patients whose disease is lenalidomide resistant or refractoryRequires thromboprophylaxis
Proteasome inhibitors
BortezomibNeuropathyCritical component for any high-risk myelomaRequires herpes prophylaxis
CarfilzomibFatigue, cytopenias,
nausea, hypertension
Useful agent in patients with preexisting neuropathyRare reports of thrombotic
microangiopathy
IxazomibGastrointestinal toxicity, rashUseful agent for relapse
Monoclonal antibodies
DaratumumabInfusion reactions are commonUseful agent for relapseCan interfere with crossmatching
techniques; must
type and screen before initiation
ElotuzumabWell toleratedUseful agent for frail patients
DNA-alkylating agents
CyclophosphamideNausea, vomiting,
cytopenias
Used in combination with multiple agentsProlonged use is associated with myelodysplastic syndrome and leukemia
MelphalanNausea, vomiting,
cytopenias
Reserved for patients who are not candidates for stem cell transplantProlonged use is associated with myelodysplastic syndrome and leukemia

Citation: Data from Dingli D et al: Therapy for relapsed multiple myeloma: guidelines from the Mayo Stratification for Myeloma and Risk-Adapted Therapy. Mayo Clin Proc. 92:578-98, 2017.

Nondrug and supportive care

Vaccinations

  • Pneumococcal immunizations should be given to all patients 
    • Administer pneumococcal conjugate vaccine first, followed by pneumococcal polysaccharide vaccine 1 year later
  • Inactivated influenza immunization should be considered for all patients annually

Herpes zoster prophylaxis

  • Prescribe acyclovir (or famciclovir or valacyclovir) for patients treated with proteasome inhibitors, daratumumab, or elotuzumab 

Pneumocystis pneumonia, herpes zoster, and antifungal prophylaxis for patients treated with high-dose dexamethasone 

Consider short-term antibiotic prophylaxis for patients at high risk of infection at time of diagnosis 

Immunoglobulin therapy 

  • Consider IV immunoglobulin therapy in the setting of recurrent life-threatening infection

Monitor for and manage renal dysfunction 

  • Monitor fluid status and maintain hydration
  • Treat abnormalities such as hypercalcemia and hyperuricemia
  • Dialysis may be required
  • Discontinue nephrotoxic medications and use renal dosing for prescribed medications

Consider erythropoiesis-stimulating therapy for patients with anemia 

Thromboprophylaxis 

  • Prescribe full-dose aspirin for patients treated with immunomodulator-based therapies
    • Immunomodulatory therapy with thalidomide or lenalidomide greatly increases risk of venous thromboembolism, particularly in combination with high-dose dexamethasone or doxorubicin 
  • Prescribe therapeutic anticoagulation for those at high risk for thrombosis
    • Risk factors are many, including poor performance status, older age, familial predisposition to hypercoagulability, use of erythropoiesis-stimulating agents, BMI more than 35 kg/m², active smoking, prior venous thromboembolism, and several medical comorbidities (eg, acute infection, chronic kidney disease, pulmonary disease, diabetes, congestive heart failure) 
    • Anticoagulation doses should be adjusted for presence of class III obesity (BMI of 40 kg/m² or more) or thrombocytopenia (platelet count less than 50,000 cells/µL) 
Procedures
Autologous stem cell transplant 

General explanation

  • Process begins with induction therapy, followed by collection of peripheral blood stem cells adequate for 1 to 2 stem cell transplants
  • Peripheral blood stem cells are collected with the use of granulocyte colony-stimulating factor (eg, filgrastim, lenograstim, or biosimilars) with or without plerixafor (a chemokine receptor type 4 inhibitor) or cyclophosphamide to aid in mobilization 
  • Conditioning regimen using melphalan follows stem cell collection 
  • After stem cell collection, patients can either proceed with transplant upfront (ie, early transplant) or continue with chemotherapy with a plan to pursue transplant at time of relapse 
  • Final step is infusion of the peripheral blood stem cells
  • After stem cell transplant, long-term outcomes are improved by administration of lenalidomide maintenance; in intermediate- and high-risk multiple myeloma, bortezomib maintenance administered every 2 weeks is preferred 
  • Tandem transplant (in which patients receive a planned second transplant after recovery from the first procedure) is restricted to select cases because data on its benefits are contradictory 
    • Tandem transplant is considered only in (1) patients with less than very good partial response to the first autologous bone marrow transplant or (2) selected patients with del(17p) cytogenetics 

Indication

  • Active multiple myeloma

Contraindications

  • Poor performance status
  • Age older than 75 years is an absolute contraindication 
  • Age 65 to 75 years is a relative contraindication, but procedure may be considered in patients with excellent organ function and performance status

Complications

  • Bone marrow cytopenias
  • Opportunistic infections
  • Graft versus host disease
  • Graft failure

Interpretation of results

  • Patients who do not achieve a complete or very good partial response with the first autologous transplant can be considered for a second autologous transplant 
Radiotherapy

General explanation

  • Low-dose radiotherapy can be used for palliative treatment of bone disease that occurs with active multiple myeloma
    • Dosing for palliation is 8 Gy (1 time) or 10 to 30 Gy in 2 to 3 fractions each 
  • Local radiotherapy is the primary therapy for solitary osseous or extraosseous plasmacytomas 
    • Dosing is 40 to 50 Gy total (in 1.8-2 Gy per fraction) to the involved field 

Indication

  • Patients with multiple myeloma who have disabling pain and a well-defined focal process that has not responded to chemotherapy 
  • Solitary osseous or extraosseous plasmacytoma 
  • Patients with spinal cord compression 

Contraindications

  • Planned stem cell harvest for stem cell transplant

Complications

  • Nausea or gastrointestinal distress 
  • Possible pain flare in the first week 
Plasmapheresis

General explanation

  • Extracorporeal treatment that selectively removes plasma, followed by separation from the blood using centrifugation or filtration, and return of the plasma after purification
  • Requires venous access with either 2 large bore peripheral catheters or a central venous catheter
  • Plasmapheresis should occur daily until serum free light chain levels are less than 50 mg/dL and then should be repeated as needed until chemotherapy is fully effective 

Indication

  • Renal failure due to light chain cast nephropathy (serum free light chain level more than 150 mg/dL) 
  • Hyperviscosity syndrome 

Complications

  • Hypocalcemia
  • Metabolic alkalosis
  • Vascular catheter issues such as infection, thrombosis, or arteriovenous fistulas

Interpretation of results

  • Aggressive treatment of acute renal failure due to light chain cast nephropathy (with plasmapheresis) is necessary for long-term overall survival

Comorbidities

  • Patients with renal insufficiency 
    • Proteasome inhibitor–based regimens, such as VCd (bortezomib-cyclophosphamide-dexamethasone), are favored in patients with acute kidney injury
    • In patients with renal failure, immunomodulators such as lenalidomide are contraindicated; alternative drugs such as cyclophosphamide are incorporated into their regimens
    • Renoprotective strategies include:
      • Maintain hydration and avoid NSAIDs to reduce chances of worsening renal function
      • Avoid IV contrast medium during imaging
      • Monitor renal function with chronic use of bisphosphonates

Special populations

  • Frail or elderly patients
    • 3-drug regimens are most effective for multiple myeloma, but 2-drug regimens may be preferable for frail or elderly patients, at least until a third drug can be added as tolerated 
    • Lenalidomide-dexamethasone is the preferred chemotherapy regimen
      • This combination has been shown to improve progression-free and overall survival compared with older melphalan-based therapy 
  • Patients with smoldering myeloma (indolent myeloma)
    • Premalignant condition at risk for progression to multiple myeloma
    • Patients with indolent disease are typically asymptomatic and have no end-organ damage (eg, lytic bone lesions, renal dysfunction, hypercalcemia, anemia) 
    • Observation with periodic monitoring is the standard of care 
    • There is some evidence that early treatment with lenalidomide in smoldering myeloma can delay progression to symptomatic multiple myeloma and development of end-organ damage 

Monitoring

  • Monitoring after treatment of active multiple myeloma
    • Monitoring schedule after primary myeloma therapy is similar after stem cell transplant or after primary myeloma therapy for non–transplant recipients
    • Monitor patients on treatment every month for response to therapy and for symptoms related to disease and/or treatment; monitor every 3 to 4 months when off therapy 
    • After each cycle, obtain laboratory tests for M protein with imaging and, if necessary, bone marrow examination to determine whether disease is responding to treatment, stable, or progressive
    • Follow-up tests after primary myeloma therapy to be obtained in all patients include those used for initial diagnosis: 
      • CBC with differential and platelet count
      • Serum chemistry (creatinine and calcium levels are most pertinent)
      • Quantification of M protein and immunoglobulin levels in serum and urine
      • If patients have oligo- or nonsecretory multiple myeloma, serum free light chain assay
      • Bone marrow aspiration biopsy with fluorescence in situ hybridization as clinically indicated
      • Imaging, with one of the following (preferably same modality as at diagnosis) as clinically indicated:
        • Whole body low-dose CT
        • Whole body MRI
        • Whole body fludeoxyglucose F 18 PET with CT
  • Monitoring smoldering (asymptomatic) myeloma 
    • Observe at 3- to 6-month intervals with the following tests:
      • CBC with differential and platelet count
      • Creatinine level and corrected calcium level
      • Serum quantitative immunoglobulin tests, serum protein electrophoresis, and serum immunofixation electrophoresis
      • 24-hour urine for total protein, urine protein electrophoresis, and urine immunofixation electrophoresis
      • Serum free light chain assay, as indicated
      • Bone marrow aspiration biopsy with fluorescence in situ hybridization and multiparameter flow cytometry, as indicated
      • Imaging, with one of the following (preferably same modality as at diagnosis), annually or as clinically indicated (eg, new-onset bone pain, progressive cytopenias, recurring infections):
        • Whole body MRI
        • Whole body low-dose CT scan
        • Whole body fludeoxyglucose F 18 PET with CT

Complications

  • Skeletal complications
    • Lytic lesions of bones
      • Most frequent sites of skeletal involvement are vertebrae, calvaria, thoracic cage, pelvis, and proximal portions of humeri and femora
    • Hypercalcemia
      • Present in 15% to 20% of patients initially 
      • Results primarily from destruction of bone, but contributing factors include dehydration and hyperuricemia
      • Immediate treatment to lower serum calcium level is required when level exceeds 14 mg/dL; use the following: 
        • Volume expansion with 0.9% normal saline IV fluid
        • IV bisphosphonates: zoledronic acid (preferably) or pamidronate
        • IV corticosteroids
        • Rarely, hemodialysis is required for very severe symptomatic hypercalcemia
    • Pathologic fractures
    • Osteoporosis (Related: Postmenopausal osteoporosis)
  • Renal insufficiency (Related: Acute kidney injury)
    • Common complication, but it can even be found at time of diagnosis in about 20% to 25% of patients 
      • Can be reversible with treatment in some cases
      • Renal biopsy is not always necessary, but it may be helpful to clarify the underlying cause in patients in whom other conditions (eg, diabetes, chronic hypertension) are present 
        • Renal biopsy is recommended in patients with suspected cast nephropathy, especially if serum involved free light chain levels are less than 500 mg/L 
    • 2 major causes of renal dysfunction are light chain cast nephropathy and hypercalcemia; several other mechanisms are possible
      • Light chain cast nephropathy
        • Most common cause of acute kidney injury in myeloma is light chain cast nephropathy in patients who have excess excretion of monoclonal protein in urine (myeloma kidney)
        • Precipitated monoclonal light chains form large, waxy, laminated casts in the distal and collecting tubules
        • If the patient is not oliguric, IV fluids and furosemide are needed to maintain a high urine flow rate (100 mL/hour)
        • If underlying cause is thought to be light chain cast nephropathy, initiate plasmapheresis daily for 5 days
        • Renal failure caused by light chain cast nephropathy is regarded as a myeloma-defining event, but other renal disease is not. Evaluation of other causes of acute kidney injury and chronic kidney disease is required 
      • Light chain amyloidosis
        • Occurs in nearly 10% of patients with myeloma and may produce nephrotic syndrome, renal insufficiency, or both 
      • Acquired Fanconi syndrome
        • A proximal tubular dysfunction resulting in glycosuria, phosphaturia, and aminoaciduria
      • Light chain deposition disease
        • Deposition of monoclonal light chains in the renal glomeruli may also produce renal insufficiency and nephrotic syndrome
      • Monoclonal gammopathy–associated proliferative glomerulonephritis
        • Presents with hematuria and renal insufficiency
  • Neurologic complications 
    • Radiculopathy usually occurs in the thoracic or lumbosacral area and results from compression of the nerve by the vertebral lesion or by the collapsed bone itself
    • Spinal cord compression occurs in 10% to 20% 
      • Usually results from a plasmacytoma arising from a vertebral body or from vertebral collapse
      • Onset can be abrupt, leading to severe paraparesis within a few hours
      • Lumbar vertebral involvement can lead to a cauda equina syndrome, with low back and radicular pain and weakness of legs
      • Bowel or bladder incontinence are other worrisome symptoms
      • Obtain MRI immediately for any suspected case of spinal cord compression
      • If confirmed, treat with dexamethasone plus radiotherapy
      • In cases where spinal cord compression is caused by vertebral collapse or spinal instability (very rare situations), urgent surgical decompression followed by insertion of a prosthesis or bone graft is required
    • Peripheral neuropathy (uncommon) is generally caused by amyloidosis
    • Central nervous system infiltration (leptomeningeal) by myelomatous cells is rare, as are intracranial plasmacytomas
  • Infections
    • Susceptibility to infections, including recurrent infections, is multifactorial, with the major cause being impaired antibody production leading to a decrease in uninvolved immunoglobulins 
    • The more common agents causing respiratory tract infections are Streptococcus pneumoniaeStaphylococcus aureus, and Haemophilus influenzae 
    • The more common agents causing urinary tract infections are Escherichia coliPseudomonasProteusEnterobacter, and Klebsiella 
    • Most infections in newly diagnosed patients and during the first cycles of chemotherapy are caused by Streptococcus pneumoniae 
    • In patients with renal failure or in those with advanced disease who are receiving salvage chemotherapy, more than 90% of the infectious episodes are caused by gram-negative bacilli or Staphylococcus aureus 
  • Hyperviscosity syndrome
    • Occasionally occurs in multiple myeloma, especially the IgA type
    • Chronic nasal bleeding and oozing from the gums are the most frequent symptoms of hyperviscosity
    • Retinal hemorrhages are common, and venous congestion with sausage-like segmentation and papilledema may be seen
  • Type I cryoglobulinemia
    • Type I (monoclonal) cryoglobulinemia is most commonly of the IgM or IgG class, but IgA and Bence Jones cryoglobulins have been reported 
    • Most patients, even with large amounts of type I cryoglobulin, are asymptomatic, but if monoclonal cryoglobulin levels reach the range of 1 to 2 g/dL, there may be evidence of vasculitis with pain, purpura, Raynaud phenomenon, cyanosis, and ulceration with sloughing of skin on exposure to cold 
  • Chemotherapy-related toxicities
    • Infection
    • Fatigue
    • Nausea and vomiting

Prognosis

  • Multiple myeloma is considered incurable at present 
  • Median survival is approximately 5 years, but it varies widely according to clinical stage and risk stratification factors
  • 5-year survival rates by stage (Revised International Staging System for myeloma) 
    • Stage I: 82%
    • Stage II: 60%
    • Stage III: 40%
  • Median overall survival based on cytogenetic risk 
    • High risk: 3 years
      • Characterized by any of the following: translocations t(14;16), t(14,20); deletion 17p
    • Intermediate risk: 5 years
      • Characterized by any of the following: translocation t(4;14); amplification 1q
    • Standard risk: 7 to 10 years
      • All other cytogenetic profiles, such as translocations t(11;14), t(6; 14); trisomies
  • Progression of smoldering myeloma 
    • 10% risk during first 5 years after diagnosis
    • 3% over the next 5 years
    • 1% over the next 10 years

Summary

  • Multiple myeloma is a form of cancer. It develops when abnormal plasma cells grow out of control.
  • There is no cure for multiple myeloma. However, treatments can manage symptoms and slow the progression of the disease. Treatment options may vary depending on how much the disease has advanced.
  • Do not lift anything that is heavier than 10 lb (4.5 kg), or the limit that you are told, until your health care provider says that it is safe.
  • Contact your health care provider if you have any new symptoms or sudden severe pain, especially back pain.

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