Multiple Myeloma – Causes, Symptoms, Diagnosis, Treatment

Multiple Myeloma – Causes, Symptoms, Diagnosis, Treatment

Multiple Myeloma (MM) is a fatal, malignant B-cell neoplasm characterized by uncontrolled, destructive growth of mutated plasma cells within the bone marrow (BM). Patients over age 65 are most commonly affected by this disease and, as indicated by its name, MM is characterized by the dissemination of multiple tumor cells throughout the BM. A mnemonic sometimes used for the common MM pathologies is CRAB: C (calcium, elevated), R (renal failure), A (anemia), B (bone lesions). Additionally, a hallmark of MM is heterogeneous chromosomal aberrations and numerous mutations in a range of genres, both of which make the disease very difficult to target therapeutically.

Multiple myeloma (MM) is a clonal plasma cell proliferative disorder characterized by the abnormal increase of monoclonal paraprotein leading to evidence of specific end-organ damage. MM is part of the spectrum of monoclonal gammopathy. Monoclonal gammopathy of undetermined significance (MGUS), in other words, detection of monoclonal immunoglobulin in blood or urine without evidence of end-organ damage, has a progression risk to MM of about 1% per year. Smoldering multiple myeloma (SMM), the next stage in the spectrum of monoclonal gammopathy, is at a much higher progression risk of 10% per year.

Synonyms of Multiple Myeloma

  • Kahler disease
  • myelomatosis
  • plasma cell myeloma

Subdivisions of Multiple Myeloma

  • extramedullary plasmacytoma
  • nonsecretory myeloma
  • osteosclerotic myeloma
  • plasma cell leukemia
  • smoldering myeloma
  • solitary plasmacytoma of bone

Types of multiple myeloma

There are two main types of multiple myeloma. They’re categorized by their effect on the body:

  • Indolent myeloma causes no noticeable symptoms. It usually develops slowly and doesn’t cause bone tumors. Only small increases in M protein and M plasma cells are seen.
  • A solitary plasmacytoma causes a tumor to form, typically in bone. It usually responds well to treatment but needs close monitoring.

Pathophysiology

MM is thought to arise from a pre-malignant, asymptomatic stage of clonal plasma cell growth called monoclonal gammopathy of undetermined significance (MGUS), which is known to be detectable in over 3 percent of persons above age 50. It appears that the cell of origin is a post-germinal center plasma cell. Clinical progression to overt MM occurs at a rate of approximately 1% per year.

Although the exact causes of MGUS development and progression to MM remain unknown, the 2 fundamental steps in MM pathogenesis are:

  • Establishment of MGUS – Possibly because of cytogenetic abnormalities generated during an abnormal response to antigenic challenge, which results in monoclonal immunoglobulin production;
  • Progression from MGUS to MM – Under the “second hit” hypothesis, progression is thought to be a consequence of additional cytogenetic lesions gained by the original plasma cell clone, caused either by genetic instability or abnormalities in the hematopoietic microenvironment.

Malignant plasma cells in MM are especially sensitive to interleukin-6, which appears to be essential for tumor growth and survival.

Excess monoclonal immunoglobulin can cause hyperviscosity, platelet dysfunction and renal tubular damage, leading respectively to neurologic derangement, bleeding, and renal failure. Bone marrow occupation by the expanding plasma cell clone usually manifests as anemia, thrombocytopenia, and leukopenia.

The interaction between myeloma cells and the bone microenvironment ultimately leads to the activation of osteoclasts and suppression of osteoblasts, resulting in bone loss. Several intracellular and intercellular signaling cascades, numerous chemokines and interleukins are implicated in this complex process.

Causes of Multiple Myeloma

The exact etiology of MM is unknown. However, there is evidence that suggests genetic abnormalities in oncogenes such as CMYC, NRAS, and KRAS may play a role in the development of plasma cell proliferation. MM has also been associated with other factors such as drinking alcohol, obesity, environmental causes such as insecticides, organic solvents), and radiation exposure.

It’s not known exactly what causes multiple myeloma. However, there is a close link between multiple myeloma and a condition called monoclonal gammopathy of unknown significance (MGUS).

MGUS is where there is an excess of protein molecules, called immunoglobulins, in your blood. This doesn’t cause any symptoms and doesn’t need treatment.

Every year, around 1 in every 100 people with MGUS go on to develop multiple myeloma. There is no known way to delay or prevent this, so people with MGUS will have regular tests to check for cancer.

Multiple myeloma is also more common in:

  • men
  • adults over 60 – most cases are diagnosed at around the age of 70, and cases affecting people under the age of 40 are rare
  • black people – multiple myeloma is about twice as common in black populations than white and Asian populations
  • people with a family history of MGUS or multiple myeloma

Symptoms of Multiple Myeloma

In multiple myeloma, abnormal plasma cells (myeloma cells) build up in the bone marrow and form tumors in many bones of the body. These tumors may keep the bone marrow from making enough healthy blood cells. Normally, the bone marrow makes stem cells (immature cells) that become three types of mature blood cells:

  • Red blood cells that carry oxygen and other substances to all tissues of the body.
  • White blood cells that fight infection and disease.
  • Platelets that form blood clots to help prevent bleeding.

As the number of myeloma cells increases, fewer red blood cells, white blood cells, and platelets are made. The myeloma cells also damage and weaken the bone.

Sometimes multiple myeloma does not cause any signs or symptoms. This is called smoldering multiple myeloma. It may be found when a blood or urine test is done for another condition. Signs and symptoms may be caused by multiple myeloma or other conditions. Check with your doctor if you have any of the following:

  • Calcium: serum calcium >0.25 mmol/l (>1mg/dl) higher than the upper limit of normal or >2.75 mmol/l (>11mg/dl)
  • Renal insufficiency: creatinine clearance <40 ml per minute or serum creatinine >1.77mol/l (>2mg/dl)
  • Anemia: hemoglobin value of >2g/dl below the lowest limit of normal, or a hemoglobin value <10g/dl
  • Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT
  • Bone pain, especially in the back or ribs.
  • Bones that break easily.
  • Fever for no known reason or frequent infections.
  • Easy bruising or bleeding.
  • Trouble breathing.
  • A weakness of the arms or legs.
  • Feeling very tired.

A tumor can damage the bone and cause hypercalcemia (too much calcium in the blood). This can affect many organs in the body, including the kidneys, nerves, heart, muscles, and digestive tract, and cause serious health problems.

Hypercalcemia may cause the following signs and symptoms:

  • Loss of appetite.
  • Nausea or vomiting.
  • Feeling thirsty.
  • Frequent urination.
  • Constipation.
  • Feeling very tired.
  • Muscle weakness.
  • Restlessness.
  • Confusion or trouble thinking.

When signs and symptoms do occur, they can include:

  • Bone pain, especially in your spine or chest
  • Nausea
  • Constipation
  • Loss of appetite
  • Mental fogginess or confusion
  • Fatigue
  • Frequent infections
  • Weight loss
  • Weakness or numbness in your legs
  • Excessive thirst

Diagnosis of Multiple Myeloma

Histopathology

A bone marrow aspirate and biopsy are usually performed to estimate the percentage of abnormal plasma cells. This percentage is required in the diagnostic criteria for myeloma.

The plasma cells seen in MM have several possible morphologies. First, they could take the form of a mature, normal plasma cell (a large cell, 2 or 3-times the size of a lymphocyte, with a single eccentric nucleus displaced by an abundant, basophilic cytoplasm). The Golgi apparatus will typically produce a light-colored area next to the nucleus, called a perinuclear halo. Second, they can have features of immaturity, such as low nuclear-cytoplasmic ratio, larger size, loose chromatin (i.e., a plasmablast). Other possible morphologies are bizarre, multinucleated cells, “flame cells” with fiery red cytoplasm, or Mott cells that show multiple clustered cytoplasmic droplets. Bone marrow is usually hypercellular and diffusely infiltrated by plasma cells. Rarely, plasma cells can be seen in peripheral blood (plasma cell leukemia).

Immunohistochemistry can detect plasma cells that express immunoglobulin in the cytoplasm and occasionally on the cell surface; myeloma cells are typically CD56, CD38, CD 138, CD319-positive, and CD19 and CD45-negative. Clonality is confirmed by kappa or lambda light chain restriction.

History and Physical

The presentation can vary from asymptomatic to severely ill. Usually, the patient is an older adult complaining of constitutional symptoms such as fatigue, weight loss, and bone pain, particularly in the back and chest. Pathological fractures and vertebral collapse lead to a reduction in height, spinal cord compression, radicular pain or kyphosis. Anemia usually causes pallor, palpitation and worsening of previous heart failure or angina. Renal failure (acute and/or chronic) can lead to edema, acidosis, and electrolyte disturbances. Hypercalcemia, dehydration, and hypergammaglobulinemia further aggravate renal injury and may lead to confusion, obtundation, and coma. Secondary amyloidosis can cause peripheral neuropathy and carpal tunnel syndrome, which manifest as paresthesias and muscle weakness. A few patients may present with hepatomegaly, splenomegaly, lymphadenopathy, and fever.

Those with hyperviscosity may have symptoms like paresthesia, headache, dyspnea, nasal bleeding, blurry vision. Lung involvement in the form of pleural effusion or diffuse pulmonary infiltration by plasma cells is a rare presentation.

MM patients are more prone to infections, mostly pneumonia, and pyelonephritis. Findings on physical examination are variable depending on the extent of disease, but will usually include pallor, tachycardia, tachypnea, petechiae or ecchymoses, bone tenderness, edema or signs of dehydration and central or peripheral neurologic signs. Fundoscopic signs include exudative macular detachment, retinal hemorrhage or cotton-wool spots. Carpal tunnel syndrome may cause positive Tinel and Phalen signs. Extra-medullary plasmacytomas can present as deep-seated or superficial tumors. Macroglossia, papules, or nodules can occur in amyloidosis.

Evaluation

According to the National Comprehensive Cancer Network (NCCN) criteria, MM is defined as smoldering (asymptomatic) or active (symptomatic).

NCCN criteria for smoldering MM:

  • Serum monoclonal protein: IgG or IgA equal to 3 g/dL or
  • Bence Jones protein equal to 500 mg per 24 hours and/or
  • Clonal bone marrow plasma cells 10% to 59%  and
  • The absence of myeloma-defining events or amyloidosis

The NCCN also recommends that a patient whose bone survey is negative be assessed for bone disease with whole-body or skeletal MRI, with contrast, or whole-body PET/CT to differentiate active from smoldering MM.

Per NCCN guidelines, an active multiple myeloma is no longer diagnosed using the CRAB criteria (hypercalcemia, renal failure, anemia, bone lesions) for end-organ damage. The current diagnostic criteria are:

  • Bone marrow clonal plasma cells equal to 10% or bony or extramedullary plasmacytoma (confirmed by biopsy) and
  • One or more myeloma-defining events, including:
  • Serum calcium level greater than 0.25 mmol/L (greater than 1 mg/dL) higher than the upper limit of normal or greater than 2.75 mmol/L (greater than 11 mg/dL)
  • Renal insufficiency (creatinine greater than 2 mg/dL [greater than 177 micromol/L] or creatinine clearance less than 40 mL per minute)
  • Anemia (hemoglobin less than 10 g/dL or hemoglobin greater than 2 g/dL below the lower limit of normal)
  • One or more osteolytic bone lesions on skeletal radiography, CT, or PET-CT

In November 2014, the International Myeloma Working Group (IMWG) added the following criteria to the CRAB criteria for MM:

  • Bone marrow plasma cells (BMPCs) equal to 60%
  • Involved/uninvolved serum free light chain ratio equal to 100
  • Abnormal MRI with more than one focal lesion, with each lesion greater than 5 mm

The IMWG noted that these findings have been “associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smoldering multiple myeloma.” The presence of any CRAB criterium or any of these three additional criteria justifies therapy.

Suspected MM workup is targeted to check if the patient meets diagnostic criteria and, if so, what is the stage. Depending on the stage, the most appropriate management strategy is chosen.

The NCCN guidelines recommend the following diagnostic studies:

  • Complete blood count (CBC) with differential, platelet count
  • BUN, creatinine, electrolytes, albumin, calcium levels
  • Serum LDH and beta-2 microglobulin
  • Serum immunoglobulins, serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE)
  • 24-hour proteinuria, urine protein electrophoresis (UPEP), urine immunofixation electrophoresis (UIFE)
  • Serum free light chain (FLC) assay
  • Skeletal survey
  • Unilateral bone marrow aspirate and biopsy, including immunohistochemistry and/or flow cytometry, and cytogenetics
  • Plasma cell FISH [del 13, del 17p13, t(4;14), t(11;14), t(14;16), 1q21 amplification], 1p abnormality

In patients with severe hypergammaglobulinemia, “rouleaux” formation of RBCs can be evident at hematoscopy.

A skeletal survey usually shows lytic lesions of any bone. The classic image on skull x-ray studies is the punched-out, round, radiolucent lesion (“pepper pot skull”). Less often, lesions may take a sclerotic appearance. MRI is more sensitive than plain X-rays in the detection of lytic lesions. Occasionally, CT scan is performed to measure the size of soft tissue plasmacytomas.

Laboratory parameters in serum

  • Differential blood count, electrolytes, creatinine, LDH, CRP, β2-microglobulin
  • Plasma coagulation, total protein, albumin
  • Serum electrophoresis with the densitometric determination of M protein
  • Quantitative determination of immunoglobulins (IgG, IgA, IgM, IgD)
  • Determination of free light chains (including FLC ratio), immunofixation electrophoresis

Laboratory parameters in urine

  • 24-h urine collection, determination of free light chains
  • Immunofixation electrophoresis, albumin

Bone marrow diagnosis

  • Cytology and/or histology, cytogenetic investigation (chromosome analysis and FISH) to detect unfavorable cytogenetic aberrations
The following tests and procedures may be used:
  • Physical exam and health history – An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Blood and urine immunoglobulin studies – A procedure in which a blood or urine sample is checked to measure the amounts of certain antibodies (immunoglobulins). For multiple myeloma, beta-2-microglobulin, M protein, free light chains, and other proteins made by the myeloma cells are measured. A higher-than-normal amount of these substances can be a sign of disease.
  • Bone marrow aspiration and biopsy – The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for abnormal cells.
    Bone marrow aspiration and biopsy. After a small area of skin is numbed, a bone marrow needle is inserted into the patient’s hip bone. Samples of blood, bone, and bone marrow are removed for examination under a microscope. The following tests may be done on the sample of tissue removed during the bone marrow aspiration and biopsy:
  • Cytogenetic analysis – A laboratory test in which the chromosomes of cells in a sample of bone marrow are counted and checked for any changes, such as broken, missing, rearranged, or extra chromosomes. Changes in certain chromosomes may be a sign of cancer. Cytogenetic analysis is used to help diagnose cancer, plan treatment, or find out how well treatment is working.
  • FISH (fluorescence in situ hybridization) – A laboratory test used to look at and count genes or chromosomes in cells and tissues. Pieces of DNA that contain fluorescent dyes are made in the laboratory and added to a sample of a patient’s cells or tissues. When these dyed pieces of DNA attach to certain genes or areas of chromosomes in the sample, they light up when viewed under a fluorescent microscope. The FISH test is used to help diagnose cancer and help plan treatment.
  • Flow cytometry – A laboratory test that measures the number of cells in a sample, the percentage of live cells in a sample, and certain characteristics of the cells, such as size, shape, and the presence of tumor (or other) markers on the cell surface. The cells from a sample of a patient’s bone marrow are stained with a fluorescent dye, placed in a fluid, and then passed one at a time through a beam of light. The test results are based on how the cells that were stained with the fluorescent dye react to the beam of light. This test is used to help diagnose and manage certain types of cancers, such as leukemia and lymphoma.
  • Skeletal bone survey – In a skeletal bone survey, x-rays of all the bones in the body are taken. The x-rays are used to find areas where the bone is damaged. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • Complete blood count (CBC) with differential – A procedure in which a sample of blood is drawn and checked for the following:
    -The number of red blood cells and platelets.
    -The number and type of white blood cells.
    -The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
    -The portion of the blood sample made up of red blood cells.
  • Blood chemistry studies – A procedure in which a blood sample is checked to measure the amounts of certain substances, such as calcium or albumin, released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
  • Twenty-four-hour urine test – A test in which urine is collected for 24 hours to measure the amounts of certain substances. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. A higher than normal amount of protein may be a sign of multiple myeloma.
  • MRI (magnetic resonance imaging) – A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI). An MRI of the spine and pelvis may be used to find areas where the bone is damaged.
  • PET scan (positron emission tomography scan) – A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
  • CT scan (CAT scan) – A procedure that makes a series of detailed pictures of areas inside the body, such as the spine, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • PET-CT scan – A procedure that combines the pictures from a positron emission tomography (PET) scan and a computed tomography (CT) scan. The PET and CT scans are done at the same time with the same machine. The combined scans give more detailed pictures of areas inside the body, such as the spine, than either scan gives by itself.
International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma and Related Plasma Cell Disorders
Disorder Disease Definition
Non-IgM monoclonal gammopathy of undetermined significance (MGUS) All 3 criteria must be met:

  • Serum monoclonal protein (non-IgM type) <3gm/dL

  • Clonal bone marrow plasma cells <10%*

  • Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) that can be attributed to the plasma cell proliferative disorder
Smoldering multiple myeloma Both criteria must be met:

  • Serum monoclonal protein (IgG or IgA) ≥3gm/dL, or urinary monoclonal protein ≥500 mg per 24h and/or clonal bone marrow plasma cells 10–60%

  • Absence of myeloma defining events or amyloidosis
Multiple Myeloma Both criteria must be met:

  • Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma

  • Any one 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 >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
      • ▪ Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177 μmol/L (>2 mg/dL)
      • ▪ Anemia: hemoglobin value of >2 g/dL below the lower limit of normal, or a hemoglobin value <10 g/dL
      • ▪ Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography-CT (PET-CT)
    • ○ Clonal bone marrow plasma cell percentage ≥60%)
    • ○ Involved: uninvolved serum free light chain (FLC) ratio ≥100 (involved free light chain level must be ≥100 mg/L))
    • ○ >1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5mm in size)

     
IgM Monoclonal gammopathy of undetermined significance (IgM MGUS) All 3 criteria must be met:

  • Serum IgM monoclonal protein <3gm/dL

  • Bone marrow lymphoplasmacytic infiltration <10%

  • No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.
Light Chain MGUS All criteria must be met:

  • Abnormal FLC ratio (<0.26 or >1.65)

  • Increased level of the appropriate involved light chain (increased kappa FLC in patients with ratio > 1.65 and increased lambda FLC in patients with ratio < 0.26)

  • No immunoglobulin heavy chain expression on immunofixation

  • Absence of end-organ damage that can be attributed to the plasma cell proliferative disorder

  • Clonal bone marrow plasma cells <10%

  • Urinary monoclonal protein <500 mg/24h
Solitary Plasmacytoma All 4 criteria must be met

  • Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells

  • Normal bone marrow with no evidence of clonal plasma cells

  • Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)

  • Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lympho-plasma cell proliferative disorder
Solitary Plasmacytoma with minimal marrow involvement** All 4 criteria must be met

  • Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells

  • Clonal bone marrow plasma cells <10%

  • Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)

  • Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lympho-plasma cell proliferative disorder

Treatment for Multiple Myeloma

Initial Evaluation

The initial approach to the patient is to evaluate the following parameters:

  • Detection and quantification of a monoclonal (or myeloma) protein (M protein) in the serum or urine, and possible immunoparesis (suppression of the other uninvolved immunoglobulins).[]
  • Detection of more than 10% of plasma cells on a bone marrow examination, along with flow cytometry, cytogenetics, and fluorescence in situ hybridization testing.
  • Detection of lytic bone lesions or generalized osteoporosis in skeletal x-rays, or whole-body or spinal and pelvic magnetic resonance imaging (MRI) scans, or focal bone lesions on positron emission tomography-computed tomography (CT) scan.[,]
  • Presence of soft tissue plasmacytomas.
  • Serum albumin and beta-2-microglobulin levels.
  • Detection of free kappa and free lambda serum immunoglobulin light chain, with the calculation of the serum-free light chain ratio.[,]
  • Presence of hypercalcemia.
  • Detection of renal dysfunction attributable to the plasma cell dyscrasia (induced by gammopathy or amyloidosis).
  • Presence of anemia.
  • Presence of circulating plasma cells.
  • Presence of hyperviscosity. Asymptomatic patients usually respond to myeloma therapy; plasma exchange is indicated with hemorrhagic or central nervous system manifestations.[]

Treatment selection is influenced by the age and general health of the patient, previous therapy, and the presence of complications of the disease.[]

Therapeutic Overview

Despite the introduction of many new therapeutic agents over the past two decades, there is still no confirmed curative approach.

Indolent myeloma

Newly diagnosed patients with the indolent disease historically referred to as smoldering myeloma, can be followed on a watchful waiting approach.[] These patients are typically asymptomatic and free of lytic bone lesions, renal dysfunction, hypercalcemia, or significant anemia. Serial measurements of paraprotein parameters can help to confirm stable disease over months or years.

Symptomatic myeloma

Newly diagnosed patients who require therapy fall into two categories: 1) the younger fit patient who is transplant-eligible or 2) the older more unfit patient with comorbidities who is not transplanted eligible. Patients younger than 65 years are usually considered younger and fit, while patients older than 75 years are usually not transplanted eligible. Comorbidities and performance status are important determinants at all ages, especially between the ages of 65 years and 75 years, to help decide about transplant eligibility. Nomograms exist for geriatric patients to define life expectancy independent of the myeloma diagnosis.[] Age, organ dysfunction, and risk of cardiovascular and thrombotic complications influence the choice of induction therapies and consideration of consolidation therapies, such as autologous stem cell transplantation (ASCT) consolidation. Most patients also receive medication with a bisphosphonate or RANKL inhibitor to prevent skeletal-related complications.[,]

The International Myeloma Working Group has issued guidance for the diagnosis and management of patients with renal impairment.[]

Younger fit patients (transplant eligible)

The younger fit patient will receive induction chemotherapy with a triple-drug (triplet) approach that includes bortezomib in the absence of a clinical trial. The most commonly used triplets include:

  • VRd: lenalidomide + bortezomib + dexamethasone.[–]
  • CyBorD: cyclophosphamide + bortezomib + dexamethasone.[,] This regimen is preferred in the presence of significant renal dysfunction (creatinine clearance less than 45 cc/min). If the renal function recovers rapidly, some clinicians switch to VRd.

After 4 to 8 months of therapy, responding patients usually undergo ASCT consolidation.[,] After recovery from the ASCT, maintenance therapy is then implemented until the time of relapse.[–] At relapse, subsequent therapies are applied sequentially by using previously successful drugs (if the interval of time since previous exposure is >1 year) or newer drugs not previously tried.

Older unfit patients (not transplant eligible)

The older less-fit patient will receive induction chemotherapy with a triplet (as described for the younger fit patient) plus the monoclonal antibody to CD38, daratumumab, or with a doublet and daratumumab, which might be better tolerated.[] Therapy is continued until maximal response and then maintenance therapy is applied until relapse.[] At relapse, subsequent therapies are applied sequentially (as described for the younger fit patient).

High risk versus standard risk

Newly diagnosed patients and relapsing patients can be allocated to standard-risk versus high-risk disease on the basis of cytogenetics, genetic aberrations detected by fluorescence in situ hybridization, and possibly the genetic expression profile analyses that are in the process of standardization.[] Higher-risk patients are candidates for clinical trials employing newer agents upfront or for use of newer combination therapies currently used for the relapsed disease at the discretion of the clinician. Beyond induction therapy, the high-risk disease can lead to more aggressive strategies, such as tandem transplantation or consideration of allogeneic SCT. More intensive maintenance therapies may also be applied for high-risk disease; instead of using lenalidomide alone, lenalidomide plus bortezomib has been chosen based on prior trials using thalidomide.[] These more aggressive strategies have been implemented because of poor responsiveness to standard regimens and the worse prognosis of high-risk patients. Ultimately, randomized prospective trials will be needed to establish improved outcomes with these newer approaches for high-risk patients.

Unresolved questions regarding therapy for multiple myeloma include the following:

  • How do we incorporate the newer agents such as daratumumab and elotuzumab upfront and create four or five drug regimens? Should these regimens be applied to all patients or just high-risk patients? Can we find a more personalized targeted approach and create a smaller drug cocktail?
  • As newer agents, such as carfilzomib and pomalidomide, move upfront into triplets, and with the introduction of the anti-CD38 monoclonal antibody daratumumab and the monoclonal antibody targeting signal lymphocyte activating molecule F7 (SLAMF7) elotuzumab, will the stringent complete remissions equal or surpass ASCT with less long-term toxicities? Can ASCT be omitted in some patients?
  • The assessment of minimal residual disease is mandatory for the assessment of efficacy in clinical trials.[,] Does this testing outside of the trial setting yield meaningful clinical improvement in patient outcomes by informing selection or duration of therapy?
  • How do we deal with the financial toxicity of all these advances?

Achievement of minimal residual disease after induction therapy (with or without consolidation therapy) is associated with improved overall survival (OS).[–] While this interim marker may be useful for the design of clinical trials, there are no data suggesting that this interim marker improves outcomes by altering subsequent therapy.

Induction Therapy

Myeloma patients who are symptomatic or require therapy because of progression or adverse laboratory findings will require induction therapy. Ideally, induction therapy should reduce tumor burden, provide symptomatic relief, and prevent further end-organ damage.

Younger fit patients (transplant eligible)

Two randomized prospective trials have established three-drug regimens (triplets) for induction therapy in younger fit transplant-eligible patients).

  1. In a prospective randomized trial of 525 newly diagnosed patients with myeloma, VRd (bortezomib, lenalidomide, and dexamethasone) was compared with Rd (lenalidomide and dexamethasone).[]

    • With a median follow-up of 55 months, the VRd group had superior progression-free survival (PFS) (median PFS, 43 months vs. 30 months [hazard ratio (HR), 0.71; 95% confidence interval (CI), 0.56–0.91; one-sided P = .0018]) and superior OS (median OS, 75 months vs. 64 months [HR, 0.79; 95% CI, 0.52‒0.97; P = .025]).[]

  2. A prospective randomized trial of 682 patients older than 65 years compared VMP (bortezomib, melphalan, and prednisone) with melphalan and prednisone alone.[]

    • With a median follow-up of 60 months, the median OS favored the triplet with bortezomib: 56.4 versus 43.1 months (P < .001).[]

The U.S. Intergroup and French Inter-Groupe Francophone du Myélome (IFM) study chose VRd as the induction therapy for their prospective randomized trial of 700 patients aged 65 years or younger, which investigated ASCT consolidation after three cycles of VRd compared with time to relapse.[] In the United States, VRd has become the standard regimen that is compared to newer combinations for induction therapy. Because lenalidomide is metabolized erratically in the setting of renal failure, clinicians often choose the CyBorD regimen (cyclophosphamide, bortezomib, and dexamethasone),[,] but this selection is empiric and not based on randomized trial results.

Older unfit patients (not transplant eligible)

Triplet therapies such as VRd and CyBorD can be used in patients in whom fitness is adequate and concurrent morbidities are minimal. When triplets are deemed too difficult, doublets with VD (bortezomib plus dexamethasone) or RD (lenalidomide plus dexamethasone) can be used, or even a triplet such as VMP as described in the section for younger fit patients.[,] The advent of daratumumab, the monoclonal antibody directed at CD38, has changed the options since this biologic therapy has been studied with the aforementioned doublets and triplets in both phase II and phase III trials.

  • In a prospective randomized trial of 737 patients with newly diagnosed myeloma who were ineligible for transplantation, daratumumab plus lenalidomide and dexamethasone was compared with lenalidomide and dexamethasone alone.[]

    • With a median follow-up of 28.0 months, the 30-month PFS favored the daratumumab combination, 70.6% (95% CI, 65.0%−75.4%) versus 55.6% (95% CI, 49.5%−61.3%) (HR, 0.56; 95% CI, 0.43−0.73; P < .001).[]
    • Patients without minimal residual disease (<1 tumor cell per 105 white cells) favored the daratumumab combination 24.2% versus 7.3% (P < .001).

  • In a prospective randomized trial in 706 patients with newly diagnosed myeloma who were ineligible for transplantation, daratumumab plus VMP was compared with VMP alone.[]

    • With a median follow-up of 40.1 months, the 3-year OS rate favored the daratumumab-combination group at 78% (95% CI, 73.2%−83.0%) versus 67.9% in the VMP-alone group (95% CI, 62.6%−72.6%) (HR, 0.60; 95% CI, 0.46−0.80, P = .003).[]
    • With a median follow-up of 40.1 months, the 3-year PFS rate favored the daratumumab-combination group at 50.7% (95% CI, 45.1%−55.9%) versus 18.5% in the VMP group (95% CI, 14.4%−23.1%) (HR, 0.42; 95% CI, 0.34−0.51; P < .0001).[]
    • Patients without minimal residual disease favored daratumumab 22.3% (threshold of one tumor cell per 105 white cells) versus 6.2% in the control group (P < .001).
    Immunologic reaction to the initial dose of daratumumab can be modulated by splitting the first infusion over 2 days or using the subcutaneous version (not U.S. Food and Drug Administration‒approved).

  • In a prospective randomized trial of 955 patients with newly diagnosed multiple myeloma who were ineligible for transplantation, the combination of carfilzomib plus melphalan and prednisone was compared with the combination of bortezomib plus melphalan and prednisone.[]

    • With a median follow-up of 23 months, there was no difference in median PFS (22.3 vs. 22.1 months; HR, 0.91; 95% CI, 0.75−1.10; P = .159) or in median OS (HR, 1.1; 95% CI, 0.82−1.4).[]
  • Many other phase II and phase III trials, published in preliminary abstract form, show results similar to the trial that combined daratumumab with melphalan and prednisone, and used daratumumab with other triplets and doublets in both previously untreated and previously treated patients.[,] Further follow-up is required to establish OS benefits.

Consolidation of Chemotherapy

Autologous bone marrow or peripheral stem cell transplantation

Evidence (autologous bone marrow or peripheral stem cell transplantation):

The failure of conventional therapy to cure myeloma has led investigators to test the effectiveness of much higher doses of drugs such as melphalan. The development of techniques for harvesting hemopoietic stem cells, from marrow aspirates or the peripheral blood of the patient, and infusing these cells to promote hemopoietic recovery made it possible for investigators to test very large doses of chemotherapy.

Based on the experience of treating thousands of patients in this way, it is possible to draw a few conclusions, including the following:

  • The risk of early death caused by treatment-related toxic effects has been reduced to less than 3% in highly selected populations.[]
  • Extensive prior chemotherapy, especially with alkylating agents, compromises marrow hemopoiesis and may make the harvesting of adequate numbers of hemopoietic stem cells impossible.[]
  • Younger patients in good health tolerate high-dose therapy better than older patients with a poor performance status.[–]
  • A review of eight updated trials encompassing more than 3,100 patients found, at 10 years’ follow-up, a 10% to 35% event-free survival (EFS) rate and a 20% to 50% OS rate.[] New monoclonal gammopathies of an isotype (heavy and/or light chain) distinct from the original clone can emerge in long-term follow-up.[]

Single autologous bone marrow or peripheral stem cell transplantation

Evidence (single autologous bone marrow or peripheral stem cell transplantation):

  • While some prospective, randomized trials showed improved survival for patients who received autologous peripheral stem cell or bone marrow transplantation after induction chemotherapy versus chemotherapy alone,[,–] other trials have not shown any survival advantage.[–]

  • Between 2010 and 2012, 700 newly diagnosed patients, aged 65 years or younger, were randomly assigned to receive VRd for three cycles followed by ASCT consolidation and two more cycles of VRd versus VRd alone for eight cycles, with maintenance lenalidomide given to both groups.[] At relapse, patients on the chemotherapy-only arm were re-induced and offered transplantation if they were still responding. This trial compared ASCT at first induction with transplant at relapse.

    • With a median follow-up of 44 months, the median PFS favored early transplantation (50 months vs. 36 months; HR, 0.65; 95% CI, 0.53–0.80; P < .001), but the 4-year OS was unchanged (81% vs. 82%; HR, 1.16; 95% CI, 0.80–1.68; P = .87).[]
    • Long-term follow-up of this U.S. Intergroup and French IFM study will establish whether transplantation during induction therapy is better, the same, or worse than a strategy of delay until after first relapse.
  • Three meta-analyses of almost 3,000 patients showed no survival advantage.[–]

Even the trials suggesting improved survival showed no signs of a slowing in the relapse rate or a plateau to suggest that any of these patients had been cured.[,–,] The role of ASCT has also been questioned with the advent of novel induction therapies with high rates of complete remission.[,] However, ASCT consolidation remains the standard approach for younger fit patients with no contraindications to the procedure.[]

Tandem autologous bone marrow or peripheral stem cell transplantation followed by autologous or allogeneic transplantation

Another approach to high-dose therapy has been the use of two sequential episodes of high-dose therapy with stem cell support (tandem transplants).[–]

Evidence (tandem autologous bone marrow or peripheral stem cell transplantation):

  • A meta-analysis of six randomized clinical trials enrolling 1,803 patients compared single autologous hematopoietic cell transplantation with tandem autologous hematopoietic cell transplantation.

    • There was no difference in OS (HR, 0.94; 95% CI, 0.77–1.14) or in EFS (HR, 0.86; 95% CI, 0.70–1.05).[]

  • A prospective randomized trial of 758 patients who completed induction therapy in less than 12 months compared ASCT plus lenalidomide maintenance, tandem ASCT, and ASCT plus VRd maintenance.[]

    • There was no difference in 38-month PFS (53.9%−58.5%) and OS (81.8%−85.4%) among these three randomized groups.[]
  • Five different groups have compared single or tandem autologous transplants with one autologous transplant followed by a reduced-intensity conditioning allograft from a human leukocyte antigen (HLA)-identical sibling; treatment assignment was based on the presence or absence of an HLA-identical sibling. The results have been discordant for survival in these nonrandomized trials.[–]
  • Six clinical trials compared the outcomes of patients receiving tandem autologous transplant with those of patients receiving a reduced-intensity allogeneic SCT after autologous transplant. Patients were assigned to the latter treatments based on the availability of an HLA-matched donor. Two meta-analyses of these data showed that although the complete remission rate was higher in patients undergoing reduced-intensity allogeneic SCT, OS was comparable because of an increased incidence of nonrelapse mortality with allogeneic transplant.[,]

A Cochrane review of 14 controlled studies found none of the trials helpful for contemporary treatment decisions regarding single versus tandem transplants.[] None of the trials employed bortezomib or lenalidomide, and the sharp decrease in compliance with a second transplant complicated sample-size calculations for sufficient statistical power.

Allogeneic bone marrow or peripheral stem cell transplantation

Evidence (allogeneic bone marrow or peripheral stem cell transplantation):

Many patients are not young enough or healthy enough to undergo these intensive approaches. A definite graft-versus-myeloma effect has been demonstrated, including regression of myeloma relapses after the infusion of donor lymphocytes.[]

Favorable prognostic features included the following:

  • Low tumor burden.
  • Responsive disease before transplant.
  • Application of transplantation after first-line therapy.

Myeloablative ASCT has significant toxic effects (15%–40% mortality), but the possibility of a potent and possibly curative graft-versus-myeloma effect in a minority of patients may offset the high transplant-related mortality.[–] In one anecdotal series of 60 patients who underwent ASCT, six of the patients relapsed between 6 and 12 years, suggesting that late relapses still occur with this type of consolidation.[]

The lower transplant-related mortality from nonmyeloablative approaches has been accompanied by a greater risk of relapse.[] Since the introduction of lenalidomide and bortezomib, a trial exploring donor versus no donor comparison of ASCT versus autologous SCT and nonmyeloablative allogeneic SCT in 260 untreated patients showed no difference in PFS or OS.[] This result contrasted with two older trials (before introduction of lenalidomide and bortezomib), which suggested improvement of PFS and OS with a sibling donor.[,] Given the lack of evidence so far that the high-risk patients benefit from allogeneic SCT in this era of novel new agents, it remains debatable whether ASCT should be offered in the first-line setting outside the context of a clinical trial.[,]

Six clinical trials compared the outcomes of patients receiving tandem autologous transplant to those of patients receiving a reduced-intensity ASCT after autologous transplant. Patients were assigned to the latter treatments based on the availability of an HLA-matched donor. Two meta-analyses of these data showed that although the complete remission rate was higher in patients undergoing reduced-intensity ASCT, OS was comparable because of an increased incidence of nonrelapse mortality with allogeneic transplant.[,]

Salvage autologous bone marrow or peripheral stem cell transplantation after relapse from first transplantation

After relapsing more than 24 months after ASCT, 174 patients received reinduction therapy and were then randomly assigned to receive either high-dose melphalan and salvage ASCT or oral weekly cyclophosphamide.[] With a median follow-up of 52 months, the median OS was superior for salvage ASCT: 67 months (95% CI, 55–not estimable) versus 52 months (42–60); HR, 0.56 (0.35–0.90, P = .017).[,]

In a retrospective review of 233 patients with refractory myeloma or relapsed and refractory myeloma who underwent a salvage autologous SCT, 81% of patients achieved a partial response (PR) or better.[]

Maintenance Therapy

Myeloma patients who respond to treatment show a progressive fall in the M protein until a plateau is reached; subsequent treatment with conventional doses does not result in any further improvement. This has led investigators to question how long treatment should be continued. No clinical trial has directly compared a consolidation approach with a maintenance approach to assess which is better in prolonging remission and, ultimately, survival.[] Most clinical trials employ one or both.[,] Maintenance trials with glucocorticosteroids [,] and with interferon [] showed very minor improvements in remission duration and survival but with toxicities that outweighed the benefits. The efficacy and tolerability of thalidomide, lenalidomide, and bortezomib in the induction and relapse settings has made these agents attractive options in maintenance trials.[]

Lenalidomide maintenance therapy

Evidence (lenalidomide maintenance therapy):

  • A prospective randomized trial of 460 patients with newly diagnosed multiple myeloma who had completed induction therapy and ASCT compared lenalidomide maintenance with placebo.[]

    • With a median follow-up of 91 months, the median OS for the lenalidomide maintenance group was 113.8 months (95% CI, 100.4 to not reached) versus 84.1 months for the placebo group (range, 73.8−106.0 months; HR, 0.61; 95% CI, 0.46−0.80; P = .0004).[]
    • This translated to a 5-year OS of 76% (95% CI, 70%−81%) for the lenalidomide group versus 64% (95% CI, 58%−70%) for the placebo group.

  • A prospective randomized trial evaluated lenalidomide maintenance in 1,917 patients newly diagnosed with or without transplantation.[]

    • With a median follow-up of 31 months, lenalidomide showed improved median PFS, 39 months (95% CI, 36−42) versus 20 months (range, 18−22 months) (HR, 0.46; 95% CI, 0.41−0.53; P < .0001), but lenalidomide failed to significantly improve 3-year OS, 78.6% (95% CI, 75.6%−81.6%) versus 75.8% (72.4%−79.2%) (HR, 0.87; 95% CI, 0.73−1.05; P = .15).[]

  • A meta-analysis included 1,208 patients newly diagnosed after autologous SCT.[]

    • With a median follow-up of 79.5 months, OS was not reached for the lenalidomide maintenance group versus 86 months for the placebo or observation group (HR, 0.75; 95% CI, 0.63‒0.90, P = .001).[]

  • A meta-analysis of 7,730 patients in randomized clinical trials investigated lenalidomide or thalidomide maintenance in patients with newly diagnosed myeloma, with or without transplantation.[]

    • The immunomodulatory maintenance therapy significantly improved PFS (HR, 0.62; 95% CI, 0.57−0.67; P <.001), but failed to significantly improve OS (HR, 0.93; 95% CI, 0.85−1.01; P = .082).[]

  • A meta-analysis of 5,073 patients in randomized clinical trials investigated maintenance therapy in patients with newly diagnosed myeloma.[]

    • Lenalidomide (with or without prednisone) significantly improved PFS (HR, 0.47; 95% CI, 0.39−0.55), but also failed to significantly improve OS (HR, 0.76; 95% CI, 0.51−1.16).[]

  • A randomized, prospective trial of lenalidomide maintenance versus no maintenance after induction with melphalan and prednisone or melphalan, prednisone, and lenalidomide included patients aged 65 years and older who were not eligible for transplantation.[]

    • The results showed a 66% reduction in the rate of progression (HR, 0.34; P < .001), which translated to an EFS of 31 months versus 14 months in favor of maintenance lenalidomide.[]

All of these trials showed an increase in myelodysplasia or acute leukemia from 3% to 7%, consistent with other studies of lenalidomide. This increased risk is mostly seen in patients with previous exposure to alkylating agents. Doses of 5 mg to 15 mg a day have been utilized either continuously or with 1 week off every month.

Proteasome inhibitor maintenance therapy

Evidence (proteasome inhibitor maintenance therapy):

  • In a prospective randomized trial of 656 newly diagnosed patients with at least a PR after standard induction therapy followed by autologous SCT, ixazomib (the oral proteasome inhibitor) was compared with placebo.[]

    • With a median follow-up of 31 months, the ixazomib maintenance improved medial PFS, 26.5 months (95% CI, 23.7−33.8) versus 21.3 months (18.0−24.7) (HR, 0.72; 95% CI, 0.58−0.89; P = .0023).[] There was no increase in second malignancies with the proteasome inhibitor (3% for both groups).

  • In 511 previously untreated patients not eligible for transplant and aged 65 years or older, a randomized comparison of bortezomib, melphalan, prednisone, thalidomide and subsequent maintenance using bortezomib plus thalidomide versus bortezomib, melphalan, and prednisone (with no maintenance) showed superiority of the arm with thalidomide and bortezomib during induction and maintenance.

    • With a median follow-up of 47 months, 3-year PFS was 55% versus 33% (P < .01), and 5-year OS was 59% versus 46% (P = .04).[]
    • Because of trial design, it is unclear whether the improved results were caused by the addition of thalidomide during the induction or by the use of maintenance therapy with bortezomib and thalidomide.

Summary: After ASCT, patients are offered lenalidomide maintenance therapy based on the consistent PFS and occasional OS benefits previously described. But short-term and long-term toxicities, and financial toxicities, may prevent implementation.[,] High-risk patients, especially those with del(17p) or t(14;16), may require bortezomib maintenance (with or without lenalidomide), but this approach is not evidence-based and confirmatory clinical trials are required.[,]

Management and Prevention of Myeloma Bone Disease

Myeloma bone disease is a consequence of increased osteoclastic activity and agents that inhibit osteoclasts are an important component of myeloma therapy.[] The bisphosphonates pamidronate and zoledronate are used most often, via intravenous infusion, but the RANKL monoclonal antibody inhibitor denosumab, given subcutaneously, is also effective, especially when renal dysfunction precludes the use of bisphosphonates.[,]

Zoledronate (bisphosphonate)

Evidence (zoledronate):

  • A randomized, prospective trial of 1,970 patients compared intravenous zoledronate with oral clodronate in newly diagnosed patients receiving induction chemotherapy with or without consolidation.[] With a median follow-up of 3.7 years, zoledronate improved median OS from 44.5 months to 50.0 months (HR, 0.84; CI, 0.74–0.96; P = .0118).[] In this trial, both bisphosphonates were continued until the time of relapse. As expected, skeletal-related events were also reduced in the zoledronate group (27% vs. 35%; P = .004).[,]
  • The improvement of the median OS with zoledronate was confirmed in a Cochrane network meta-analysis.[] This meta-analysis also showed that 6 to 15 patients need treatment with bisphosphonates to prevent one skeletal-related event.
  • A clinical trial of zoledronate given once a month compared with zoledronate given every 12 weeks showed noninferiority for the 12-week regimen in 1,822 patients with bone metastases from breast cancer, prostate cancer, or multiple myeloma.[] However, this study included only 278 myeloma patients, and the evaluation of this subgroup was insufficiently powered to establish noninferiority for the 12-week regimen. Nonetheless, this trial is used as justification for implementing a 12-week schedule at the start of therapy or as soon as the maximal response has been reached.
  • Bisphosphonates are associated with infrequent long-term complications (in 3%–5% of patients), including osteonecrosis of the jaw and avascular necrosis of the hip.[,] (Refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation for more information on osteonecrosis of the jaw.) These side effects must be balanced against the potential benefits of bisphosphonates when bone metastases are evident.[] Bisphosphonates are usually given intravenously on a monthly basis for 2 years and then extended at the same schedule or at a reduced schedule (i.e., once every 3–4 months), if there is evidence of active myeloma bone disease.[,] The aforementioned randomized trial,[] which showed OS advantage, continued patients on bisphosphonates monthly until time of relapse.

Pamidronate (bisphosphonate)

Evidence (pamidronate):

  • A randomized, double-blind study of patients with stage III myeloma showed that monthly intravenous pamidronate significantly reduced pathologic fractures, bone pain, spinal cord compression, and the need for bone radiation therapy (38% skeletal-related events were reported in the treatment group vs. 51% in the placebo group after 21 months of therapy, P = .015).[] (Refer to the Pharmacologic Therapies for Pain Control section in the PDQ summary on Cancer Pain for more information on bisphosphonate therapy.)
  • A double-blind, randomized, controlled trial with 504 patients with newly diagnosed multiple myeloma compared 30 mg of pamidronate to 90 mg of pamidronate and found there was no difference in skeletal-related events, but there was less osteonecrosis (2 events vs. 8 events) seen in the low-dose group.[]
  • A randomized comparison of pamidronate versus zoledronic acid in 518 patients with multiple myeloma showed equivalent efficacy in regard to skeletal-related complications (both were given for 2 years).[]

Denosumab (RANKL inhibitor)

Evidence (denosumab):

  1. In a prospective randomized double-blind trial, 1,718 patients with newly diagnosed myeloma and at least one documented lytic bone lesion received either zoledronate or denosumab.[]

    • The study met its primary endpoint of noninferiority for denosumab compared with zoledronate (HR, 0.98; 95% CI, 0.85‒1.14; P = .01 for noninferiority).[]
    • Denosumab is significantly more expensive than the bisphosphonates, which are available in generic form.

Unlike bisphosphonates, the reversible mechanism of action for denosumab may result in rebound fractures if it is discontinued, although this theoretical concern for myeloma patients may be mitigated by continuous maintenance therapy.[]

Radiation therapy for bone lesions

Lytic lesions of the spine generally require radiation if any of the following are true:

  1. They are associated with an extramedullary (paraspinal) plasmacytoma.
  2. A painful destruction of a vertebral body occurred.
  3. CT or MRI scans present evidence of spinal cord compression.[]

Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy. (Refer to the PDQ summary on Cancer Pain for more information on back pain.)

Extensive radiation of the spine or long bones for diffuse osteoporosis may lead to prolonged suppression of hemopoiesis and is rarely indicated.[]

Bisphosphonates are useful for slowing or reversing the osteopenia that is common in myeloma patients.[]

Initial therapy of MM varies depending on disease risk stratification and functional status, which will help determine transplant eligibility. Patients who are fit for transplant typically receive induction therapy for a few months to decrease the tumor burden, followed by peripheral blood stem cell mobilization and harvesting, and finally, an autologous transplant. For transplant-ineligible patients, common regimens include lenalidomide and dexamethasone, bortezomib and dexamethasone, melphalan/prednisone/bortezomib, and other bortezomib-based regimens. Novel agents such as oral proteasome inhibitors (e.g., ixazomib) and monoclonal antibodies (e.g., daratumumab) have shown promising results.

For symptomatic anemia, blood transfusion and sometimes erythropoiesis-stimulating agents are used.

Plasmapheresis is used for hyperviscosity syndrome.

Hypercalcemia and renal failure treatments include hydration, glucocorticoids, bisphosphonates, calcitonin, and hemodialysis. Patients with MM should take measures to reduce renal damage by avoiding nephrotoxic agents (e.g., NSAIDs, contrast agents, diuretics, aminoglycosides) and maintaining good hydration. Many medications used for MM treatment may require dose adjustment in order to reduce kidney damage.

MM patients are more prone to infections. Prophylactic measures include yearly influenza vaccine, pneumococcal vaccine at the time of diagnosis, prophylactic antibiotics and hematopoietic growth factors during the first few months of chemotherapy induction, intravenous immunoglobulin for patients with recurrent infections.

Bone pain usually requires opioids for control.

Spinal cord compression by vertebral fracture or plasmacytoma is a medical emergency and should be managed aggressively with radiotherapy and orthopedic consultation.

Medical Oncology

Initial Therapy

The preferred treatment for those under the age of 65 is chemotherapy, commonly with bortezomib-based regimens, and lenalidomide-dexamethasone, followed by high-dose therapy with melphalan and autologous hematopoietic stem-cell transplantation (ASCT). Autologous transplantation prolongs overall survival and complete remission, but is not considered curative. Allogenic stem cell transplantation can be theoretically curative but is not used as frontline therapy owing to its high treatment-related mortality in older patients, who make up most MM cases.

People older than age 65 and those with a significant concurrent illness often cannot tolerate stem cell transplantation. The standard of care has been chemotherapy with combinations of melphalan, bortezomib, and lenalidomide plus low-dose dexamethasone or prednisone. Newer agents like carfilzomib and elotuzumab are also being used recently.

Relapse

Several newer options have been recently approved for the management of advanced disease:

  • Ixazomib, an orally available proteasome inhibitor, in combination with lenalidomide and dexamethasone
  • Panobinostat, an orally available histone deacetylase inhibitor, in combination with bortezomib and dexamethasone
  • Carfilzomib, a newer generation proteasome inhibitor used for the treatment of relapsed or refractory disease, either as a single agent or in combination with dexamethasone and/or lenalidomide
  • Elotuzumab, an immunostimulatory humanized monoclonal antibody against SLAMF7 (CD139)
  • Daratumumab, a monoclonal antibody against CD38

Treatment Options for Relapsed or Refractory Multiple Myeloma

Relapses occur for almost all patients after induction therapy, consolidation with autologous stem cell transplantation (ASCT), and maintenance therapy. During initial therapy, some patients respond poorly or their disease progresses. The general strategy is to apply new therapies sequentially as required. In younger fit patients, reinduction therapy with response may be consolidated with an ASCT or allogeneic SCT in some cases. Sometimes, when relapse occurs 1 year or more after initial therapy, the same drugs can be administered a second time.

A subgroup of patients who do not achieve a response to induction chemotherapy have stable disease and enjoy a survival prognosis that is as good as that for responding patients.[,] When the stable nature of the disease becomes established, these patients can discontinue therapy until the myeloma begins to progress again. Others with primary refractory myeloma and progressive disease require a change in therapy.

Monoclonal antibodies

Daratumumab

Daratumumab is a monoclonal antibody targeting CD38 that can be given on its own but is usually given in combination with other drugs. Although it is given as an infusion, the subcutaneous formulation has equivalent efficacy and fewer adverse events.[]

Evidence (daratumumab):

  • In a prospective, randomized trial, 498 previously treated patients were randomly assigned to receive daratumumab plus bortezomib plus dexamethasone or bortezomib plus dexamethasone.[]

    • With a median follow-up of 7.4 months, the median progression-free survival (PFS) was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio [HR], 0.39; 95% confidence interval [CI] 0.28‒0.53; P < .001).[]

  • In a prospective, randomized trial, 569 previously treated patients were randomly assigned to receive daratumumab plus lenalidomide plus dexamethasone or lenalidomide plus dexamethasone.[]

    • With a median follow-up of 13.5 months, the 1-year PFS was 81.5% in the daratumumab group versus 59.0% in the control group (HR, 0.37; 95% CI, 0.27‒0.52; P < .001).[]

  • Several phase I and phase II trials evaluated daratumumab as a single agent for relapsed or refractory multiple myeloma.[–]

    • With a median follow-up of 12 to 17 months, the overall response rate (ORR) was 31% and 36%, with minimal response or stable disease in about 40% of patients.[–]

Daratumumab has also been combined with carfilzomib and dexamethasone in a phase I study of 85 patients with refractory or resistant disease.[]

Elotuzumab

Elotuzumab is a monoclonal antibody directed at SLAMF7 (single-lymphocyte activating molecular F7).

Evidence (elotuzumab):

  • A prospective randomized trial of 117 patients who had relapsed or were refractory to both lenalidomide and a proteasome inhibitor were randomly assigned to receive elotuzumab, pomalidomide, and dexamethasone versus pomalidomide and dexamethasone alone.[]

    • With a median follow-up of 9.1 months, the median PFS was 10.3 months for the elotuzumab combination compared with 4.7 months for the control group (HR, 0.54; 95% CI, 0.34‒0.86; P = .008).[]

  • In a prospective, randomized trial of 646 patients with relapsed or refractory myeloma, elotuzumab was combined with lenalidomide and dexamethasone and compared with lenalidomide and dexamethasone alone.[]

    • With a median follow-up of 2.8 years, the group receiving elotuzumab had a superior 3-year PFS of 26% versus 18% (HR, 0.73; 95% CI, 0.60–0.89; P = .0014) and improved 3-year OS of 44% versus 39% (P = .0257).

Proteasome inhibitors

Bortezomib

Bortezomib is the first-in-class proteasome inhibitor that is given subcutaneously on a weekly basis for 3 of every 4 weeks; the subcutaneous route is preferred to the IV route because it causes significantly less neuropathy and no loss of responsiveness.[–] Bortezomib is metabolized and cleared by the liver, and it appears to be active and well tolerated in patients with renal impairment.[,] More than 6 months after completion of bortezomib induction therapy, bortezomib can be given again with a 40% ORR, according to a meta-analysis of 23 phase II studies.[]

Evidence (bortezomib):

  • A prospective randomized study of 669 patients with relapsed myeloma compared bortezomib given by IV with high-dose oral dexamethasone.[]

    • With a median follow-up of 22 months, the median OS was 29.8 months for bortezomib versus 23.7 months for dexamethasone (HR, 0.77; P = .027) even though the trial allowed crossover after relapse.[]

  • A prospective, randomized trial (NCT00103506) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone.[]

    • With a median follow-up of 7.0 months, the combination was better for 1-year OS (82% vs. 75%, P = .05).[]

  • A prospective, randomized trial of 260 newly diagnosed patients aged 65 years and older compared bortezomib, melphalan, and prednisone (VMP) with bortezomib, thalidomide, and prednisone (VTP).[]

    • With a median follow-up of 72 months, the median OS favored the VMP arm, 63 months versus 43 months for the VTP group (HR, 0.67; 95% CI, 0.49–0.91; P = .01).[]
Carfilzomib

Carfilzomib is a second-generation proteasome inhibitor that is given intravenously (IV) (unlike the subcutaneous route for bortezomib); most studies have employed twice-weekly administration, but once-weekly administration appears at least equally efficacious and safe.[]

Evidence (carfilzomib):

  • A randomized prospective trial included 578 relapsed or refractory myeloma patients.[]

    • The median PFS of patients who received carfilzomib once a week was significantly better, 11.2 months (95% CI, 8.6‒13.0 months), than twice a week, 7.6 months (95% CI, 5.8‒9.2 months) (HR, 0.69; 95% CI, 0.54‒0.83; P = .0029).[]

  • In a prospective randomized trial of 792 patients with relapsed or refractory myeloma, the combination of carfilzomib, lenalidomide, and dexamethasone was compared with lenalidomide plus dexamethasone.[]

    • With a median follow-up of 67.1 months, median overall survival (OS) in the carfilzomib arm was 48.3 months (95% CI, 42.4‒52.8 months) versus 40.4 months (95% CI, 33.6‒44.4 months) (HR, 0.79; 95% CI, 0.67‒0.95; one-sided P = .009).[]
    • In a preplanned subgroup analysis, patients with high-risk cytogenetics (i.e., t(4;14), t(14;16), del(17p)) also had improved PFS for the triplet (23 months vs. 14 months; HR, 0.70; 95% CI, 0.43−1.16; one-sided P = .083) and response rates, but the carfilzomib combination did not abrogate the worse prognosis.[]

  • A prospective, randomized study (NCT01568866) of 929 patients compared carfilzomib and dexamethasone with bortezomib and dexamethasone.[]

    • With a median follow-up of 37 months, the median OS was 47.6 months (95% CI, 42.5–not evaluable) for the carfilzomib combination compared with 40.0 months (95% CI, 32.6–42.3) for the bortezomib combination (HR, 0.79; 95% CI, 0.65–0.96; P = .020).[]
  • Cardiovascular adverse events such as heart failure, chest pain, and acute coronary syndrome (grade 3 or higher) occurred in 25% of patients, especially in the first 3 months of therapy.[,]
Ixazomib

Ixazomib is a second-generation proteasome inhibitor that is given orally on a weekly basis for 3 of every 4 weeks.

Evidence (ixazomib):

  • In a prospective, randomized trial involving 722 patients with relapsed or refractory myeloma, ixazomib combined with lenalidomide and dexamethasone was compared with a placebo combined with lenalidomide and dexamethasone.[,]

    • With a median follow-up of 2 years, the median PFS with the ixazomib combination was 20.6 months versus 14.7 months for the placebo group (HR, 0.66; 95% CI, 0.47–0.93; P = .016).[]
    • Improved PFS was also seen for high-risk patients (defined by fluorescence in situ hybridization and cytogenetics).[]
    • No grade 3 or 4 neuropathy was seen in any patient treated with ixazomib.

Immunomodulatory agents

Pomalidomide

Pomalidomide is a third-generation immunomodulatory agent that shows some myelosuppression and an increased incidence of thromboembolic events, as noted with lenalidomide and thalidomide (requiring thromboprophylaxis with aspirin at least), but very little peripheral neuropathy compared with other agents.

Evidence (pomalidomide):

  • In a prospective randomized trial of 117 patients who had relapsed or were refractory to both lenalidomide and a proteasome inhibitor, patients were randomly assigned to receive elotuzumab, pomalidomide, and dexamethasone versus pomalidomide and dexamethasone alone.[]

    • With a median follow-up of 9.1 months, the median PFS was 10.3 months for the elotuzumab combination compared with 4.7 months for the control group (HR, 0.54; 95% CI, 0.34‒0.86; P = .008).[]

  • In a prospective randomized trial of 559 patients with relapsed or refractory myeloma and previous treatment with lenalidomide, patients were randomly assigned to receive pomalidomide plus bortezomib and dexamethasone versus bortezomib and dexamethasone alone.[]

    • With a median follow-up of 15.9 months, the median PFS favored the pomalidomide combination, 11.2 months (95% CI, 9.7−13.7) versus 7.1 months (95% CI, 5.9−8.9) (HR, 0.61; 95% CI, 0.49−0.77; P <.001).[]

  • For 302 patients with relapsed or refractory disease, pomalidomide and dexamethasone (40 mg weekly) was compared with a higher-dose dexamethasone regimen (40 mg daily for 4 days every 8 days).[]

    • With a median follow-up of 10.0 months, the PFS was superior for the pomalidomide arm, 4.0 months versus 1.9 months (HR, 0.48; 95% CI, 0.39–0.60; P < .0001)[]
Lenalidomide

Lenalidomide is a second-generation immunomodulatory agent that shows increased incidence of thromboembolic events as noted with pomalidomide and thalidomide (requiring thromboprophylaxis with aspirin at least), increased incidence of myelosuppression (more than pomalidomide), and an increased incidence of neuropathy (less than thalidomide, but more than pomalidomide).[–]

Evidence (lenalidomide):

  • Two prospective randomized and placebo-controlled studies of 351 and 353 patients with relapsed myeloma compared lenalidomide plus high-dose dexamethasone versus high-dose dexamethasone alone.[,]

    • With a median follow-up of 16 to 26 months, the median OS was 29.6 months or more (not reached in one trial) versus 20.2 months to 20.6 months in the control group (HR, 0.66; 95% CI, 0.45‒0.96; P = .03 in one study [] and P < .001 in the other study).[]

  • A prospective, randomized study of 1,623 transplant-ineligible, previously untreated myeloma patients compared lenalidomide and dexamethasone given until disease progression with a 72-week induction regimen with melphalan, prednisone, and thalidomide (MPT) for 72 weeks.[]

    • With a median follow-up of 46 months, there was improved OS for the lenalidomide group, with 4-year OS of 52% versus 38% (HR, 0.72; 95% CI, 0.54–0.96; P = .02).[]
Thalidomide

Thalidomide is a first-generation immunomodulatory agent that is not often used because of its sedative and constipating effects, its significant and potentially debilitating neuropathy, and its thrombogenic effect (thromboprophylaxis is required).[,] Very little myelosuppression is seen with this agent.

Late in the disease course, when all other options have failed, thalidomide can be employed, sometimes with durable responses.[] By utilizing a low dose (50 mg by mouth every day), significant sedation, constipation, and neuropathy may be avoided. Thromboprophylaxis with aspirin, warfarin, or low-molecular-weight heparin is required; the choice of therapy depends on pre-existing risk factors.

Evidence (thalidomide):

  1. A meta-analysis of 1,685 previously untreated patients considered six randomized prospective trials comparing thalidomide, melphalan, and prednisone versus melphalan and prednisone alone.[]

    • The addition of thalidomide improved median OS from 32.7 months to 39.3 months (HR, 0.83; 95% CI, 0.73–0.94; P = .004).[]

Chemotherapy (cytotoxic agents)

Regimens:

  • Melphalan and prednisone.[,]
  • Vincristine + doxorubicin (infusion) + dexamethasone (VAD).[,]
  • Cyclophosphamide (+ bortezomib + dexamethasone in the CyBorD regimen).[,]
  • Pegylated liposomal doxorubicin (in a modified VAD regimen) [,] or combined with bortezomib and dexamethasone.[]

Evidence (chemotherapy):

  • A meta-analysis of randomized prospective trials compared melphalan and prednisone to combinations of other cytotoxic agents; no differences were noted in PFS or OS.[]
  • The VAD regimen has shown activity in previously untreated patients and in relapsed patients, with response rates ranging from 60% to 80%.[,]Because of logistics problems delivering a 96-hour infusion of doxorubicin, substitution with pegylated liposomal doxorubicin provides comparable response rates.[,]

Chemotherapy alone has been used to obtain a clinical remission after exhausting most of the new regimens, allowing improvement in performance status that may permit subsequent use of clinical trials investigating alternative therapies.

CAR T-cells

Cellular therapy for refractory myeloma has been introduced, consisting of autologous T-cells transduced with an anti-CD19 chimeric antigen receptor (so-called CAR T-cells) after myeloablative chemotherapy and ASCT, with anecdotal responses.[–] Other molecular targets and expanded clinical approaches are being investigated.[]

Selinexor

Selinexor is a selective inhibitor of nuclear export compounds that blocks exportin 1 (which activates tumor suppressor proteins), inhibits nuclear factor κB, and reduces oncoprotein mRNA translation.

Selinexor (evidence):

  • In a phase IIB multicenter study, 122 patients with multiply resistant myeloma refractory to a proteasome inhibitor, an immunomodulatory agent, and daratumumab received oral selinexor and dexamethasone. High-risk cytogenetics were present in 53% of patients. Patients had received a median of seven previous regimens.

    • A partial response (PR) rate or better was observed in 26% of patients (95% CI, 19%−35%), with a median duration of response of 4.4 months. The median PFS was 3.7 months; the median OS was 8.6 months.[]

  • In a phase II study of 42 patients with relapsed or refractory disease, selinexor was combined with bortezomib and dexamethasone.[]

    • A partial response or better was observed in 63% of patients, with a median PFS of 9.0 months.[]

Venetoclax

Venetoclax is a selective BCL-2 inhibitor that induces apoptosis in myeloma cells, particularly in those with t(11;14) which expresses high levels of bcl2.

Evidence (venetoclax):

  1. In a phase I study of 66 heavily pretreated patients with relapsed or refractory myeloma, 30 patients harbored a t(11;14) translocation.[]

    • Among all 66 patients, the ORR was 21%, and 15% of patients achieved very good partial response or better. For those with t(11;14), the ORR was 40%, with 27% achieving a very good partial response or better.[]

Histone deacetylase inhibitors

Panobinostat is a potent pan-deacetylase inhibitor that combines with proteasome inhibition to block removal of overproduced, misfolded proteins from the myeloma cell, which impairs myeloma cell survival.

  1. A prospective, randomized, placebo-controlled study of 768 patients with relapsed or relapsed and refractory myeloma compared panobinostat, bortezomib, and dexamethasone with bortezomib plus dexamethasone alone.[]

    • With a median follow-up of 6 months, the median PFS was longer in the panobinostat group, 12 months versus 8 months (HR, 0.63; 95% CI, 0.52–0.76; P < .0001).[]

Corticosteroids

Dexamethasone dosage has been evaluated in two prospective randomized trials.

  1. A prospective, randomized study (ECOG-E4A03) of 445 previously untreated patients with myeloma compared lenalidomide and high-dose dexamethasone (40 mg on days 1–4, 9–12, and 17–20, every 28 days) with lenalidomide and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22, every 28 days).[]

    • With a median follow-up of 36 months, 2-year OS favored the low-dose dexamethasone arm (87% vs. 75%, P = .006), despite no difference in PFS.[]
    • The increased deaths on the high-dose dexamethasone arm were attributed to cardiopulmonary toxicity.
    • Deep venous thromboses (DVTs) were also more frequent in the high-dose arm (25% vs. 9%). Patients in the low-dose dexamethasone arm with lenalidomide experienced less than 5% DVT with aspirin alone.
  2. A prospective randomized trial of melphalan and prednisone versus melphalan and high-dose dexamethasone showed no difference in PFS or OS, but there was an increase in infection in the high-dose dexamethasone arm.[]

On the basis of these trials, all ongoing trials and regimens utilize the low-dose dexamethasone schedule in combination with other therapeutic agents: 40 mg dexamethasone (oral or IV) weekly in younger patients or fit older patients, or 20 mg (oral or IV) in less-fit older patients.

Several newer options are approved for the management of advanced disease:

  • Belantamab mandolin — a monoclonal antibody against B-cell maturation antigen (BCMA), also known as CD269, indicated for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.[rx][rx]
  • Carfilzomib — a proteasome inhibitor that is indicated:
    • as a single agent in people who have received one or more lines of therapy
    • in combination with dexamethasone or with lenalidomide and dexamethasone in people who have received one to three lines of therapy[rx]
  • Daratumumab — a monoclonal antibody against CD38 indicated in people who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to a proteasome inhibitor and an immunomodulatory agent[rx]
  • Elotuzumab — an immunostimulatory humanized monoclonal antibody against SLAMF7 (also known as CD319) indicated in combination with lenalidomide and dexamethasone in people who have received one to three prior therapies[rx]
  • isatuximab – a monoclonal antibody against CD38 indicated in combination with pomalidomide and dexamethasone for the treatment of adults with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.[rx][rx]
  • ixazomib — an orally available proteasome inhibitor indicated in combination with lenalidomide and dexamethasone in people who have received at least one prior therapy[rx]
  • panobinostat — an orally available histone deacetylase inhibitor used in combination with bortezomib and dexamethasone in people who have received at least two prior chemotherapy regimens, including bortezomib and an immunomodulatory agent[rx]
  • selinexor — an orally available selective inhibitor of nuclear export indicated in combination with dexamethasone in people who have received at least four prior therapies and whose disease does not respond to at least two proteasome inhibitors, two immunomodulatory agents and an anti-CD38 monoclonal antibody[rx]

Stem cell transplant

Stem cell transplant can be used to treat multiple myeloma.[rx] Stem cell transplants come with a risk of a graft-versus-host-disease. Mesenchymal stromal cells may reduce the all-cause mortality if they are used for a therapeutic reason and the therapeutic use of MSCs may increase the complete response of acute and chronic GvHD, but the evidence is very uncertain.[rx] The evidence suggests that MSCs for prophylactic reason result in little to no difference in the all-cause mortality, in the relapse of malignant diseases and in the incidence of acute GvHD.[rx] The evidence suggests that MSCs for prophylactic reason reduce the incidence of chronic GvHD.[rx]

Staging

Main Staging Systems

International Staging System (ISS)

Incorporates data on the levels of serum-beta-2 microglobulin (B2M) and serum albumin to divide disease burden into three stages with prognostic significance:

  • Stage 1: B2M less than 3.5 mg/L and serum albumin greater than or equal to 3.5 g/dl
  • Stage 2: Neither stage 1 nor stage 3
  • Stage 3: B2M greater than or equal to 5.5 mg/L

Median overall survival for patients with ISS stages 1, 2, and 3 are 62, 44, and 29 months, respectively.

Revised International Staging System (R-ISS)

Provides prognostic information that is more robust than that from the original ISS.

  • Stage 1: B2M less than 3.5 mg/L, albumin greater than or equal to 3.5 g/dL, normal LDH, and standard-risk cytogenetics
  • Stage 2: Neither stage 1 nor stage 3
  • Stage 3: B2M greater than 5.5 mg/L and high-risk cytogenetics* or elevated LDH

del(17p), and/or t(4;14), and/or t(14,16)

Durie-Salmon Staging System

For many years, before the introduction of the ISS, the Durie-Salmon staging system was the standard for risk stratification. It is based on the amount of hemoglobin and calcium in the blood, the presence of bone damage on x-rays, and the amount of monoclonal protein in the blood or urine. It divides patients into three stages (I, II, and III) and sub-classifies them further into groups A and B according to serum creatinine level.

Complications

Common manifestations and complications of multiple myeloma include hypercalcemia, renal insufficiency, infection, skeletal lesions, and anemia. Less common complications include venous thromboembolism and hyperviscosity syndrome. 

  • Renal insufficiency – Can be acute or chronic. A variety of etiologic mechanisms may be involved, including those related to the excess production of monoclonal light chains (light- chain cast nephropathy), deposition of intact light chains causing the nephrotic syndrome, light chain amyloidosis, hypercalcemia, hyperuricemia, dehydration. Treatment is directed at the underlying cause.
  • Infection – The risk of infection is highest in the first 3 to 4 months of induction therapy, so prophylactic antibiotics are required for the first few months. Factors contributing to the increased risk of infection include impaired lymphocyte function, suppression of normal plasma cell function, hypogammaglobulinemia, and chemotherapy-induced neutropenia. The most common infections are pneumonia and urinary tract infections, mostly with organisms such as Streptococcus pneumonia, Haemophilus influenza, and Escherichia coli.
  • Skeletal lesions – Myeloma bone disease results from overexpression of RANKL by bone marrow stroma. RANKL activates osteoclasts, which resorb bone. Bone breakdown leads to the release of calcium into the blood, leading to hypercalcemia and symptoms of kidney failure that may develop acutely or chronically. It manifests as severe bone pain, pathological fractures, spinal cord compression.
  • Hypercalcemia – May be asymptomatic or cause anorexia, fatigue, constipation, polydipsia, polyuria, confusion, or stupor. Treatment depends on clinical severity and rapidity of installation of hypercalcemia. It includes hydration, glucocorticoids, bisphosphonates, calcitonin, and/or hemodialysis.
  • Hyperviscosity syndrome – Presents as oronasal bleeding, blurred vision, retinal hemorrhage, seizure, and other neurologic symptoms, confusion, dyspnea, and heart failure. Plasmapheresis promptly relieves symptoms.
  • Neuropathy – Related to the disease itself or side effects of treatment with drugs such as thalidomide, bortezomib, or vincristine
  • Thrombosis – Immunomodulating agents such as thalidomide and lenalidomide are associated with increased thrombotic risk.
  • Anemia – The use of erythropoietin or darbepoetin is recommended if hemoglobin is <10 g/dL. Hemoglobin should not be allowed to increase over 12 g/dL (risk of thrombosis). Patients with severe symptomatic anemia should also receive red cell transfusions.
  • Bony lesions and bone pain – Patients should be assessed thoroughly for pain especially back pain, which may be a sign of impending cord compression. NSAIDs should be avoided (risk of renal damage). Patients with mild pain benefit from regular paracetamol while patients with moderate-severe pain will require tramadol or opioids. Focal lytic lesions causing severe pain not responding to therapy may respond to a single fraction 8-10Gy of RT. Pathologic fractures or impending fractures of long bones require stabilization with an intramedullary rod. Vertebral compression fractures may benefit from kyphoplasty or vertebroplasty.
  • Cord compression – This is treated as an emergency with RT plus high dose dexamethasone. Surgical decompression is only necessary if the neurologic deficit does not improve or in cases where the compression is due to a bony fragment or retropulsion bone.
  • Peripheral neuropathy – This is present in a minority of patients at diagnosis but is a frequent complication of treatment and progressive disease. It is managed by gabapentin or pregabalin, treating the disease, dose-adjustment of the causative drug, and treating any concomitant B12 deficiency.
  • Hyperuricemia and tumor lysis – Tumor lysis syndrome is uncommon in MM. Hydration and allopurinol (dose-adjusted in renal dysfunction) are used in patients with high disease burden.

References

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