Multiple Myeloma

Continuing Education Activity

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. This activity reviews the cause, pathophysiology, presentation, and diagnosis of MM and highlights the role of the interprofessional team in the management of this malignancy.


  • Describe the pathophysiology of multiple myeloma.
  • Review the evaluation of a patient suspected of having multiple myeloma.
  • Summarize the treatment options for multiple myeloma.
  • Outline the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by multiple myeloma.


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.


The exact etiology of multiple myeloma (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.[1]


Multiple myeloma represents 1.8% of all new cancer cases in the United States. It occurs predominantly in the geriatric population with a median age at diagnosis of about 70 years. The number of cases diagnosed annually is expected almost to double in 20 years. It has a male-to-female ratio of 3 to 2 and is more common among African-Americans.[2]


Multiple myeloma 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% 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.[3]

Although the exact causes of MGUS development and progression to MM remain unknown, the two 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.


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 multiple myeloma have several possible morphologies. Firstly, 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. Secondly, 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 the 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. Extramedullary plasmacytomas can present as deep-seated or superficial tumors. Macroglossia, papules, or nodules can occur in amyloidosis.


According to the National Comprehensive Cancer Network (NCCN) criteria, multiple myeloma is defined as smoldering (asymptomatic) or active (symptomatic).[4]

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%
  • 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, 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 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, a CT scan is performed to measure the size of soft tissue plasmacytomas.

Treatment / Management

Initial therapy of multiple myeloma 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.

Differential Diagnosis

Following is a list of important differentials of multiple myeloma:

Waldenstrom macroglobulinemia: Type of M protein is IgM, and the clinical features differ from those in MM.

Monoclonal gammopathy of undetermined significance (MGUS) 

  • No end-organ damage
  • Serum monoclonal protein less than 3 g/dl
  • Clonal bone marrow plasma cells less than 10%

Smoldering multiple myeloma

  • No end-organ damage
  • Monoclonal protein equal to or over 3 g/dl
  • Clonal bone marrow plasma cells 10% to 59%

Medical Oncology

Initial Therapy[5] 

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.


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


Main Staging Systems

International Staging System (ISS)[6]

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)[7]

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[8]

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.


Older patients will often have serious concomitant diseases, which affect survival. Younger patients have less treatment-related morbidity, and consequently, fare better.

In 2003, with high-dose therapy followed by autologous stem cell transplantation, median survival was estimated to be approximately 4.5 years, compared to a median of approximately 3.5 years with standard therapy. Overall, the 5-year survival rate is around 35%.[9]


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.[10]

  • 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 influenzae, 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 the 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.

Postoperative and Rehabilitation Care

According to multiple national center treatment guidelines, early palliative care for people with advanced MM at the time of diagnosis is highly recommended. It helps to address the symptoms and eases the unwanted side effects.

Deterrence and Patient Education

Patient education is crucial in the management of multiple myeloma. Patients should be given information on what multiple myeloma is and how it affects the body. They should also know the causes of multiple myeloma and what are the treatment options. They should also be made aware of the adverse effects of the drugs used in the management of multiple myeloma.

Enhancing Healthcare Team Outcomes

Treatment of multiple myeloma often requires an interprofessional approach:

  • Radiotherapy, neurosurgery, and/or orthopedic consultation in patients with spinal cord compression.
  • Nephrology consultation in cases of a severe renal compromise requiring dialysis.
  • Hematology-Oncology for bone marrow studies, plasmapheresis, transfusion support, chemo- and immunotherapy, stem cell harvesting, and transplantation.

Diagnosis is not always obvious, especially in older patients, given their increased comorbidities. MM should always be suspected in an elderly patient with normocytic anemia, bone pain, and evidence of renal dysfunction. The overall survival in MM has improved over the last decade due to more accurate diagnosis and risk stratification, a better understanding of how toxicity and frailty can affect prognosis, the discovery of novel agents, and advances in supportive care during the post-transplant period. Although still considered an incurable disease, the present 5-year survival rate is 48.5%.

Article Details

Article Author

Sara Albagoush

Article Editor:

Alexandre Azevedo


7/25/2021 6:30:24 PM

PubMed Link:

Multiple Myeloma



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