Multiple Myeloma

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Continuing Education Activity

Multiple myeloma is a clonal plasma cell proliferative disorder characterized by the abnormal increase of monoclonal paraprotein leading to evidence of specific end-organ damage. The consequences of undiagnosed disease are severe. This activity reviews the underlying cause, presentation, diagnosis, and treatment of multiple myeloma. The importance of early recognition, treatment, and an interprofessional approach is highlighted in this activity.


  • Describe the pathophysiology of multiple myeloma.
  • Review the appropriate steps in evaluating a patient suspected of having multiple myeloma.
  • Summarize the first-line therapy options for multiple myeloma.
  • Outline the adverse effects of the disease process as well as treatment-related side effects.


Multiple myeloma (MM) is a clonal plasma cell proliferative disorder characterized by the abnormal increase of monoclonal immunoglobulins. Unchecked, the excess production of these plasma cells can ultimately lead to specific end-organ damage. Most commonly, this is seen when at least one of the following clinical manifestations are present: hypercalcemia, renal dysfunction, anemia, or bone pain accompanied by lytic lesions. Obviously, the differential is broad with any of these symptoms and/or findings, but it is imperative MM be kept in mind as part of the differential as management is unique and improved outcomes are available with timely intervention is made.[1][2]


The exact etiology of multiple myeloma is unknown. However, frequent alterations and translocations in the promoter genes, especially chromosome 14, are commonly found in multiple myeloma and likely play a role in disease development.[3] In addition, other oncogenes such as NRAS, KRAS, and BRAF may participate in plasma cell proliferation.[4] Other factors contributing to disease occurrence include obesity, alcohol consumption, environmental causes such as insecticides, organic solvents, agent orange, and radiation exposure.[5][6]


Multiple myeloma is relatively uncommon and only represents about 1.8% of all new cancer cases diagnosed in the United States each year. It occurs predominantly in the geriatric population with a median age at diagnosis of about 70 years and is slightly more commonly seen in males than females (1.4:1). There seems to be an increased incidence in African American and black populations by as much as two-fold compared to Whites.[7][8]


MM is essentially a stage in the spectrum of monoclonal gammopathy. It is thought to arise from a pre-malignant, asymptomatic phase of clonal plasma cell growth called monoclonal gammopathy of undetermined significance (MGUS). MGUS is defined as detecting monoclonal immunoglobulins in the blood or urine without evidence of end-organ damage. This is quite common and 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. his is typically a benign condition, although as noted above, it has a risk of progression to MM of about 1% per year.[9][10]

The exact causes of MGUS development and progression to MM remain unknown. However, as noted above, genetic alterations may cause an increased expression of promoter genes or resistance to apoptosis, both resulting in higher plasma cell proliferation and population. Under the "second hit" hypothesis, progression could also 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.[11]

Regardless of the molecular driver, once there is excess monoclonal immunoglobulins, hyperviscosity, platelet dysfunction, and renal tubular damage can occur, leading to neurologic derangements, bleeding, and renal failure respectively. one marrow occupation by the expanding plasma cell clone usually manifests as anemia, thrombocytopenia, and leukopenia. In addition, 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.[12]


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, two or three times the size of a lymphocyte, with a single eccentric nucleus displaced by an abundant, basophilic cytoplasm). The Golgi apparatus typically produces 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. The 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 of MM is quite variable. It is typically more subacute and insidious in onset but certainly can present with severe symptoms. With that said, it is often seen in an older adult with some variation of constitutional symptoms or CRAB (hypercalcemia, renal dysfunction, anemia, and/or bone pain with lytic lesions). In one retrospective single-institution study, it was found that in newly diagnosed MM, the following symptoms were most:  anemia (73%), bone pain (58%), elevated creatinine (48%), fatigue (32%), hypercalcemia (28%) and weight loss (24%).[13]

More specifically, hypercalcemia caused by bone demineralization can result in increased thirst and urination, bone pain, abdominal pain, nausea or vomiting, and/or altered mental status. Renal failure resulting from light chain case nephropathy and/or hypercalcemia can lead to edema, acidosis, and electrolyte disturbances. Anemia develops likely secondary to bone marrow replacement, or decreased erythropoietin levels can result in fatigue, pallor, palpitation, and worsening previous heart failure or angina. Bone pain resulting from the osteolytic lesions often results in pathologic fractures and vertebral collapse, reducing height, spinal cord compression, radicular pain, or kyphosis.

Although rare, peripheral neuropathy and carpal tunnel syndrome may be present. If identified, further workup should be undertaken as this is typically more related to an underlying component of amyloidosis. Also uncommon, hyperviscosity symptoms may be present, including bleeding, confusion, neurologic symptoms, vision changes, or heart failure. Despite being rare, it is crucial to identify these findings as it is a medical emergency. Finally, MM patients seem to be more prone to infections, mostly pneumonia, and pyelonephritis, so assessing for recurrent illness is important.


Multiple myeloma is simply a part of the spectrum of plasma cell proliferative disorders. This concept is restated on the National Comprehensive Cancer Network (NCCN) guidelines, where the disease is divided into MGUS, smoldering myeloma (asymptomatic), or multiple myeloma (symptomatic), as well as reiterated elsewhere.[14] As treatment and management of each category are vastly different, correct identification and diagnosis of MM are paramount.

When concern for multiple myeloma arises, there are several approaches to screening and diagnosis.

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
  • Whole Body low dose CT or PET CT
  • 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]

Historically, we have diagnosed MM if clonal bone marrow plasma cells were greater than or equal than 10% on bone marrow biopsy (or if a biopsy-proven plasmacytoma was present) in addition to at least one of the following CRAB criteria:

  • 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 often described as punched-out, round, radiolucent lesions

While this set of criteria identified the majority of cases requiring treatment, many were missed. In November 2014, the International Myeloma Working Group (IMWG) identified other factors associated with an 80% higher risk of developing myeloma-related organ damage within two years.[15] As a result, the following were added to the CRAB criteria as diagnostic alternatives to myeloma defining events:

  • Bone marrow plasma cells (BMPCs) equal to 60%
  • Involved/uninvolved serum free light chain ratio greater or equal to 100
  • Abnormal MRI with more than one focal lesion, with each lesion greater than 5 mm that were often missed on previous skeletal surveys

Now, the presence of any CRAB criteria or any of these three additional criteria justifies diagnosis and therapy. It is certainly more sensitive and identifies more of the cases needing treatment. This new set of diagnostic criteria is often referred to as SLiM CRAB.

Treatment / Management

Initial management of multiple myeloma should involve evaluation for any acute issues that must be stabilized immediately. Some of these may include administration of isotonic saline for volume expansion, calcitonin, and/or bisphosphonates to address severe hypercalcemia. If significant renal dysfunction is noted, medical optimization should be undertaken and possibly nephrology consultation to address fluid status, avoidance of nephrotoxic agents, renal dosage adjustments of necessary medications, and if severe dysfunction, discussion of hemodialysis. Spinal cord compression resulting from vertebral fracture or plasmacytoma can also be seen and is a medical emergency that should be managed aggressively by neurosurgery or orthopedic consultation and possible radiation therapy. In the rare instance that hyperviscosity is diagnosed, plasmapheresis should be completed.

Once stabilized, the patient's treatment plan is driven by risk stratification and transplant eligibility. A patient's disease can fall into one of two categories: high or standard-risk MM. High risk is defined as any of the following as seen on FISH: t(14:16), t(14:20), del17p13, t(4:14), or 1q gain. Standard risk will demonstrate either trisomies, t(11:14) or t(6:14). Transplant eligibility is made on a case-by-case basis, but typically, patients who are over 77 years old, have cirrhosis, have an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or 4, or have New York Heart Association class III or IV heart failure are typically deemed transplant ineligible. 

Patients who are fit for transplant typically receive induction therapy over 3 or 4 months to decrease the tumor burden. This is followed by peripheral blood stem cell mobilization and harvesting and then an autologous stem cell transplant (ASCT), which improves overall and progression-free survival.[16]  The ASCT can be performed early after recovery from stem cell collection or delayed at the time of the first relapse. After completing ASCT, the patient will be placed back on to a maintenance therapy until disease progression or based on tolerability. 

The ideal induction regimen is a nuanced decision, and many individual factors must be considered. In general, and based on the Mayo Stratification for Myeloma and Risk-adapted Therapy (mSMART) consensus opinion, for patients who are deemed high-risk disease and are transplant eligible, induction therapy would typically be started with four cycles of daratumumab, bortezomib, lenalidomide, and dexamethasone followed by an early ASCT. Although debatable, long-term survival seems to favor an early transplant approach in high-risk disease.[17] After completion of ASCT, proteasome inhibitor-based maintenance therapy should be initiated and continued until disease progression.

In those patients with standard-risk disease who are transplant eligible, a similar algorithm is followed with a different drug regimen being used. Typically, induction therapy with four cycles of bortezomib, lenalidomide, and dexamethasone (VRd) is completed, followed by ASCT and then maintenance therapy with lenalidomide until disease progression as tolerability permits. 

For high-risk transplant-ineligible patients, there are several options. One approach would be to employ the VRd regimen for 8 to 12 cycles followed by maintenance bortezomib-based therapy. Another option could include daratumumab, lenalidomide, and dexamethasone (DRd) continued until disease progression based on the MAIA trial showing improved progression-free survival and overall survival compared to Lenalidomide and Dexamethasone.[18]  This may be particularly helpful in patients ineligible for bortezomib-based therapy. 

For standard risk transplant-ineligible patients, options include VRd for 8 to 12 cycles followed by lenalidomide maintenance, or DRd continued until disease progression.[19][20]

Differential Diagnosis

The differential diagnosis for many of the vague symptoms accompanying multiple myeloma is broad.[21] However, several entities must be considered and ruled out before diagnosis and treatment. Following is a list of important diseases to consider and how to differentiate these from multiple myeloma:

Monoclonal Gammopathy of Undetermined Significance (MGUS)

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

Smoldering Multiple Myeloma

  • Monoclonal protein is greater than or equal to 3 g/dl
  • Clonal bone marrow plasma cells between 10% to 59%
  • No end-organ damage[22]

Solitary Plasmacytoma

  • Solitary lesion made up of clonal plasma cells
  • Normal bone marrow
  • Negative imaging outside of the single lesion
  • No end-organ damage

Waldenstrom Macroglobulinemia

  • Lymphoplasmacytic lymphoma noted in the bone marrow
  • The type of M protein is IgM which is very unusual in MM.
  • Presence of MYD88 L265P
  • Symptoms include hyperviscosity, peripheral neuropathy, anemia, lymphadenopathy, and hepatosplenomegaly[23]

AL Amyloidosis

  • Caused by deposition of amyloid fibrils or non-fibrillar material resulting in heart failure, hepatomegaly, and/or nephrotic syndrome
  • Less than 20% plasma cells in the bone marrow and lack of lytic lesions
  • Congo-red staining on bone marrow or affected tissue[24]


There are several staging systems for multiple myeloma. The two main systems used today are the Durie-Salmon Staging System and the Revised International Staging System (R-ISS). 

For many years, the Durie-Salmon staging system was the standard for risk stratification. It is based on the tumor cell mass, hemoglobin, calcium, IgA and IgG levels, urine monoclonal protein levels, and the extent of bone damage on X-rays. 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.[25]  Given that there is some subjectivity, accuracy and reproducibility are difficult. With this in mind, most often, the R-ISS is used. In addition, the R-ISS is simple and provides prognostic information that is more robust.[26]  Staging for the R-ISS is as follows:

  • 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 [del(17p), and/or t(4:14), and/or t(14,16)] or elevated LDH


The prognosis for multiple myeloma is quite variable, and many factors can affect outcomes. However, perhaps the two main drivers in prognosis would be stage and disease biology. 

The R-ISS staging was developed when evaluating newly diagnosed MM from a combination of 11 international trials. When dividing by stage, they found that in R-ISS I, the five-year overall survival (OS) was 82%, and progression-free survival (PFS) was 55%. In stage II disease, five-year OS was 62%, and PFS was 36%. Stage III demonstrated a five-year OS of 40% and PFS of 24%.[26]

High-risk cytogenetic abnormalities can adversely affect outcomes. 4:14), t(14:16), and f(14:20) are all considered high risk and have been shown to decrease OS.  In one study, the presence of t(14:16) resulted in a PFS of 2.1 years and OS of 4.1 years.[27]  17p deletions also portend worse outcomes, with one small study demonstrating a median PFS of 18.1 months and median OS of 36 months when a del(17p) was paired with mutated TP53.[28]

These factors help understand the general prognosis and can guide discussions with patients. However, it is important to note that significant therapeutic progress has been made over the last several years, with OS changes yet to reflect these advances.


Common manifestations and complications of multiple myeloma can include hypercalcemia, renal insufficiency, infection, skeletal lesions, and anemia. Less common complications include venous thromboembolism and hyperviscosity syndrome.[29]

Hypercalcemia is caused by bone demineralization and 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. As noted previously, it can include hydration, glucocorticoids, bisphosphonates, calcitonin, and/or hemodialysis.

The development of 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, or dehydration.

Myeloma bone disease is thought to result from overexpression of RANKL by bone marrow stroma. RANKL activates osteoclasts, which resorb bone. Bone breakdown leads to calcium release into the blood, leading to hypercalcemia and symptoms of kidney failure that may develop acutely or chronically. It can manifest as severe bone pain, pathological fractures, and even spinal cord compression.

Another important complication that can occur is an increased risk of infection. Infection risk seems to be highest over the first 3 to 4 months of induction therapy. 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 pneumoniae, Haemophilus influenzae, and Escherichia coli. Early identification is important to assure timely treatment and infection resolution.

Neuropathy is also commonly seen. It can be secondary to the plasma cell dyscrasia itself, direct compression, or light chain deposition. However, it can also be worsened or even caused by treatment regimens including thalidomide, bortezomib, or vincristine.[30]

Also significant is the increased risk for thrombosis. This can be secondary to the patient's comorbidities, tumor/disease-related factors, and immunomodulatory drugs, including thalidomide or lenalidomide. Practitioners should have a low threshold for workup or evaluation for any signs or symptoms of venous or arterial thrombus.[31]

A rare side effect is hyperviscosity which can have severe complications. It typically presents as oronasal bleeding, blurred vision, retinal hemorrhage, seizure, other neurologic symptoms, confusion, dyspnea, and heart failure. This is considered an emergency, and plasmapheresis should be initiated immediately to promptly relieve symptoms.

Deterrence and Patient Education

Patient education is crucial in the management of multiple myeloma. The disease itself is complex, and outcomes can be improved if early and appropriate intervention is undertaken. That said, a patient must be an active participant in shared decision-making to assure improved compliance with therapy.

Another deterrent to positive outcomes seems to be racial disparities. Compared with Whites, African Americans have a higher mortality rate and have not seen the same gains in survival. Although a specific cause has not been identified, there does seem to be less utilization and access to appropriate healthcare and treatment.[32] With this in mind, community outreach and education are imperative to gain the community's trust and offer improved access to those who fall within this demographic.

Enhancing Healthcare Team Outcomes

Multiple myeloma is a complex disease that often involves numerous systems. Given this fact, treating multiple myeloma frequently requires an interdisciplinary approach. While the oncologist will certainly be involved, several other individuals’ aid and expertise will be needed. 

From a diagnostic standpoint, pathology will provide critical diagnostic information and interpretation of serum protein electrophoresis and bone marrow biopsy evaluation and quantification of plasma cell involvement. Radiology will help determine the presence of any lytic lesions. Nephrologists may be required to aid in the management of any new or worsening renal dysfunction. Radiation oncology input may be necessary to address any symptomatic bony lesions. Orthopedic or neurosurgery can help address pathologic fractures or lesions, causing impending progression. In addition, many orthopedists see patients before an actual diagnosis of MM for pain, so assuring this is in their differential is critical in earlier diagnosis.[33] Another important team member often involved much too late in the disease process is palliative care (PC). PC is a service that focuses on symptom management. PC involvement improves not only the patient experience but also tangible outcomes. A decrease in discontinuation due to adverse reactions can be seen by involving palliative care early and improving symptom management.[34][35] In addition, and perhaps by extension, the length of survival is higher among those with PC.[36][Level 4]

Finally, another consideration for improving outcomes is that of a second opinion. Studies have demonstrated decreased mortality risk when a patient is evaluated and treated at a National Cancer Institute Comprehensive Cancer Center (NCI CCC).[37] [Level 4] With this in mind, although not always possible, an initial evaluation or review by a designated NCI-CCC is reasonable and may improve outcomes.  

While every case is unique in its presentation and progression, without a doubt, a multidisciplinary approach helps improve results. 



1/30/2023 4:28:56 PM



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Level 2 (mid-level) evidence


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Terpos E,Kleber M,Engelhardt M,Zweegman S,Gay F,Kastritis E,van de Donk NW,Bruno B,Sezer O,Broijl A,Bringhen S,Beksac M,Larocca A,Hajek R,Musto P,Johnsen HE,Morabito F,Ludwig H,Cavo M,Einsele H,Sonneveld P,Dimopoulos MA,Palumbo A, European Myeloma Network guidelines for the management of multiple myeloma-related complications. Haematologica. 2015 Oct     [PubMed PMID: 26432383]


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Level 3 (low-level) evidence


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