INTRODUCTION — Multiple myeloma (MM) is characterized by the neoplastic proliferation of plasma cells producing a monoclonal immunoglobulin. The plasma cells proliferate in the bone marrow and often results in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures. The diagnosis of MM is often suspected because of one (or more) of the following clinical presentations:
●Bone pain with lytic lesions discovered on routine skeletal films or other imaging modalities
●An increased total serum protein concentration and/or the presence of a monoclonal protein in the urine or serum
●Systemic signs or symptoms suggestive of malignancy, such as unexplained anemia
●Hypercalcemia, which is either symptomatic or discovered incidentally
●Acute renal failure with a bland urinalysis or rarely the nephrotic syndrome due to concurrent immunoglobulin light chain (AL) amyloidosis
It is important to distinguish MM both from other causes of the clinical presentations above and from other plasma cell dyscrasias for the purposes of prognosis and treatment. It is also important to evaluate patients suspected of having MM in a timely fashion since a major delay in diagnosis has been associated with a negative impact on the disease course .
The clinical manifestations, pathologic features, diagnosis, and differential diagnosis of MM are discussed here. The pathogenesis and treatment of this disorder are discussed separately. (See "Pathobiology of multiple myeloma" and "Overview of the management of multiple myeloma".)
EPIDEMIOLOGY — MM accounts for approximately 1 to 2 percent of all cancers and slightly more than 17 percent of hematologic malignancies in the United States (US) . The annual incidence in the US is approximately 4 to 5 per 100,000 . A similar incidence has been reported in the South Thames area of the United Kingdom and in Europe in general [4-6]. Worldwide, there are approximately 154,000 cases and 101,000 deaths per year attributed to MM .
The incidence appears to be stable [3,8]. While some reports have suggested an increase in incidence over time, this more likely reflects the enhanced availability and use of medical facilities, especially by older persons. Our database from Olmsted County, Minnesota, has documented a stable incidence from the 1940s to the early 21st century .
MM occurs in all races and all geographic locations . The incidence varies by ethnicity; the incidence in African Americans and Blacks from Africa is two to three times that in Whites [9-11]. In contrast, the risk is lower in Asians from Japan and in Mexicans [10,12]. MM is also slightly more frequent in men than in women (approximately 1.4:1). The risk of developing MM increases with body mass index [13,14].
MM is a disease of older adults. The median age at diagnosis is 66 years; only 10 and 2 percent of patients are younger than 50 and 40 years, respectively [9,15].
A small but unknown fraction of cases are familial. The risk of developing MM is approximately 3.7-fold higher for persons with a first-degree relative with MM . MM has been reported in clusters of two or more first-degree relatives, identical twins, and in four members spanning three generations in one family, with an incidence of approximately three familial cases per 1000 patients with myeloma [16-31]. In one report of 15 families with MM clustering, 10 occurred in siblings . The same IgG kappa monoclonal pattern was present in all cases in seven families. In addition, a genome-wide association study that genotyped 1675 patients with MM and compared them with 5903 control subjects suggested that persons with a common variation at the 3p22.1 or 7p15.3 genetic loci are at a higher risk of developing MM (odds ratios of 1.32 and 1.38, respectively) . While intriguing, such cases would be expected to account for less than 5 percent of familial risk. The low hazard ratios indicate that these markers do not have any direct clinical implications, and reflect the complexity of the disease and the etiologic mechanism involved.
Spectrum of disease — Most patients with MM present with signs or symptoms related to the infiltration of plasma cells into the bone or other organs or to kidney damage from excess light chains. As an example, a retrospective analysis of 1027 sequential patients diagnosed with MM at a single institution found the following symptoms and signs at presentation :
●Anemia – 73 percent
●Bone pain – 58 percent
●Elevated creatinine – 48 percent
●Fatigue/generalized weakness – 32 percent
●Hypercalcemia – 28 percent
●Weight loss – 24 percent, one-half of whom had lost ≥9 kg
Symptoms and signs present in 5 percent or less included: paresthesias (5 percent), hepatomegaly (4 percent), splenomegaly (1 percent), lymphadenopathy (1 percent), and fever (0.7 percent). Pleural effusion and diffuse pulmonary involvement due to plasma cell infiltration are rare and usually occur in advanced disease. As the use of "routine" blood work has become more common, patients are being diagnosed earlier in the disease course.
Extramedullary plasmacytomas (EP) are seen in approximately 7 percent of patients with MM at the time of diagnosis, and is best diagnosed by PET/CT scan; the presence of EP at diagnosis is associated with inferior survival. An additional 6 percent of patients will develop EP later in the disease course [28,33]. EP can present as large, purplish, subcutaneous masses (picture 1 and image 1) . Plane xanthomas involving the creases of the palms and/or soles may represent a paraneoplastic phenomenon . Cutaneous spicules, composed in part of the monoclonal protein, may rarely occur . (See "Diagnosis and management of solitary extramedullary plasmacytoma" and "Cutaneous manifestations of internal malignancy".)
Anemia — A normocytic, normochromic anemia (hemoglobin ≤12 g/dL) is present in 73 percent at diagnosis and in 97 percent at some time during the course of the disease . This anemia can be related to bone marrow replacement, kidney damage, and/or can be due to dilution in the case of a large M-protein. Anemia commonly results in complaints of fatigue and pallor seen on physical examination.
Macrocytosis (mean corpuscular volume >100 fL) was present in 9 percent of 1027 patients studied . In this study, 53 patients (11 percent) with a MCV >100 fL had a vitamin B12 level <200 ng/L. This finding is similar to a prevalence of vitamin B12 deficiency of 14 percent seen in a separate study of 664 consecutive patients with plasma cell dyscrasias . While the mechanism for low vitamin B12 levels in these patients is not known, investigations must be done to rule out pernicious anemia.
Bone pain — Bone pain, particularly in the back or chest, and less often in the extremities, is present at the time of diagnosis in approximately 60 percent of patients . The pain is usually induced by movement and does not occur at night except with change of position. The patient's height may be reduced by several inches because of vertebral collapse. Plasmacytomas of the ribs occur and can present either as expanding costal lesions or soft tissue masses.
Renal disease — The serum creatinine concentration is increased in almost one-half of patients at diagnosis (and is >2 mg/dL (177 micromol/L) in approximately 20 percent); renal failure may be the presenting manifestation of MM [9,31]. Two major causes of renal insufficiency in patients with MM are light chain cast nephropathy (also called myeloma kidney) and hypercalcemia. Patients who do not secrete light chains are not at risk for myeloma kidney. In the absence of other causes of renal failure, a presumptive diagnosis of light-chain cast nephropathy can be made in the setting of high involved free light chain levels (typically >1500 mg/L). In contrast, renal biopsy should be performed to document typical histologic changes in patients with suspected cast nephropathy, especially if the serum-involved FLC level is <500 mg/L . (See "Clinical features, evaluation, and diagnosis of kidney disease in multiple myeloma and other monoclonal gammopathies".)
Other causes of renal failure in a patient with myeloma include concurrent light chain (AL) amyloidosis, light chain deposition disease, and drug-induced renal damage. Renal disease in MM is discussed in more detail separately. (See "Epidemiology, pathogenesis, and etiology of kidney disease in multiple myeloma and other monoclonal gammopathies".)
Hypercalcemia — Hypercalcemia is found in 28 percent of one series of patients with MM at the time of diagnosis; serum calcium was ≥11 mg/dL (2.75 mmol/liter) in 13 percent and can require emergent treatment . The ionized calcium should be measured if the patient has a high serum calcium level but no symptoms of hypercalcemia. Elevation of the serum calcium may be due to binding of the monoclonal protein with calcium . (See "Treatment of the complications of multiple myeloma", section on 'Hypercalcemia' and "Treatment of hypercalcemia" and "Hypercalcemia of malignancy: Mechanisms", section on 'Osteolytic metastases'.)
Of note, severe hypercalcemia can act as an unmeasured cation and thereby result in a low anion gap. A decreased anion gap may also be due to the presence of a cationic IgG molecule. (See "Serum anion gap in conditions other than metabolic acidosis".)
Neurologic disease — Radiculopathy, usually in the thoracic or lumbosacral area, is the most common neurologic complication of MM. It can result from compression of the nerve by a paravertebral plasmacytoma or rarely by the collapsed bone itself.
●Cord compression – Spinal cord compression from an extramedullary plasmacytoma (image 2) or a bone fragment due to fracture of a vertebral body (image 3) occurs in approximately 5 percent of patients; it should be suspected in patients presenting with severe back pain along with weakness or paresthesias of the lower extremities, or bladder or bowel dysfunction or incontinence.
This set of symptoms constitutes a medical emergency; magnetic resonance imaging (MRI) or computed tomographic myelography of the entire spine must be performed immediately, with appropriate follow-up treatment by chemotherapy, radiotherapy, or neurosurgery to avoid permanent paraplegia. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression, including cauda equina syndrome" and "Treatment and prognosis of neoplastic epidural spinal cord compression, including cauda equina syndrome".)
●Peripheral neuropathy – Peripheral neuropathy is uncommon in MM at the time of initial diagnosis and, when present, is usually due to amyloidosis. An exception to this general rule occurs in the infrequent subset of patients with POEMS syndrome (osteosclerotic myeloma) in which neuropathy occurs in nearly 100 percent of patients. The pathogenesis of the neuropathy is uncertain but a paraneoplastic mechanism may be important; this issue is discussed separately. (See "POEMS syndrome" and "Paraneoplastic syndromes affecting peripheral nerve and muscle", section on 'Association with plasma cell dyscrasias'.)
●CNS involvement – Intracranial plasmacytomas are rare and almost always represent extensions of myelomatous lesions of the skull or plasmacytomas involving the clivus or base of the skull. Leptomeningeal myelomatosis along with abnormal cerebrospinal fluid findings is uncommon but is being recognized more frequently, especially in advanced stages of the disease [38-43]. When found it denotes a poor prognosis with survival historically measured in months despite treatment . It is usually associated with high-risk cytogenetics; lactate dehydrogenase (LDH) levels may be elevated. Survival appears to have improved slightly since the incorporation of immunomodulatory drugs and proteasome inhibitors into first-line therapy [44,45].
Rare cases of encephalopathy due to hyperviscosity or high blood levels of ammonia, in the absence of liver involvement, have been reported [46-49]. Myeloma cell lines developed from such patients produce elevated amounts of ammonia, although the mechanism is unclear . Ammonia levels and the patient's state of consciousness return to normal if and when the underlying myeloma responds to chemotherapy.
Infection — Patients with MM are at increased risk for infection due to a combination of immune dysfunction and physical factors. Immune dysfunction results from impaired lymphocyte function, suppression of normal plasma cell function, and hypogammaglobulinemia. Physical factors include hypoventilation secondary to pathologic fractures and pain involving the rib cage and spine. Streptococcus pneumoniae and gram-negative organisms are the most frequent pathogens.
Further details of immunodeficiency due to MM are discussed separately. (See "Treatment of the complications of multiple myeloma", section on 'Infection'.)
Monoclonal proteins — The vast majority (97 percent) of patients with MM will have a monoclonal (M) protein produced and secreted by the malignant plasma cells, which can be detected by protein electrophoresis of the serum (SPEP) and/or of an aliquot of urine (UPEP) from a 24-hour collection combined with immunofixation of the serum and urine .
The M-protein usually presents as a single narrow peak, like a church spire, in the gamma, beta, or alpha-2 region of the densitometer tracing (figure 1), or as a dense, discrete band on the agarose gel (image 4). Infrequently, two M proteins are present (biclonal gammopathy) (figure 2). (See "Laboratory methods for analyzing monoclonal proteins".)
Serum immunofixation confirms the presence of an M-protein and determines its type (figure 3). The malignant plasma cells can produce immunoglobulin heavy chains plus light chains, light chains alone, or neither with the following frequencies on serum immunofixation :
●IgG – 52 percent
●IgA – 21 percent
●Kappa or lambda light chain only (Bence Jones) – 16 percent
●IgD – 2 percent
●Biclonal – 2 percent
●IgM – 0.5 percent
●Negative – 6.5 percent
Kappa is the predominant light chain isotype compared with lambda, by a factor of 2 to 1 with the exception that lambda light chains are more common in IgD myeloma and myeloma associated with amyloidosis (figure 4) .
Typical pattern — Serum protein electrophoresis (SPEP) will demonstrate a localized band or peak in 82 percent of patients with myeloma . Addition of serum protein immunofixation increases the sensitivity to 93 percent. If, in addition, either the serum free light chain (FLC) assay or urine monoclonal protein studies (urine protein electrophoresis and urine immunofixation) are done, the sensitivity increases to 97 percent or more. Patients who lack detectable M protein by any of these tests are considered to have "non-secretory myeloma." Among the 20 percent with no localized band on SPEP, hypogammaglobulinemia is seen in approximately one-half (due in part to suppression of normal gamma globulin production) and no apparent abnormality in the remainder.
The level of one or both of the major uninvolved immunoglobulins (ie, IgM and IgA in the case of IgG myeloma) is reduced in 91 percent of patients overall, and both are reduced in 73 percent. Normal levels of the uninvolved immunoglobulins were present at diagnosis in 3, 8, 12, and 13 percent of our patients with IgA, nonsecretory, IgG, and light chain myeloma, respectively . In a retrospective analysis, normal levels of uninvolved immunoglobulins were associated with better clinical outcomes, including longer progression-free survival and overall survival, independent of treatment received . In another study, patients with myeloma had lower median levels of IgE (11 international units/mL) than normal subjects (38 international units/mL) .
Light chain myeloma — Up to 20 percent of myeloma is characterized by only a light chain in the serum or urine, lacking expression of the immunoglobulin heavy chain. These patients are detected readily by serum FLC and UPEP and urine immunofixation. The incidence of renal failure is much higher in light-chain myeloma, as the serum creatinine is ≥2 mg/dL (177 micromol/L) in approximately one-third of these patients at presentation. (See "Treatment of the complications of multiple myeloma", section on 'Renal insufficiency' and "Clinical features, evaluation, and diagnosis of kidney disease in multiple myeloma and other monoclonal gammopathies".)
Non-secretory myeloma — Approximately 3 percent of patients with MM have no M-protein in the serum or urine on immunofixation at the time of diagnosis . In approximately 60 percent of patients with myeloma who have a normal serum and urine immunofixation, monoclonal FLC can be detected in the serum using FLC assays [54,55]. The FLC assay measures serum kappa and lambda light chain levels, which can then be expressed as a FLC kappa to lambda ratio. Patients without proliferative disorders of plasma cells or B-lymphocytes have normal FLC ratios . In comparison, patients with plasma cell disorders will have greater than expected proportions of kappa or lambda light chains resulting in an abnormal ratio. Patients with myeloma who have no M-protein in the serum or urine on immunofixation but have an abnormal serum FLC ratio are considered to have "nonmeasurable FLC only myeloma" . (See 'Free light chain assay' below and "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains'.)
Patients with myeloma who have normal serum and urine immunofixation as well as a normal serum FLC ratio are considered to have true nonsecretory myeloma . Of these, the majority (approximately 85 percent) will have M-protein that can be detected in the cytoplasm of the neoplastic plasma cells by immunochemistry, but have impaired secretion of this protein. The other 15 percent do not have immunoglobulin detectable in the plasma cells (ie, non-producer myeloma). Patients with true non-secretory myeloma need to be monitored mainly on the basis of imaging tests and bone marrow studies.
In a Mayo Clinic study, 124 patients diagnosed with MM who had no monoclonal protein detected on serum and urine immunofixation at diagnosis and on all subsequent follow-up testing were studied . The median follow-up was 102 months (range, 1 to 204 months). The median progression-free survival with initial therapy was 28.6 months, and the median overall survival (OS) was 49.3 months. The OS of this cohort was compared with patients with secretory myeloma. Prior to 2001, OS was similar in non-secretory myeloma (n = 86) and secretory myeloma (n = 4011), median 3.6 versus 3.5 years, respectively. However, among patients diagnosed between 2001 and 2012, OS was superior in non-secretory myeloma (n = 36) compared with secretory myeloma (n = 2942), median 8.3 versus 5.4 years, respectively. OS was superior in patients with true nonsecretory myeloma (n = 10) compared with patients with nonmeasurable FLC only myeloma (n = 19), medians not reached in both groups. Patients with nonsecretory MM are not at risk for myeloma kidney as long as light chains cannot be detected in the urine, but they are at risk for other complications of MM.
Oligo-secretory myeloma — Approximately 5 to 10 percent of patients with MM have oligo-secretory myeloma at diagnosis, defined as absence of measurable disease in serum or urine by the following parameters:
●Serum M protein <1 g/dL, and
●Urine M protein <200 mg/24 hours
Monitoring of these patients is difficult using the standard serum and urine electrophoretic tests since it will be difficult to determine if small variations are real or due to expected laboratory variability. In most of these patients, the serum free light chain (FLC) assay can be used to monitor the disease, provided that the serum FLC ratio is abnormal and the involved (affected) FLC level is ≥10 mg/dL . As with non-secretory myeloma, patients with oligo-secretory disease may also need to be monitored by imaging and bone marrow studies, particularly if the baseline FLC levels are unmeasurable (<10 mg/dL) or if there is concern about the reliability of the results.
Laboratory artifacts — Circulating monoclonal proteins may interfere with one or more laboratory tests performed on liquid-based automated analyzers, either by precipitating during the analysis, or by virtue of their specific binding properties. The most common artifacts are a low value for HDL cholesterol, a high value for bilirubin, as well as altered measurement of inorganic phosphate. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Interference with laboratory tests'.)
Although not a laboratory artifact, monoclonal protein can increase the serum viscosity and erythrocyte sedimentation rate (ESR). The ESR is >20 mm/hour in 84 percent, and >100 mm/hour in one-third of patients with MM.
Urinalysis — As mentioned above, patients with MM frequently present with renal insufficiency due to cast nephropathy. Alternatively, kidney disease associated with MM can be due to amyloidosis or light chain deposition disease. Care must be taken in interpreting the urinalysis results. Urine dipstick examinations primarily detect albumin, not light chains, which can be detected by sulfosalicylic acid or a 24-hour urine collection including electrophoresis and immunofixation. (See "Clinical features, evaluation, and diagnosis of kidney disease in multiple myeloma and other monoclonal gammopathies" and "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)".)
Findings on urinalysis in MM depend upon the etiology of the kidney damage:
●Myeloma cast nephropathy is characterized by the presence of large, waxy, laminated casts in the distal and collecting tubules; the casts are mainly composed of precipitated monoclonal light chains (picture 2A-C). The urine dipstick is typically negative for protein, since most of the proteinuria is comprised of urinary monoclonal protein (Bence Jones proteinuria) rather than albumin. (See "Clinical features, evaluation, and diagnosis of kidney disease in multiple myeloma and other monoclonal gammopathies".)
●In contrast to myeloma cast nephropathy, renal involvement in other related plasma cell disorders, namely AL amyloidosis and light chain deposition disease, typically present with a markedly positive dipstick for protein, since most of the urinary protein is comprised of albumin (nephrotic syndrome). Bence Jones proteinuria is minimal.
Cast nephropathy and amyloidosis rarely occur in the same patients because the biochemical characteristics of the individual monoclonal light chain are an important determinant of the type of renal disease that may be seen. (See "Epidemiology, pathogenesis, and etiology of kidney disease in multiple myeloma and other monoclonal gammopathies".)
Peripheral smear — The most frequent findings on peripheral smear are rouleaux formation (>50 percent), leukopenia (20 percent), and thrombocytopenia (5 percent) . Rouleaux formation is the phenomenon when red cells take on the appearance of a stack of coins in diluted suspensions of blood and is seen in patients with elevated serum protein levels (picture 3). A leukoerythroblastic reaction is uncommonly seen. (See "Evaluation of the peripheral blood smear", section on 'Initial approach'.)
Monoclonal plasma cells are rarely seen in the peripheral smear in patients with myeloma; a detectable absolute peripheral blood plasma cell count ≥100 cells/microL (≥0.1 x 109/L) is found in approximately 10 percent (picture 4). Plasma cell leukemia, a rare, yet aggressive form of MM characterized by high levels of plasma cells circulating in the peripheral blood, should be considered whenever circulating plasma cells are readily detected on conventional complete blood count evaluation. (See "Plasma cell leukemia".)
Circulating monoclonal plasma cells can be detected using a slide-based immunofluorescence assay, a two-color immunoassay technique (ELISPOT), or flow cytometry by gating on CD38+/CD45- cells. Using these sensitive techniques, circulating monoclonal plasma cells can be identified in the majority of patients with MM; the absolute percentage depends upon the sensitivity of the test used. (See "Staging and prognostic studies in multiple myeloma", section on 'Circulating plasma cells'.)
Bone marrow examination
Percent plasma cells — A bone marrow aspirate and biopsy are a key component to the diagnosis of MM (picture 5 and picture 6). The bone marrow plasma cell percentage should be estimated from a core biopsy specimen, when possible. However, if the percent plasma cells in the aspirate and core biopsy differ, the higher value should be used. Flow cytometry is not used to determine bone marrow plasma cell percentage for diagnostic purposes. Clonality can be established by demonstrating kappa/lambda light chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence.
The bone marrow of the vast majority of patients contains 10 percent or more clonal plasma cells. However, due to patchy bone marrow involvement, bone marrow aspirate and biopsy may show less than 10 percent plasma cells in approximately 4 percent of patients. As an example, in the Mayo Clinic series, plasma cells constituted more than 10 percent of all nucleated cells in 96 percent of patients, but this value ranged from less than 5 percent to almost 100 percent, with a median value of 50 percent .
A diagnosis of MM can be made in patients with less than 10 percent clonal plasma cells on biopsy if other diagnostic criteria are fulfilled and after histopathologic confirmation of a soft tissue or bony plasmacytoma . Since bone marrow involvement may be more focal than diffuse, some patients may require bone marrow aspirate/biopsy from several different sites or a guided biopsy of a focal lesion diagnosed by either MRI or PET/CT (integrated positron emission tomography and computed tomography) scan in order to establish the diagnosis.
In addition, asymptomatic patients who have ≥60 percent clonal plasma cells in the bone marrow have a risk of progression to end-organ damage in the next two years of greater than 80 percent and a median progression-free survival of approximately seven months [60,61]. In this setting, the percent of clonal plasma cells in the bone marrow is diagnostic of MM . (See 'Diagnostic criteria' below.)
Morphology — The morphological features of plasma cells can differ depending upon their maturity and, at times, they may be morphologically indistinguishable from myeloblasts. Mature plasma cells are oval with abundant basophilic cytoplasm. The nucleus is round and eccentrically located with a marked perinuclear hof, or cytoplasmic clearing (picture 4). The nucleus contains "clock-face" or "spoke wheel" chromatin without nucleoli. Immature plasma cells have dispersed nuclear chromatin, prominent nucleoli and a high nuclear to cytoplasmic ratio.
The cytoplasm of myeloma cells may contain condensed or crystallized cytoplasmic immunoglobulin resulting in the following unusual findings, which are not limited to MM :
●Multiple pale bluish-white, grape-like accumulations (eg, Mott cells, Morula cells)
●Cherry-red refractive round bodies (eg, Russell bodies)
●Vermilion staining glycogen-rich IgA (eg, Flame cells)
●Overstuffed fibrils (eg, Gaucher-like cells, thesaurocytes)
Immunophenotype — Immunohistochemical staining, immunofluorescent studies, and flow cytometry detect either kappa or lambda light chains, but not both, in the cytoplasm of bone marrow plasma cells in patients with myeloma; surface immunoglobulin is absent. The normal kappa/lambda ratio in the bone marrow is 2:1. A ratio of more than 4:1 or less than 1:2 is considered to meet the definition of kappa or lambda monoclonality, respectively. This finding distinguishes the monoclonal gammopathies from reactive plasmacytosis due to autoimmune diseases, metastatic carcinoma, chronic liver disease, acquired immunodeficiency syndrome (AIDS), or chronic infection, in which the plasma cells show reactivity for both light chain types and the kappa/lambda ratio is within the normal range. A CD138 stain can identify plasma cells and aid in the accurate determination of percentage involved.
Much like normal plasma cells, myeloma cells express CD79a, VS38c, CD138, and CD38 . In contrast to normal plasma cells which usually express CD19, myeloma cells infrequently express CD19. CD45 expression is variable, with most myeloma cells typically being CD45 negative. Approximately 70 percent of myeloma cells will express CD56, which is typically negative in normal plasma cells and in plasma cell leukemia. Multiparametric flow cytometry that can detect six or more antigens (commonly CD38, CD45, CD56, CD19, kappa, and lambda) simultaneously is used in many laboratories to identify and ascertain the clonality of plasma cells in myeloma. (See "Plasma cell leukemia".)
Cytogenetics — There is no single cytogenetic abnormality that is typical or diagnostic of MM. The majority of myeloma tumors have genetic abnormalities that can be detected with sensitive molecular genetic techniques, such as interphase fluorescence in situ hybridization (FISH). In contrast, only 20 to 30 percent of patients will have cytogenetic abnormalities detected in bone marrow plasma cells by conventional karyotyping, due to a low number of metaphases in myeloma cells in such specimens [64,65]. The genetic changes found in MM are discussed in more detail separately. (See "Pathobiology of multiple myeloma", section on 'Cytogenetic abnormalities' and "Staging and prognostic studies in multiple myeloma", section on 'Fluorescence in situ hybridization (FISH)'.)
Free light chain assay — The free light chain (FLC) assay measures kappa and lambda light immunoglobulin chains that are unbound to heavy chains in the serum. The normal kappa/lambda FLC ratio is 0.26 to 1.65. Abnormal FLC ratios are seen in clonal plasma cell disorders when there is excess production of one type of light chain (kappa or lambda). Abnormal FLC ratios are seen in approximately 90 percent of patients with MM [66,67].
Patients with otherwise asymptomatic myeloma who have an involved/uninvolved FLC ratio of 100 or greater have a risk of progression to end-organ damage in the next two years of approximately 80 percent [68-70]. In these patients, if the absolute involved FLC level was also increased at 100 mg/dL (1000 mg/L) or more, the risk of progression in the next two years increased to 93 percent. Given the high rate of progression, an FLC ratio of 100 or more is now considered diagnostic of MM . (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains'.)
IMAGING — Imaging is a key part of the evaluation of all patients with suspected MM. Cross sectional imaging is preferred because these modalities are more sensitive than plain radiographs for the detection of most skeletal lesions in myeloma.
These tests are also appropriate in patients receiving intensive therapies to monitor disease response. (See "Evaluating response to treatment of multiple myeloma", section on 'Imaging'.)
Choice of modality — Cross sectional imaging is preferred over plain radiographs for the detection of bone involvement in patients being evaluated for suspected multiple myeloma. One of three modalities can be used:
●Whole body low-dose computerized tomography (CT) without contrast
●Whole body combined fluorine-18-labeled FDG positron emission tomography/CT (PET/CT)
●Whole body magnetic resonance imaging (MRI) (or at a minimum MRI of the spine and pelvis)
All three modalities are more sensitive than plain radiographs for the detection of most skeletal lesions in myeloma. A choice among these depends on availability, cost, institutional preference, and clinical features as follows:
●For most patients with suspected MM, we perform a whole body low-dose CT as a baseline assessment of bone involvement. CT is quick, convenient, relatively sensitive, and cost effective in this scenario.
●For patients with suspected smoldering MM (no bone lesions on CT and no other myeloma-defining features), we also perform a whole body MRI or MRI of the spine and pelvis to confirm the absence of bone lesions, especially if there is a high percentage of bone marrow plasma cells or other concerning features. MRI is more sensitive than CT and PET/CT for focal bone marrow lesions and has no radiation exposure, but it is more cumbersome for the patient.
●For patients with suspected extramedullary disease outside of the spine, we perform a whole body PET/CT. When compared with low-dose CT, PET/CT appears to be more sensitive for the detection of extramedullary disease but is associated with greater radiation exposure and cost. MRI is preferred for patients with spinal involvement and concern for cord compression.
CT, MRI, and PET — Studies evaluating CT, PET/CT, and MRI have clearly demonstrated that cross section imaging is more sensitive than skeletal surveys for the detection of bone lesions and suggest that detection of these lesions is predictive of a shorter time to symptomatic progression. MRI is the most sensitive modality for bone involvement, while PET/CT may be more sensitive for extramedullary involvement. Despite its lower sensitivity, CT is often preferred for its convenience and relatively low cost. Depending on the technique used, metastatic bone surveys may be more sensitive for the detection of non-axial bone lesions.
Patients who previously would have met criteria for smoldering myeloma based on negative skeletal surveys, but who have lesions detected by CT, have a shorter time to progression than similar patients with negative CT imaging. This was illustrated in a retrospective analysis of 212 patients with histologically proven MM who had both a whole body CT and a skeletal survey obtained within 30 days of each other . Approximately two-thirds had no lytic lesions detected using either modality or had lesions detected with both modalities. When compared to those with negative imaging, the 54 patients with lesions detected by CT only had a shorter time to symptomatic progression.
PET/CT scanning using fluorine-18-labeled FDG is more sensitive than skeletal survey for the detection of bone lesions and may be more sensitive than CT for the detection of extramedullary disease [74-77]. False negative results can occur in those with hyperglycemia or in the setting of high-dose steroids. In a study prospectively comparing PET/CT versus MRI of the spine and pelvis versus skeletal survey, PET/CT was superior to skeletal survey for the detection of bone lesions and was able to detect bone changes in sites out of the MRI field in one-third of patients, while MRI was more sensitive than PET/CT for the detection of diffuse infiltration of the bone marrow by plasma cells .
MRI is highly sensitive for the detection of bone and bone marrow focal lesions and predictive of progression. Unlike CT and PET/CT, MRI can detect focal bone lesions that are not yet lytic (ie, without advanced cortical bone destruction). Up to half of patients without other evidence of end-organ damage with normal plain films may demonstrate tumor-related lesions on MRI [79-81]. Patients with otherwise asymptomatic myeloma who have more than one focal bone lesion (≥5 mm) on MRI have a risk of progression to end-organ damage in the next two years of greater than 80 percent [82-84].
In one study in which 611 patients with myeloma had both MRI (limited to the axial bone marrow) as well as a standard metastatic bone survey, MRI detected focal lesions in 52 percent of those with negative bone surveys, while bone surveys detected focal lesions in 20 percent of those with a negative MRI . Significantly higher proportions of patients had focal lesions detected on MRI in the spine, pelvis, and sternum, while bone surveys outperformed MRI for lesions in the ribs and long bones.
Among patients with moderate to advanced renal failure (dialysis-dependent or estimated glomerular filtration rate <30 mL/min), the administration of gadolinium has been associated with the potentially severe syndrome of nephrogenic systemic fibrosis. In such patients, gadolinium-based imaging should be avoided if possible. This issue and the role of hemodialysis after the procedure if gadolinium-based imaging must be performed are discussed separately. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced renal failure", section on 'If gadolinium must be given'.)
Skeletal surveys — Skeletal surveys are reserved for patients who are unable to undergo low-dose whole body CT, MRI, and PET. The skeletal survey for patients with MM includes a posteroanterior view of the chest, anteroposterior and lateral views of the cervical spine, thoracic spine, lumbar spine, humeri and femora, anteroposterior and lateral views of the skull and anteroposterior view of the pelvis . Symptomatic areas are also imaged.
Conventional skeletal surveys reveal punched-out lytic lesions (image 5 and image 6), diffuse osteopenia (image 7), or fractures in nearly 80 percent of patients with MM at the time of diagnosis (table 1) [9,86,87]. Focal lytic lesions are found in nearly 60 percent; osteoporosis, pathologic fractures, or compression fractures of the spine each occur in approximately 20 percent of patients. The most frequent sites of involvement include areas with active hematopoiesis, such as the vertebral bodies, skull, thoracic cage, pelvis, and proximal humeri and femora. Osteosclerotic lesions (ie, areas of intense increased bone density) are rare. (See 'POEMS syndrome' below and "POEMS syndrome".)
DIAGNOSIS — The diagnosis of MM is often suspected because of one (or more) of the following clinical presentations:
●Bone pain with lytic lesions discovered on routine skeletal films or other imaging modalities
●An increased total serum protein concentration and/or the presence of a monoclonal protein in the serum or urine
●Systemic signs or symptoms suggestive of malignancy, such as unexplained anemia
●Hypercalcemia, which is either symptomatic or discovered incidentally
●Acute renal failure with a bland urinalysis or rarely the nephrotic syndrome due to concurrent primary amyloidosis
Evaluation — Patients suspected of having MM should initially undergo a complete history and physical examination. The history should pay specific attention to complaints of bone pain, constitutional symptoms, neurological symptoms, and infections. The physical examination should include a detailed neurologic exam.
In addition, we perform the following laboratory studies as an initial screen to look for MM [88-91]:
●A complete blood count and differential with examination of the peripheral blood smear.
●A chemistry screen that includes measurements of serum calcium, creatinine, albumin, lactate dehydrogenase, beta-2 microglobulin, and C-reactive protein. (See "Staging and prognostic studies in multiple myeloma".)
●Serum free monoclonal light chain (FLC) analysis.
●A serum protein electrophoresis (SPEP) with immunofixation and quantitation of immunoglobulins. (See "Laboratory methods for analyzing monoclonal proteins".)
●A routine urinalysis and a 24-hour urine collection for electrophoresis (UPEP) and immunofixation. Serum FLC analysis may be used in place of a 24-hour urine collection in conjunction with SPEP and immunofixation for screening purposes only . However, if a plasma cell proliferative disorder is identified, the UPEP and immunofixation are necessary. (See "Laboratory methods for analyzing monoclonal proteins".)
●Serum viscosity should be measured if the M-protein concentration is high (ie, >5 g/dL) or there are symptoms suggestive of hyperviscosity. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Hyperviscosity syndrome'.)
●Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH). Although a bone marrow evaluation is indicated for all patients with MM at diagnosis, it may be deferred for persons that are clinically suspected of having MGUS with a small monoclonal protein (less than 1.5 g/100 mL), minimal or no abnormalities in serum free light chains, and no end-organ damage.
●Cross sectional imaging is preferred over plain radiographs for the detection of bone involvement in patients being evaluated for suspected multiple myeloma. A choice among these depends upon availability, cost, institutional preference, and clinical features. (See 'Choice of modality' above.)
The diagnosis of MM requires the fulfillment of the following criterion:
●Clonal bone marrow plasma cells ≥10 percent or biopsy-proven bony or soft tissue plasmacytoma – Clonality should be established by showing a kappa/lambda light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should be estimated from a core biopsy specimen, when possible. If there is disparity between the aspirate and core biopsy, the highest value should be used. Approximately 4 percent of patients may have fewer than 10 percent bone marrow plasma cells since marrow involvement may be focal, rather than diffuse. Repeat bone marrow biopsy should be considered in such patients.
PLUS one of the following:
●Presence of related organ or tissue impairment (often recalled by the acronym CRAB) – End-organ damage is suggested by increased plasma calcium level, renal insufficiency, anemia, and bone lesions. In order to be included as diagnostic criteria, changes in these factors must be felt to be related to the underlying plasma cell proliferative disorder. (See "Overview of the management of multiple myeloma", section on 'Verification of the diagnosis'.)
For these purposes, the following definitions are used:
•Anemia – Hemoglobin <10 g/dL (<100 g/L) or >2 g/dL (>20 g/L) below normal
•Hypercalcemia – Serum calcium >11 mg/dL (>2.75 mmol/liter). Consider other causes of hypercalcemia (eg, hyperparathyroidism). (See "Diagnostic approach to hypercalcemia".)
•Renal insufficiency – Estimated or measured creatinine clearance <40 mL/min (calculator 1 and calculator 2) or serum creatinine >2 mg/dL (177 µmol/liter). Of these, creatinine clearance is the preferred measure of renal insufficiency because normal serum creatinine levels vary by age, sex, and race. Using creatinine clearance ensures that a similar level of renal dysfunction is required to end organ damage.
•Bone lesions – One or more osteolytic lesions ≥5 mm in size on skeletal radiography, MRI, CT, or PET/CT. In the absence of osteolytic lesions, the following are not sufficient markers of bone lesions: increased FDG uptake on PET, osteoporosis, or vertebral compression fracture. When a diagnosis is in doubt, biopsy of the bone lesion should be considered.
Manifestations of non-CRAB end-organ damage (eg, hyperviscosity, recurrent bacterial infections, AL amyloidosis, peripheral neuropathy) are nonspecific and not diagnostic of MM.
●Presence of a biomarker associated with near inevitable progression to end-organ damage – ≥60 percent clonal plasma cells in the bone marrow; involved/uninvolved FLC ratio of 100 or more (provided involved FLC level is at least 100 mg/L); or MRI with more than one focal lesion (involving bone or bone marrow).
Most but not all patients will have an M-protein in serum (figure 1 and figure 3) and/or urine (figure 5 and figure 6). Approximately 40 percent of patients with symptomatic MM will have an M-protein of less than 3 g/dL. In true non-secretory MM (approximately 3 percent of MM), an M protein will not be detectable in the serum or urine with immunofixation (see "Laboratory methods for analyzing monoclonal proteins").
DIFFERENTIAL DIAGNOSIS — It is important to distinguish MM both from benign causes, which can present with similar manifestations, and from other plasma cell dyscrasias for the purposes of prognosis and treatment. The diagnostic approaches to patients with hypercalcemia or acute renal failure are discussed separately. (See "Diagnostic approach to hypercalcemia" and "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting".)
The main conditions to consider in the differential diagnosis of MM are monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) , Waldenström macroglobulinemia (WM), solitary plasmacytoma, primary amyloidosis (AL), POEMS syndrome, and metastatic carcinoma (table 3 and table 4). Distinguishing features of these conditions are listed below.
●Serum monoclonal protein (whether IgA, IgG, or IgM) <3 g/dL
●Clonal bone marrow plasma cells <10 percent
●Absence of lytic lesions, anemia, hypercalcemia, and renal insufficiency (end-organ damage) that can be attributed to the plasma cell proliferative disorder
MGUS carries a risk of progression to MM of approximately 1 percent per year . Differentiation of MGUS from MM can be difficult and is primarily based on presence or absence of related end-organ damage. In comparison to overt MM or plasma cell leukemia, most patients with MGUS or SMM have few or no circulating monoclonal plasma cells. The use of other clinical and laboratory factors to differentiate between these two entities is discussed in more detail separately. (See "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Multiple myeloma'.)
Smoldering multiple myeloma — Smoldering multiple myeloma (SMM) is defined as:
●M-protein ≥3 g/dL and/or 10 to 60 percent bone marrow plasma cells, plus
Thus, for the diagnosis of SMM, patients should not have any of the following myeloma-defining events:
●End-organ damage (lytic lesions, anemia, renal disease, or hypercalcemia) that can be attributed to the underlying plasma cell disorder
●≥60 percent clonal plasma cells in the bone marrow [60,61]
●Involved/uninvolved free light chain (FLC) ratio of 100 or more [68-70]
●Magnetic resonance imaging (MRI) with more than one focal lesion (involving bone or bone marrow) [82-84]
Asymptomatic patients with one or more of the myeloma-defining events listed above are considered to have MM rather than SMM because they have a risk of progression with complications of greater than 80 percent within two years  (see 'Diagnostic criteria' above).
The management of SMM is presented in more detail separately. (See "Smoldering multiple myeloma".)
If there are doubts about the differentiation of MGUS/SMM from myeloma, and whether to begin chemotherapy immediately, one should withhold treatment and reevaluate in two or three months. Patients with SMM may remain stable for prolonged periods.
Waldenström macroglobulinemia and IgM multiple myeloma — Waldenström macroglobulinemia (WM) is a distinct clinicopathologic entity demonstrating lymphoplasmacytic lymphoma (LPL) in the bone marrow with an IgM monoclonal gammopathy in the blood. Patients may present with symptoms related to the infiltration of the hematopoietic tissues or the effects of monoclonal IgM in the blood. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)
In most cases, the distinction between WM and MM is straightforward since the clinical features are different, and the type of M protein seen in WM is unique (IgM). The lymphoplasmacytic lymphoma seen in the bone marrow of patients with WM can be distinguished from plasma cells seen in the bone marrow of patients with MM by the absence of CD56 and the presence of a substantial small lymphocytic component that expresses a clonal surface immunoglobulin, CD19, and CD20. Some patients with MM and t(11;14) may have lymphoplasmacytic or small mature plasma cell morphology, along with CD20 expression that may resemble WM. However, the t(11;14) translocation is not seen in WM. (See "Staging and prognostic studies in multiple myeloma", section on 'Fluorescence in situ hybridization (FISH)'.)
Classic MM with an IgM paraprotein (IgM multiple myeloma) is extremely rare, comprising only 0.5 percent of the Mayo Clinic series . The Mayo Clinic criteria for diagnosis of IgM myeloma (and its differentiation from WM) require presence of either lytic bone lesions felt secondary to the plasma cell disorder and/or evidence of the t(11;14) translocation . The criteria are conservative and designed to emphasize specificity over sensitivity, and ensure that patients with WM are not misclassified and treated as myeloma patients based on less reliable and subjective measures such as CD20 expression or morphology.
Solitary plasmacytoma — Plasmacytomas are tumors composed of plasma cells of variable maturity, which are histologically identical to those seen in MM. If they occur solely in the bone, they are designated solitary plasmacytoma of bone. If they arise outside bone in soft tissues, they are called solitary extramedullary plasmacytoma. (See "Diagnosis and management of solitary plasmacytoma of bone" and "Diagnosis and management of solitary extramedullary plasmacytoma".)
To make the diagnosis of solitary plasmacytoma, the following four criteria must be met:
●Biopsy-proven solitary lesion of the bone or soft tissue that demonstrates clonal plasma cells.
●Normal bone marrow with no evidence of clonal plasma cells.
●Skeletal survey and MRI of the spine and pelvis are normal except for the primary solitary lesion.
●Absence of lytic lesions, anemia, hypercalcemia, and renal insufficiency.
Note that patients who have a biopsy-proven solitary medullary or extramedullary lesion with evidence of clonal plasma cells in the bone marrow are usually treated in a similar fashion to those with solitary plasmacytoma, but technically are considered to have either "solitary plasmacytoma with minimal marrow involvement" if clonal bone marrow plasma cells are <10 percent, or MM (typically Durie-Salmon stage 1) if clonal bone marrow plasma cells are ≥10 percent. (See "Staging and prognostic studies in multiple myeloma".)
AL amyloidosis — As with MM, AL (amyloid light chain) amyloidosis (previously referred to as primary amyloidosis) and light chain deposition disease are plasma cell proliferative disorders associated with the overproduction of monoclonal light chains. However, patients with primary amyloidosis or light chain deposition disease develop tissue deposits of amyloid fibrils or non-fibrillar material that can produce the nephrotic syndrome, heart failure, hepatomegaly, and other findings that are not seen in MM.
In contrast to patients with MM, patients with AL amyloidosis usually demonstrate less than 20 percent bone marrow plasma cells, no lytic bone lesions on imaging, and a modest amount of Bence Jones proteinuria. The diagnosis of primary amyloidosis is established by demonstrating amyloid on a biopsy of affected tissue, such as abdominal fat, bone marrow, rectum, or kidney. (See "Pathogenesis of immunoglobulin light chain (AL) amyloidosis and light and heavy chain deposition diseases" and "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)
Rarely, MM can develop in patients with primary amyloidosis. In a series of 1596 patients with primary amyloidosis seen at the Mayo Clinic between 1960 and 1994, only six (0.4 percent) showed delayed progression (at 10 to 81 months) to overt MM . This usually occurs in patients without cardiac or hepatic amyloid who live long enough to develop MM. On the other hand, the development of dipstick-positive proteinuria, hypoalbuminemia, and edema or heart failure in a patient with known MM suggests superimposed amyloidosis or light chain deposition disease.
POEMS syndrome — POEMS syndrome (osteosclerotic myeloma: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) is a monoclonal plasma cell disorder accompanied by symptoms and/or signs of peripheral neuropathy, osteosclerotic lesions, Castleman's disease, organomegaly, endocrinopathy (excluding diabetes mellitus or hypothyroidism), edema, typical skin changes, and/or papilledema. These patients typically have elevated serum VEGF (vascular endothelial growth factor) levels. (See "POEMS syndrome".)
Polyneuropathy is uncommon in classical MM and, when present, is usually due to the presence of amyloidosis. The presence of anemia, hypercalcemia, renal failure, pathologic fractures, and a high percent of plasma cells in the bone marrow all serve to distinguish classical MM from POEMS syndrome.
In rare instances, MM may be associated with the presence of diffuse and not focal osteosclerotic bone lesions. Such patients have the typical clinical and laboratory features of MM and do not have the other characteristics of POEMS syndrome.
Metastatic carcinoma — The presence of lytic bone lesions in a patient with a monoclonal gammopathy suggests the possibility of MM. However, metastatic carcinoma (eg, kidney, breast, non-small cell lung cancer) can produce lytic lesions, and a subset of patients presenting in this way will have metastatic cancer with an associated, unrelated monoclonal gammopathy (eg, MGUS). Persons presenting with lytic bone lesions, constitutional symptoms, a small M component, and fewer than 10 percent clonal plasma cells in the bone marrow are more likely to have metastatic carcinoma with an unrelated MGUS rather than MM. This can be confirmed with a biopsy of the bone lesion. (See "Epidemiology, clinical presentation, and diagnosis of adult patients with bone metastasis".)
Similarly, for patients with lytic lesions in whom no M-protein is found in the serum or urine, metastatic carcinoma should be excluded before the diagnosis of nonsecretory myeloma is seriously considered, by performing a biopsy of one of the lytic lesions (table 1).
PROGNOSIS — MM is a heterogeneous disease with some patients progressing rapidly despite treatment and others not requiring therapy for a number of years. Distinction between these two groups is important so that treatment can be initiated in appropriate patients and postponed in those who do not need it. The prognosis of MM is presented separately. (See "Staging and prognostic studies in multiple myeloma".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Plasma cell dyscrasias".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Multiple myeloma (The Basics)")
●Beyond the Basics topics (see "Patient education: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")
●Multiple myeloma (MM) is characterized by the neoplastic proliferation of immunoglobulin-producing plasma cells. Most patients with MM present with signs or symptoms related to the infiltration of plasma cells into the bone or other organs or to kidney damage from excess light chains. Common presentations include anemia, bone pain, elevated creatinine or serum protein, fatigue, and hypercalcemia. Less common, but emergent presentations include spinal cord compression and severe hypercalcemia. (See 'Clinical presentation' above.)
●In patients with suspected myeloma or related disorders, appropriate initial screening tests include a serum protein electrophoresis along with immunofixation, and a serum free light chain assay. A 24-hour urine collection for electrophoresis and immunofixation must be done if a diagnosis of MM is made. (See 'Evaluation' above and 'Pathologic features' above.)
●Further evaluation to confirm the diagnosis of MM includes a bone marrow aspiration and biopsy, imaging, a complete blood count with differential and a chemistry screen. (See 'Evaluation' above.)
●The diagnosis of MM requires ≥10 percent clonal plasma cells in the bone marrow or biopsy-proven bony or soft tissue plasmacytoma plus one of the following (table 2) (see 'Diagnostic criteria' above):
•Presence of related organ or tissue impairment that can be attributed to the plasma cell proliferative disorder (eg, increased calcium, renal insufficiency, anemia, lytic bone lesions)
•Presence of a biomarker associated with near inevitable progression to end-organ damage (ie, ≥60 percent clonal plasma cells in the bone marrow; involved/uninvolved free light chain [FLC] ratio of 100 or more [the involved FLC level must also be at least 100 mg/L or more]; or magnetic resonance imaging [MRI] with more than one focal lesion).
●Infiltration with malignant plasma cells may be focal, requiring aspiration/biopsy at multiple sites. Imaging with MRI and/or positron emission tomography (PET) scan can be helpful in locating focal disease. (See 'Bone marrow examination' above and 'Imaging' above.)
●The differential diagnosis for MM includes monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), Waldenström macroglobulinemia (WM), solitary plasmacytoma, AL amyloidosis, POEMS syndrome, and metastatic carcinoma (table 3). (See 'Differential diagnosis' above.)