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Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis

Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis
Author:
Jacob P Laubach, MD, MPP
Section Editor:
S Vincent Rajkumar, MD
Deputy Editor:
Rebecca F Connor, MD
Literature review current through: Jul 2022. | This topic last updated: May 26, 2022.

INTRODUCTION — Multiple myeloma (MM) is typically characterized by the neoplastic proliferation of plasma cells producing a monoclonal immunoglobulin. The plasma cells proliferate in the bone marrow and can result 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 kidney 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.

The clinical manifestations, pathologic features, diagnosis, and differential diagnosis of MM are discussed here. The pathogenesis and treatment of this disorder are discussed separately, as are laboratory methods for analyzing monoclonal proteins.

(See "Multiple myeloma: Pathobiology".)

(See "Multiple myeloma: Overview of management".)

(See "Laboratory methods for analyzing monoclonal proteins".)

EPIDEMIOLOGY — MM is a relatively uncommon cancer accounting for approximately 1 to 2 percent of all cancers and slightly more than 17 percent of hematologic malignancies [1,2]. It is more common in men than women, and more common among individuals of African American descent.

Annual incidence – Data from the US Surveillance, Epidemiology, and End Results (SEER) registry estimate 34,000 new cases of MM and 13,000 deaths from MM annually in the US. This correlates with an annual incidence of approximately 7 per 100,000 men and women per year [1-3]. A similar incidence has been reported in Canada, the South Thames area of the United Kingdom, and in Europe in general [4-7]. Worldwide, there are approximately 180,000 cases and 117,000 deaths per year attributed to MM (GLOBOCAN database).

The true incidence appears to be stable [1,3,8]. While some reports have suggested an increase in incidence over time, this likely reflects an increased use of routine laboratory testing, greater awareness of MM, and the enhanced availability and use of medical facilities, especially by older persons. A database from Olmsted County, Minnesota, has documented a stable incidence from the 1940s to the early 21st century [3].

Age and sex distribution – MM is largely a disease of older adults. The median age at diagnosis is 65 to 74 years; only 10 and 2 percent of patients are younger than 50 and 40 years, respectively [9,10]. MM is also slightly more frequent in men than in women (approximately 1.4:1).

Variation with ethnicity – MM occurs in all races and all geographic locations [11]. The incidence varies by ethnicity; the incidence in African Americans and Black populations is two to three times that in Whites populations in studies from the United States and United Kingdom [9,12-14]. In contrast, the risk is lower in Asians from Japan and in Mexicans [12,15].

Risk factors – The risk of MM increases with body mass index [16-18]. There is also an association between Agent Orange exposure and MM. Data also suggest that among patients with monoclonal gammopathy of undetermined significance (MGUS), there is an increased risk of progression to MM among those who have been exposed to Agent Orange [19].

Familial risk – A small fraction of cases are familial with an estimated 3 familial cases per 1000 patients with MM [20-34]. The risk of developing MM is approximately 3.7-fold higher for persons with a first degree relative with MM [20,35]. In one report of 15 families with MM clustering, 10 occurred in siblings [30]. The same immunoglobulin G (IgG) kappa monoclonal pattern was present in all cases in seven families. In addition, a genome-wide association study (GWAS) suggested that persons with a common variation at the 3p22.1 or 7p15.3 genetic loci are at a slightly higher risk of developing MM (odds ratios of 1.32 and 1.38, respectively) [36]. 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.

CLINICAL PRESENTATION

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 immunoglobulin deposition. While the clinical presentation is usually subacute, a small percentage of patients present acutely with findings that require rapid attention and intervention (eg, spinal cord compression, kidney failure, hyperviscosity).

The acronym "CRAB" is sometimes used to remember myeloma-defining events that are used in the diagnosis of MM: calcium elevation; renal insufficiency (kidney impairment); anemia; and bone disease.

A retrospective analysis of 1027 sequential patients diagnosed with MM at a single institution found the following symptoms and signs at presentation [9]:

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.

Sometimes MM is suspected based on an increased total serum protein level, most often in conjunction with other symptoms or signs suggestive of MM. However, the total serum protein level may be normal in patients with MM; this is especially common in those with light chain MM as the free light chains (FLC) seldom rise to a level that affects the total protein.

Extramedullary plasmacytomas (EP) are seen in approximately 7 percent of patients with MM at the time of diagnosis and are best detected by positron emission tomography/computed tomography (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 [37,38]. EP can present as large, purplish, subcutaneous masses (picture 1 and image 1) [39]. Plane xanthomas involving the creases of the palms and/or soles may represent a paraneoplastic phenomenon [40]. Cutaneous spicules, composed in part of the monoclonal (M) protein, may rarely occur [32]. (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 [9]. This anemia may reflect [41]:

Bone marrow replacement

Relative erythropoietin deficiency (in part due to kidney damage)

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 [MCV] >100 fL) with low vitamin B12 levels (<200 ng/L) is seen in a minority of patients with MM (11 to 14 percent in two studies) [9,33]. While the mechanism for low vitamin B12 levels in these patients is not known, evaluation for other causes (eg, pernicious anemia) is indicated. (See "Macrocytosis/Macrocytic anemia", section on 'Evaluation'.)

Bone pain — Osteolytic bone disease is a major feature of MM that can result in bone pain and pathologic fractures. The frequency of bone lesions detected at diagnosis depends on the imaging modality used. In one large series from 2003, pathologic fractures, compression fractures, and osteoporosis were each found in 20 to 25 percent of patients at diagnosis [9]. The incidence of such bone complications at the time of diagnosis may have decreased as diagnostic criteria have incorporated more advanced imaging and biomarkers leading to earlier diagnosis of overt myeloma. (See 'Imaging' below.)

In the same study described above, MM-related bone pain was present at the time of diagnosis in approximately 60 percent of patients [9]. MM-related pain typically:

Involves the central skeleton (back, neck, shoulders, pelvis, hip), rather than the extremities

Is often induced by movement and is less common at night during sleep though can occur with change of position

Is usually mild or moderate in intensity but is severe in up to 10 percent

The patient's height may be reduced by several inches because of vertebral collapse. Bone pain may also reflect plasma cell tumors (ie, plasmacytomas), which can present as expanding tumor emanating from bone or as non-osseous soft tissue masses.

Kidney 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); kidney failure may be the presenting manifestation of MM [9,34].

Two major causes of kidney impairment 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 kidney failure, a presumptive diagnosis of light chain cast nephropathy can be made in the setting of high involved FLC levels. In contrast, kidney biopsy should be performed to characterize the histologic changes in patients with other potential risk factors for kidney impairment, in whom the mechanism of kidney injury is not known with certainty [42]. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)

Other causes of kidney failure in a patient with MM include concurrent light chain (AL) amyloidosis, light chain deposition disease, and drug-induced kidney damage. Kidney disease in MM is discussed in more detail separately. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)

Hypercalcemia — Hypercalcemia can occur in MM as a result of MM-induced bone demineralization. Hypercalcemia was 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 emergency treatment [9]. The ionized calcium should be measured if the patient has a high serum calcium level but no symptoms of hypercalcemia, noting that elevation of the serum calcium concentration may occur due to binding of the M protein with calcium [43]. (See "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 — While rare, neurologic findings may require urgent evaluation for spinal cord compression or hyperviscosity.

Extradural spinal 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" and "Treatment and prognosis of neoplastic epidural spinal cord compression".)

Hyperviscosity – Rare cases of hyperviscosity have been reported, usually in association with immunoglobulin M (IgM) MM [44]. Symptomatic hyperviscosity is a medical emergency. This syndrome is characterized by oronasal bleeding, blurred vision, neurologic symptoms, confusion, and/or heart failure. Serum viscosity measurements do not correlate well with symptoms or the clinical findings. Therapeutic plasma exchange promptly relieves the symptoms and should be performed regardless of the viscosity level if the patient is experiencing symptoms believed to be related to hyperviscosity [45]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

Radiculopathy – 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 by the collapsed bone itself in the case of a vertebral body compression fracture.

Peripheral neuropathy – MM-related peripheral neuropathy is uncommon in MM at the time of initial diagnosis and, when present, is usually due to coexisting AL amyloidosis. An exception to this general rule occurs in the infrequent subset of patients with POEMS syndrome (osteosclerotic myeloma), a condition in which neuropathy occurs in all patients. The pathogenesis of the neuropathy is uncertain in POEMS but a paraneoplastic mechanism may be important; this issue is discussed separately. (See "POEMS syndrome".)

Central nervous system (CNS) involvement – True intracranial plasmacytomas are rare, and most often plasmacytomas involving the brain parenchyma 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 [46-51]. When found it denotes a poor prognosis with survival historically measured in months despite treatment [50]. 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 [52-54].

Encephalopathy due to high ammonia – Rare cases of encephalopathy due to high blood levels of ammonia, in the absence of liver involvement, have been reported [55-57]. Myeloma cell lines developed from such patients produce elevated amounts of ammonia, although the mechanism is unclear [58]. 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.

Further details of immunodeficiency due to MM and infections in patients with MM are discussed separately. (See "Infections in patients with multiple myeloma".)

PATHOLOGIC FEATURES

Monoclonal proteins

Detection — The vast majority of patients with MM will have a monoclonal (M) protein produced and secreted by the malignant plasma cells, which can be detected by serum free light chain (FLC) analysis and/or protein electrophoresis of the serum (SPEP) and/or urine (UPEP) from a 24-hour collection combined with immunofixation of the serum and urine [9].

SPEP will demonstrate a localized band or peak in approximately 80 percent of patients with MM [9]. Addition of serum protein immunofixation increases the sensitivity to over 90 percent. If, in addition, either the serum FLC assay or urine M protein studies (UPEP and urine immunofixation) are done, the sensitivity increases to 97 percent or more. Patients without detectable M protein by SPEP, UPEP, immunofixation, and FLC analysis are considered to have "nonsecretory myeloma." (See 'Nonsecretory myeloma' below.)

Among the 20 percent with no localized band on SPEP, most of whom have light chain MM, approximately one-half will have hypogammaglobulinemia due in part to suppression of normal gamma globulin production.

Mass spectrometry (MS) is being evaluated as a technique to evaluate for and quantify the M-protein. MS and other laboratory methods for analyzing monoclonal proteins in the serum and urine are discussed in more detail separately (table 1). (See "Laboratory methods for analyzing monoclonal proteins".)

SPEP, UPEP, and immunofixation — When used in combination, SPEP, UPEP, and immunofixation of the serum and urine will demonstrate an M protein in 97 percent of patients with MM [9]. Uninvolved immunoglobulins (Ig) will be suppressed in approximately 90 percent. (See "Laboratory methods for analyzing monoclonal proteins".)

Presence of a monoclonal protein – 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). Serum immunofixation confirms the presence of an M protein and determines its type (figure 3). (See "Laboratory methods for analyzing monoclonal proteins".)

Suppression of uninvolved immunoglobulins (immunoparesis) – 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 are present at diagnosis in 3, 8, 12, and 13 percent of patients with IgA, nonsecretory, IgG, and light chain myeloma, respectively [9]. In one study, patients with MM had lower median levels of IgE (11 international units [IU]/mL) than normal subjects (38 IU/mL) [59].

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 [60,61].

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 that has been reported to be as high as 70 to 80 percent [62-64]. 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 in conjunction with an involved FLC level of 10 mg/dL (100 mg/L) or more is considered diagnostic of MM [65]. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains'.)

Patterns

Distribution of subtypes — A 2003 analysis demonstrated the prevalence of various MM subtypes as being [9]:

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 (nonsecretory or oligo-secretory MM) – 6.5 percent

The prevalence of non-secretory myeloma has decreased since then with routine use of the FLC assay. 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 MM associated with amyloidosis (figure 4) [66].

Light chain myeloma — Up to 20 percent of MM 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 with urine immunofixation. Total serum protein is often normal or even decreased in these patients as the FLCs seldom rise to a level that affects the total protein, and levels of the immunoglobulin heavy chains are often suppressed in patients with light chain disease.

The incidence of kidney failure is significantly higher in light chain MM, as the serum creatinine is ≥2 mg/dL (177 micromol/L) in approximately one-third of these patients at presentation. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)

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 oligo-secretory MM can be challenging using SPEP and UPEP since it is difficult to determine if small variations are real or due to expected laboratory variability. The FLC ratio is often abnormal in patients with oligo-secretory MM, making the serum FLC assay an important method of assessing and monitoring disease [67]. Patients can also be monitored using imaging and bone marrow studies, particularly if the baseline FLC levels are normal or only minimally elevated (<10 mg/dL).

Nonsecretory myeloma — Nonsecretory MM represents approximately 3 percent of MM, and is defined by the following [68]:

Normal serum and urine immunofixation

Normal serum FLC ratio

The majority of nonsecretory MM (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 MM). Patients with true nonsecretory MM need to be monitored mainly on the basis of imaging tests and bone marrow evaluation. Patients with nonsecretory MM are not at risk for myeloma kidney, but they are at risk for other complications of MM, including kidney impairment related to other mechanisms such as hypercalcemia.

In a Mayo Clinic study that assessed outcomes of 124 patients diagnosed with MM who had no M protein detected on serum and urine immunofixation at diagnosis and on all subsequent follow-up testing, progression-free survival and overall survival were similar to if not slightly better than those observed in patients with secretory myeloma [69].  

Laboratory artifacts — Circulating M 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 high-density lipoprotein (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, M 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 — Patients with MM frequently present with kidney impairment 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 "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)

Findings on urinalysis in MM depend on 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 M protein (Bence Jones proteinuria) rather than albumin.

In contrast to myeloma cast nephropathy, kidney involvement in other related plasma cell disorders, namely AL amyloidosis and light chain deposition disease, is typically associated 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 kidney disease that may be seen. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)

Peripheral smear — The most frequent findings on peripheral smear are [9]:

Rouleaux formation (>50 percent)

Leukopenia (20 percent)

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). Rarely, the peripheral smear may demonstrate a leukoerythroblastic reaction (ie, the combined presence of tear drop-shaped red cells, circulating nucleated red cells, and early white cells). (See "Evaluation of the peripheral blood smear", section on 'Initial approach'.)

Clonal plasma cells are rarely seen in the peripheral smear in patients with MM; 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 clonal 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 on the sensitivity of the test used. (See "Multiple myeloma: Staging and prognostic studies", section on 'Extramedullary disease'.)

Bone marrow

Percent plasma cells — Bone marrow aspirate and biopsy is a key part of the diagnostic evaluation of suspected MM. Clonal bone marrow plasma cells ≥10 percent is a major criterion for the diagnosis of MM. (See 'Diagnostic criteria' below.)

The bone marrow plasma cells can be estimated from [65]:

Core biopsy using hematoxylin and eosin stain

Aspirate using Wright's stain

Core biopsy specimens are preferred. However, if the percent plasma cells in the aspirate and core biopsy differ, the higher value should be used. Flow cytometry and immunohistochemistry for CD138, kappa light chains, or lambda light chains should not be used to determine bone marrow plasma cell percentage as background staining and other technical issues can overestimate the result.

Clonality should be established by showing a kappa/lambda light chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. The percentage clonal plasma cells identified impacts the likelihood of diagnosis:

≥60 percent – Diagnostic of MM regardless of other findings [65]. Asymptomatic patients with ≥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 [70,71].

>10 to <60 percent – Found in the vast majority of patients with MM, but not diagnostic of overt myeloma in the absence of related organ or tissue impairment or identification of a biomarker.

<10 percent – Due to patchy bone marrow involvement, bone marrow aspirate and biopsy may show <10 percent plasma cells in approximately 4 percent of patients [9].

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 [15]. Since bone marrow involvement may be more focal than diffuse, some patients may require bone marrow aspirate/biopsy from several different sites or an image-guided biopsy of a focal lesion in order to establish the diagnosis.

Morphology and immunophenotype — Plasma cells are identified in the bone marrow based on morphology and immunophenotype. 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.

Morphology – The morphologic features of plasma cells can differ depending on their maturity and, at times, they may be morphologically indistinguishable from myeloblasts. Mature plasma cells are oval with abundant basophilic cytoplasm (picture 5). 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 [72]:

Multiple pale bluish-white, grape-like accumulations (eg, Mott cells (picture 6), Morula cells)

Cherry-red refractive round bodies (eg, Russell bodies)

Vermilion staining glycogen-rich IgA (eg, Flame cells (picture 7))

Overstuffed fibrils (eg, Gaucher-like cells, thesaurocytes)

Crystalline rods

Immunophenotype – Immunohistochemical staining, immunofluorescent studies, and flow cytometry can be used to determine the immunophenotype of bone marrow plasma cells in patients with MM. Key features include [72]:

Presence of either kappa or lambda light chains, but not both

Absence of surface immunoglobulin

Expression of some normal plasma cell markers (eg, CD79a, VS38c, CD138, and CD38)

Absence of CD19 in most instances

Variable expression of CD45 (usually negative), CD56 (usually positive)

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. (See 'Reactive plasmacytosis' below.)

In contrast to normal plasma cells that 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. (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 [73,74]. The genetic changes found in MM are discussed in more detail separately. (See "Multiple myeloma: Pathobiology", section on 'Cytogenetic abnormalities' and "Multiple myeloma: Staging and prognostic studies", section on 'Cytogenetic abnormalities'.)

IMAGING — Imaging is a key part of the evaluation of all patients with suspected MM. Cross-sectional imaging (ie, CT, PET/CT, MRI) is preferred because these modalities are more sensitive than plain radiographs for the detection of most skeletal lesions in MM. Our approach described below is generally consistent with that of the International Myeloma Working Group [75].

These tests are also appropriate in patients receiving intensive therapies to monitor disease response. (See "Multiple myeloma: Evaluating response to treatment", 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 MM [75]. One of three modalities can be used:

Whole body low dose computed tomography (CT) without contrast

Whole body combined fluorine-18-labeled fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG 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 MM. A choice among these depends on availability, cost, institutional preference, and clinical features as follows:

Newly diagnosed MM – At centers where it is available as a standard imaging technique, whole body low dose CT can be used as a baseline assessment of bone involvement. CT is quick, convenient, relatively sensitive, and cost effective in this scenario.

Suspected smoldering MM – For patients with suspected smoldering MM (no bone lesions on CT and no other myeloma-defining features), whole body MRI or MRI of the spine and pelvis are used 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.

Suspected extramedullary disease – For patients with suspected extramedullary disease outside of the spine, whole body PET/CT is particularly useful, as it 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.

In addition, either MRI or PET/CT scan should be performed routinely before making the diagnosis of solitary plasmacytoma or smoldering MM [65,75-77]. (See 'Diagnostic criteria' below.)

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.  

Support for each of these modalities is presented below:

CT – Patients who previously would have met criteria for smoldering MM 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 [78]. 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 – PET/CT scanning using fluorine-18-labeled (18F) FDG is more sensitive and specific than skeletal survey for the detection of bone lesions and may be more sensitive than CT for the detection of extramedullary disease [79-83]. 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 [84].

MRI – 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 [85-87]. Patients with otherwise asymptomatic MM 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 [88-90].

In one study in which 611 patients with MM 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 [85]. 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 kidney failure (dialysis-dependent or estimated glomerular filtration rate <30 mL/min), the gadolinium administration should be avoided if possible due to an increased risk for nephrogenic systemic fibrosis. This issue and the role of hemodialysis after the procedure if gadolinium-based imaging must be performed are discussed separately. (See "Patient evaluation before gadolinium contrast administration for magnetic resonance imaging", section on 'Approach to preventing nephrogenic systemic fibrosis' and "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease", section on 'Prevention'.)

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 [91]. 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 2) [9,92,93]. 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

When to suspect MM — 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 (M) 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 kidney failure with a bland urinalysis or rarely the nephrotic syndrome due to concurrent primary amyloidosis

Major delays in diagnosis have been associated with a negative impact on the disease course [94]. The urgency of evaluation of suspected MM is guided by the presenting signs and symptoms. While the presentation is usually subacute, a small percentage of patients present acutely with findings that require immediate hospitalization with urgent evaluation and intervention. This includes patients with spinal cord compression, acute kidney failure, severe hypercalcemia, and/or hyperviscosity. Asymptomatic or minimally symptomatic patients can be evaluated as outpatients.

Evaluation — When assessing a patient suspected of having MM, the history should elicit information regarding bone pain, constitutional symptoms, neurologic 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 (algorithm 1) [95-98]:

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 (LDH), and beta-2 microglobulin (B2M). (See "Multiple myeloma: Staging and prognostic studies".)

A routine urinalysis.

A serum protein electrophoresis (SPEP) with immunofixation and quantitation of immunoglobulins. (See "Laboratory methods for analyzing monoclonal proteins".)

Serum free light chain (FLC) assay. Serum FLC analysis may be used in place of a 24-hour urine collection in conjunction with SPEP and immunofixation for screening purposes [99]. However, if a plasma cell proliferative disorder is identified, a 24-hour urine collection for electrophoresis (UPEP) and immunofixation is important in order to quantify the M protein and total urine protein concentration. (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). A bone marrow evaluation is indicated for all patients with MM at diagnosis.  

Cross-sectional imaging (CT, MRI, PET/CT) is preferred over plain radiographs for the detection of bone involvement in patients being evaluated for suspected MM. A choice among these depends on availability, cost, institutional preference, and clinical features. (See 'Choice of modality' above.)

Diagnostic criteria — The International Myeloma Working Group criteria for the diagnosis of MM emphasize the importance of end-organ damage in making the diagnosis (table 3) [65].

The diagnosis of MM requires 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 (kidney impairment), 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 "Multiple myeloma: Overview of management", section on 'Verify 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 (kidney impairment) – Estimated or measured creatinine clearance <40 mL/min or serum creatinine >2 mg/dL (177 micromol/liter). Of these, creatinine clearance is the preferred measure of kidney impairment because normal serum creatinine levels vary by age, sex, and race. Using creatinine clearance ensures that a similar level of kidney dysfunction is required to define end-organ damage.

Bone lesions – One or more osteolytic lesions ≥5 mm in size on skeletal radiography, magnetic resonance imaging (MRI), computed tomography (CT), or combined positron emission tomography/computed tomography (PET/CT). In the absence of osteolytic lesions, the following are not sufficient markers of bone lesions: increased fluorodeoxyglucose (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 (often recalled by the acronym "SLiM," representing "Sixty," "Light chain ratio," MRI) – One or more of the following:

≥60 percent clonal plasma cells in the bone marrow [70,71].

Involved/uninvolved FLC ratio of 100 or more (provided involved FLC level is at least 100 mg/L) [62-64].

MRI with more than one focal lesion (involving bone or bone marrow) [88-90].

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 nonsecretory 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 kidney 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) [100], Waldenström macroglobulinemia (WM), solitary plasmacytoma, primary amyloidosis (AL), POEMS syndrome, and metastatic carcinoma (table 4 and table 5). Distinguishing features of these conditions are listed below.

Other plasma cell dyscrasias

MGUS — MGUS is diagnosed in persons who meet the following three criteria (table 3 and algorithm 1):

Serum monoclonal (M) protein (whether IgA, IgG, or IgM) <3 g/dL

Clonal bone marrow plasma cells <10 percent

Absence of lytic lesions, anemia, hypercalcemia, and kidney impairment (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 [101]. Differentiation of MGUS from MM can be difficult and is primarily based on presence or absence of related end-organ damage (table 6). 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 — SMM is defined as:

M protein ≥3 g/dL and/or 10 to 60 percent bone marrow plasma cells, plus

No end-organ damage or other myeloma-defining events, and no amyloidosis (table 3) [65]

Thus, for the diagnosis of SMM, patients should not have any of the following myeloma-defining events:

End-organ damage (lytic lesions, anemia, kidney disease, or hypercalcemia) that can be attributed to the underlying plasma cell disorder

≥60 percent clonal plasma cells in the bone marrow [70,71]

Involved/uninvolved free light chain (FLC) ratio of 100 or more [62-64]

Magnetic resonance imaging (MRI) with more than one focal lesion (involving bone or bone marrow) [88-90]

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 [65]. (See 'Diagnostic criteria' above.)

If there are doubts about the differentiation of MGUS/SMM from MM, and whether to begin chemotherapy immediately, one should withhold treatment and re-evaluate in two or three months. Patients with SMM may remain stable for prolonged periods. (See "Smoldering multiple myeloma".)

Waldenström macroglobulinemia versus IgM MM — 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 or other tissues (eg, anemia, lymphadenopathy, hepatosplenomegaly) or the effects of monoclonal IgM in the blood (eg, hyperviscosity, peripheral neuropathy). (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 (IgM) is seen in <1 percent of patients with MM. The LPL 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. Identification of the MYD88 L265P gene mutation helps differentiate WM from IgM MM as well, as it has been identified in over 90 percent of patients with WM and <5 percent of IgM MM [102].

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.

Classic MM with an IgM paraprotein (IgM MM) is extremely rare, comprising only 0.5 percent of a Mayo Clinic series [9]. The Mayo Clinic criteria for diagnosis of IgM MM (and its differentiation from WM) require presence of lytic bone lesions felt secondary to the plasma cell disorder and/or evidence of the t(11;14) translocation [103]. The criteria are conservative and designed to emphasize specificity over sensitivity and ensure that patients with WM are not misclassified and treated as MM 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.

Cross-sectional imaging (eg, MRI, PET/CT) is normal except for the primary solitary lesion.

Absence of lytic lesions, anemia, hypercalcemia, and kidney impairment.

Note that patients who have a biopsy-proven solitary medullary or extramedullary lesion with a small percentage 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 "solitary plasmacytoma with minimal marrow involvement" if clonal bone marrow plasma cells are <10 percent. Conversely, a patient with a plasmacytoma is considered to have MM (typically Durie-Salmon stage 1) if clonal bone marrow plasma cells are ≥10 percent. (See "Multiple myeloma: Staging and prognostic studies".)

AL amyloidosis and light chain deposition disease — 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 [104]. 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.

Heavy chain deposition disease — The heavy chain diseases are rare B cell proliferative disorders characterized by the production of an M protein consisting of a portion of the immunoglobulin heavy chain without a bound light chain. Three types are recognized, based on the class of immunoglobulin heavy chain produced (eg, alpha, gamma, mu) by the malignant cell. (See "The heavy chain diseases".)

Immunohistochemical staining of an affected tissue (eg, mass lesion, lymph node, bone marrow) shows a clonal population of cells staining positively for a heavy chain but negative for both kappa and lambda light chains.

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 disease, organomegaly, endocrinopathy (excluding diabetes mellitus or hypothyroidism), edema, typical skin changes, and/or papilledema. These patients typically have elevated serum vascular endothelial growth factor (VEGF) levels. (See "POEMS syndrome".)

Polyneuropathy is uncommon as a presenting symptom in classical MM and, when present, is often due to the presence of coexisting AL amyloidosis. The presence of anemia, hypercalcemia, kidney 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 bone metastasis in adults".)

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 2).

Reactive plasmacytosis — 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.

PROGNOSIS — While overall outcomes for patients with MM have improved substantially in recent decades, MM is a heterogeneous disease with some patients progressing rapidly despite treatment and others responding to treatment for many years. The prognosis of MM is presented separately. (See "Multiple myeloma: Staging and prognostic studies".)

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: Multiple myeloma".)

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 education" and the keyword(s) of interest.)

Basics topics (see "Patient education: Multiple myeloma (The Basics)" and "Patient education: Bone metastases (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)")

SUMMARY

Clinical presentation – Multiple myeloma (MM) is typically characterized by the neoplastic proliferation of immunoglobulin-producing plasma cells. Most patients 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. (See 'Clinical presentation' above.)

Common presentations include anemia, bone pain, elevated creatinine or serum protein, fatigue, and hypercalcemia.

Less common presentations that require urgent evaluation include spinal cord compression, acute kidney failure, severe hypercalcemia, and hyperviscosity.

Evaluation of suspected cases – In patients with suspected MM or related disorders, appropriate initial screening tests include a serum protein electrophoresis along with immunofixation, and a serum free light chain (FLC) assay. (See 'Evaluation' 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 (algorithm 1). A 24-hour urine collection for electrophoresis and immunofixation is important in order to quantify the monoclonal protein and total urine protein concentration. (See 'Evaluation' above.)

Bone marrow infiltration with malignant plasma cells may be focal, requiring aspiration/biopsy at multiple sites. Magnetic resonance imaging (MRI) and/or positron emission tomography (PET) can be helpful in locating focal disease. (See 'Imaging' above.)

Diagnostic criteria – The diagnosis of MM requires (table 3) (see 'Diagnostic criteria' above):

≥10 percent clonal plasma cells in the bone marrow or biopsy-proven bony or soft tissue plasmacytoma

Plus one of the following:

Organ or tissue impairment that can be attributed to the plasma cell proliferative disorder (eg, increased calcium, kidney impairment, anemia, lytic bone lesions)

A biomarker associated with near inevitable progression to end-organ damage (ie, ≥60 percent clonal plasma cells in the bone marrow; involved/uninvolved FLC ratio of 100 or more [the involved FLC level must also be at least 100 mg/L or more]; or MRI with more than one focal lesion)

Differential diagnosis – The main conditions to consider in the differential diagnosis for MM include monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, Waldenström macroglobulinemia, solitary plasmacytoma, AL amyloidosis, POEMS syndrome, and metastatic carcinoma (table 6 and table 4). (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Robert A Kyle, MD to earlier versions of this topic review.

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Topic 6649 Version 101.0

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