Multiple myeloma (MM) is a malignant proliferation and diffuse infiltration of monoclonal plasma cells in the bone marrow. Malignant plasma cells produce monoclonal proteins (also known as M proteins or paraproteins) such as abnormal immunoglobulins (e.g., IgG, IgA) and free light chains (e.g., Bence Jones proteins). MM is more common in older adults and manifests with nonspecific symptoms (fever, night sweats, weight loss), symptoms of hypercalcemia, bone pain, and/or back pain. This condition is sometimes discovered incidentally in asymptomatic individuals. The proliferation of plasma cells suppresses normal bone marrow function, which may lead to anemia, bleeding, and/or infection. Plasma cell proliferation can also result in osteolysis and hypercalcemia. Renal complications are common, including myeloma cast nephropathy, light chain deposition disease, amyloid light-chain (AL) amyloidosis with renal involvement, and nephrocalcinosis. Most patients are treated with a combination of high-dose chemotherapy and autologous stem cell transplantation; patients with impaired functional status are treated with chemotherapy alone. While advancements in treatment regimens have resulted in improved patient outcomes, most patients with MM eventually relapse.characterized by uncontrolled
- Plasma cell dyscrasia: a group of conditions characterized by the abnormal proliferation of the same type (=monoclonal) of a plasma cell that may also secrete a monoclonal immunoglobulin and/or immunoglobulin fragment (e.g., light chain)
- Solitary plasmacytoma: an early-stage plasma cell dyscrasia characterized by a single lesion that affects bones (solitary plasmacytoma of bone) or soft tissue (solitary extramedullary plasmacytoma), or in rare cases multiple solitary lesions in soft tissue, bone or both (multiple solitary plasmacytoma)
- Multiple myeloma: a malignant plasma cell dyscrasia characterized by uncontrolled proliferation and the diffuse infiltration of monoclonal plasma cells in the bone marrow
- Neoplastic proliferation of plasma cells
- Overproduction of monoclonal immunoglobulin and/or light chains → dysproteinemia (a state of pathologically increased synthesis of immunoglobulins and/or their subunits) → kidney damage (e.g., myeloma cast nephropathy) and/or paraprotein tissue deposition (may cause amyloidosis) 
- Often asymptomatic
- Mild fever, night sweats, weakness, and weight loss
- Bone pain, especially back pain (most common symptom)
- Symptoms of
- Spontaneous fractures
- Increased risk of infection
- Increased risk of petechial bleeding
- Foamy urine (caused by in urine)
Enlarged lymph nodes are not a typical finding.
- Obtain a minimum diagnostic workup.
- Refer to an oncologist for diagnostic confirmation via bone marrow biopsy.
- Evaluate for diagnostic criteria of multiple myeloma.
- Use the Revised International Staging System (R-ISS) to categorize the disease state.
- Consider differential diagnoses (e.g., other , other or bone lesions).
|International Myeloma Working Group diagnostic criteria for multiple myeloma |
Myeloma defining events
|End-organ damage (CRAB criteria)|
|Biomarkers of malignancy|
Laboratory tests 
- CBC (with differential and peripheral smear)
- Inflammatory markers: Increased ESR
- Urinalysis: : may be negative for protein
- Immunoglobulin studies (common initial tests)
- Increased β2 microglobulin 
- Increased LDH
- Urine protein electrophoresis (UPEP) with immunofixation
- 24-hour urine protein and creatinine
Further evaluation for differential diagnoses (guided by clinical features) may include:
- PTH, vitamin D levels) (e.g.,
- Biochemical evaluation for fatigue and unexplained weight loss (e.g., , )
- vitamin B12 levels, ) (e.g.,
- (e.g., testing for or )
Imaging studies 
Whole-body low-dose CT (WBLDCT)
Low sensitivity; no longer considered the best initial test
- Inconclusive WBLDCT
- Alternative option for baseline and follow-up bone surveillance
- Indication: : confirmatory test indicated for all patients with suspected multiple myeloma
- Fluorescence in situ hybridization (FISH): used for staging of multiple myeloma 
- Cytology: clusters of plasma cells
Revised International Staging System (R-ISS) 
The R-ISS is currently the most commonly used staging system.
|Revised International Staging System for multiple myeloma |
|Stage||Laboratory features||5-year overall survival rate|
|II|| || |
|III|| || |
The R-ISS for multiple myeloma incorporates LDH levels and in addition to the variables used in the International Staging System (i.e., β2 microglobulin and albumin), which improves its ability to stratify risk and determine the prognosis of patients with newly diagnosed multiple myeloma. 
International Staging System (ISS) 
|International Staging System for multiple myeloma |
|Stage||Laboratory features||Median survival from diagnosis|
> 5 years
Not stage I or stage III
β2 microglobulin ≥ 5.5 mg/L
Durie-Salmon staging system
|Durie-Salmon staging system for multiple myeloma |
|Stage I: All of the following must be present.||Stage II||Stage III: ≥ 1 of the following must be present.|
|Blood: hemoglobin||> 10 g/dL||Not stage I or stage III||< 8.5 g/dL|
|Blood: serum calcium||Normal (< 2.8 mmol/L)||> 3.0 mmol/L|
|Urine: monoclonal Ig||Low concentration||High concentration|
|X-ray: bones||One (maximum) solitary osteolytic lesion||Several advanced osteolytic lesions|
General principles 
Choice of treatment based on:
- Risk stratification (e.g., R-ISS stage)
- Eligibility for ( )
- HSCT eligible: induction chemotherapy followed by autologous HSCT
- HSCT ineligible: chemotherapy alone (e.g., dexamethasone and lenalidomide)
- Goal of therapy: the highest level of remission with the best quality of life
- Prevention and management of complications (e.g., VTE, AKI, bone lesions) is an integral part of treatment.
Refer all patients to a transplant center to determine eligibility for stem cell transplantation.
Stem cell transplantation 
- Eligibility: based on performance status (e.g., , ) and comorbidities
- Process typically includes the following:
Neither advanced age nor poor renal function are absolute contraindications for autologous stem cell transplantation.
Autologous stem cell transplantation improves median overall survival by ∼12 months but is not curative. 
There is no expert consensus regarding the optimal chemotherapeutic regimen or number of cycles.
Transplant eligible patients
- melphalan : high-dose
- Maintenance therapy
- Transplant ineligible patients: immunomodulators and/or proteasome inhibitors PLUS a steroid (e.g., Rd, VRd)
|Overview of  commonly used for multiple myeloma|
|Medication class||Common agents|
|For the mechanism of action and common adverse effects, see “.”|
Choice of regimen depends on transplant eligibility, disease risk factors (e.g., R-ISS stage, cytogenetics), patient factors (e.g., frailty, comorbidities, functional status), and patient preferences (e.g., length and quality of life).
Response to treatment
- Defined based on International Myeloma Working Group (IMWG) criteria 
- Categories range from stringent complete response to progressive disease
- Clinical relapse
Nearly all patients will relapse; the average time to first relapse is ∼ 3–4 years after initial diagnosis.
Prevention of complications 
- Recommended immunizations 
- Bacteremia and sepsis prophylaxis during the first two cycles of chemotherapy; e.g., levofloxacin (off label) 
- corticosteroids; e.g., low‑dose TMP/SMX for patients receiving high-dose
- Herpes zoster prophylaxis for patients receiving proteasome inhibitors; e.g., valacyclovir (off label) or acyclovir (off label) 
- : e.g., avoid nephrotoxic medications, maintain adequate hydration status
Management of complications 
Management should be provided under specialist guidance.
|Overview of the management of complications of multiple myeloma|
|Bone disease || |
|Renal disease |
|Peripheral neuropathy |
|Hematological complications ||Anemia|
All patients with active multiple myeloma should be treated with bisphosphonates (unless contraindicated), regardless of the presence or absence of imaging findings of bone disease related to multiple myeloma.
Bisphosphonate therapy and denosumab both increase the risk of osteonecrosis of the jaw. Ensure patients undergo a comprehensive dental evaluation and any necessary dental procedures before starting therapy for bone disease. 
Overview of plasma cell dyscrasias (PCDs)
Multiple myeloma should be differentiated from other plasma cell dyscrasias.
|Diagnostic criteria for plasma cell dyscrasias associated with multiple myeloma |
|Plasma cell dyscrasia||Diagnostic criteria|
|Plasma cell leukemia|
|POEMS syndrome|| |
|Monoclonal gammopathy of undetermined significance (MGUS)|
|Waldenstrom macroglobulinemia |
Monoclonal gammopathy of undetermined significance (MGUS) 
Characterized by complete or incomplete monoclonal immunoglobulins (of any class) detectable in patient serum without accompanying clinical symptoms
- Prevalence: ∼ 3% in general population ≥ 50 years of age 
- The most common type of plasma cell dyscrasia (PCD)
- Non-IgM MGUS (IgG, IgA, IgD MGUS): most common form of MGUS (∼ 55% of cases)
- IgM MGUS: ∼ 15% of cases
- Light-chain MGUS (LC-MGUS)
Risk stratification 
- Low-risk MGUS includes all of the following:
- Moderate to high-risk MGUS: any feature not considered low-risk
- Usually diagnosed as an incidental finding
- Universal screening is not routinely recommended.
- Diagnostic criteria may help establish a diagnosis; see “Diagnostic criteria for plasma cell dyscrasias.”
- Initial studies
- Additional studies: usually reserved for patients with moderate to high risk of progression to malignancy or if there is evidence of transformation to another plasma cell dyscrasia (i.e., M-protein concentration ≥ 3 g/dL, findings of a severe PCD) 
- Management is usually expectant.
- Long-term follow up: Monitor for progression to lymphoplasmacytic malignancy.
- Multiple myeloma
- Light chain amyloidosis: can occur with all forms of MGUS
- Waldenstrom macroglobulinemia: only arises from IgM MGUS
- Increased risk of thrombosis (thromboprophylaxis is usually not required) and developing osteoporosis (bone densitometry should be performed at the time of diagnosis)
Waldenstrom macroglobulinemia 
Mostly occurs in older adults
- Peripheral neuropathy
- Impaired platelet function → hemorrhagic diathesis with petechial bleeding
- Normochromic anemia
- Formation of cold agglutinins (IgM) with hyperviscosity syndrome
- Lymph node enlargement possible
- Constitutional symptoms (e.g., fatigue)
Diagnostic criteria may help establish a diagnosis; see “Diagnostic criteria for plasma cell dyscrasias.”
- Routine studies
- Immunoglobulin studies
- Bone marrow biopsy and aspirate: ≥ 10% abnormal plasma cells with Dutcher bodies (periodic acid-Schiff positive, cytoplasmic inclusions of IgM deposits that invaginate into the nucleus) 
- Imaging studies: Consider a of the chest, abdomen, and pelvis.
Additional studies for suspected
- Serum viscosity measurement
- Ophthalmologic evaluation
Overproduction of monoclonal IgM suggests Waldenstrom macroglobulinemia rather than multiple myeloma.
Usually reserved for symptomatic patients
- Targeted treatment: anti-CD20 antibodies (e.g., rituximab), (e.g., ibrutinib), purine nucleoside analogs (fludarabine and cladribine), alkylating agents (e.g., cyclophosphamide)
- Hyperviscosity syndrome: plasmapheresis
Good, as it is a type of indolent lymphoma
See “Diagnostic criteria for plasma cell dyscrasias” for details.
- Definition: a rare plasma cell disorder that causes chronic overproduction of proinflammatory cytokines
- Clinical features include:
The differential diagnoses listed here are not exhaustive.
Dysproteinemia-associated kidney disease 
(i.e., myeloma kidney): most common cause of renal injury and renal failure in patients with multiple myeloma
- Clinical features: oliguria, peripheral edema, dyspnea
- Pathophysiology: excessive production and filtration of light chains into the urine → precipitation of light chains in renal tubules → tubular obstruction
- Diagnosis: markedly positive urine sulfosalicylic acid test and/or urine protein electrophoresis
- May progress to ESRD) (
- Monoclonal immunoglobulin deposition disease (MIDD)
Type I cryoglobulinemia
- An immune-mediated disorder characterized by the deposition of monoclonal immunoglobulins (IgG and IgM) within blood vessels.
- Most commonly associated with protein-secreting monoclonal gammopathies, including monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, and multiple myeloma.
- Type II cryoglobulinemia
- Immunotactoid glomerulopathy
- Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID)
- Monoclonal gammopathy-associated C3 glomerulopathy
- Light-chain proximal tubulopathy
- Monoclonal IgM-mediated kidney disease
- Monotypic fibrillary glomerulonephritis
- (i.e., myeloma kidney): most common cause of renal injury and renal failure in patients with multiple myeloma
- Hypercalcemia-associated renal damage: leads to hypercalciuria and nephrocalcinosis
- Analgesic nephropathy: caused by long-term intake of NSAIDs for bone pain
- : Light chains can accumulate as amyloids and may lead to restrictive cardiomyopathy, renal insufficiency, macroglossia, and malabsorption syndromes.
- Secondary plasma cell leukemia 
- Hypercalcemic crisis: Osteolysis is associated with chronically elevated calcium levels, which can result in a hypercalcemic crisis.
We list the most important complications. The selection is not exhaustive.