Multiple myeloma (MM) is a malignant plasma cell dyscrasia characterized by uncontrolled 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.
- 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
- Based on immunoglobulin type 
Neoplastic proliferation of plasma cells
- Bone marrow infiltration by malignant plasma cells → suppression of hematopoiesis → leukopenia, thrombocytopenia, anemia
- Cell proliferation → pro-osteoclastogenic factors (e.g., TNF-α, IL-1, RANK-L) → osteolytic lesions → hypercalcemia
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) 
- Nonfunctioning antibodies → functional antibody deficiency
- ↑ Serum viscosity → hyperviscosity syndrome
- Often asymptomatic
- Mild fever, night sweats, weakness, and weight loss
- Bone pain, especially back pain (most common symptom)
- Symptoms of hypercalcemia
- Spontaneous fractures
- Increased risk of infection
- Increased risk of petechial bleeding
- Foamy urine (caused by Bence Jones proteins in urine)
Enlarged lymph nodes are not a typical finding.
- Obtain a minimum diagnostic workup.
- Initial laboratory studies (e.g., CBC, CMP, urinalysis)
- Myeloma biomarkers (e.g., serum and urine protein electrophoresis, free light chain assay, LDH)
- Imaging to assess for bone lesions (e.g., whole-body low-dose CT scan)
- 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 plasma cell dyscrasias; , other causes of hypercalcemia or bone lesions).
Evaluation of a patient with suspected multiple myeloma (e.g., a patient with CRAB criteria) should include CBC, CMP, immunoglobulin studies, LDH, β2 microglobulin, bone imaging, and a bone marrow biopsy.
|International Myeloma Working Group diagnostic criteria for multiple myeloma |
Myeloma defining events
|End-organ damage (CRAB criteria)|| |
|Biomarkers of malignancy|| |
CRAB criteria for organ damage due to a plasma cell disorder: Calcium increased, Renal insufficiency, Anemia, Bone lesions
Evaluation for biomarkers of malignancy may allow for diagnosis and treatment of multiple myeloma before end-organ damage has occurred.
Laboratory tests 
- CBC (with differential and peripheral smear)
- Increased creatinine
- Elevated total protein with paraprotein (gamma) gap
- Inflammatory markers: Increased ESR
- Urinalysis: : may be negative for protein
Immunoglobulin studies (common initial tests)
- Serum protein electrophoresis (SPEP): presence of M protein (M spike)
- Serum protein immunofixation: monoclonal gammopathy
- Serum free light chain assay (SFLC): increased κ or λ light chains, increased SFLC involved:uninvolved ratio
- Quantitative immunoglobulin levels (IgA, IgG, IgM) can help determine if proteinemia on SPEP is monoclonal.
- Increased β2 microglobulin 
- Increased LDH
- Immunoglobulin studies (common initial tests)
Urine protein electrophoresis (UPEP) with immunofixation
- Bence Jones proteins: monoclonal immunoglobulin light chains produced by neoplastic cells
- Bence Jones proteinuria is suggestive of plasma cell disorders (e.g., multiple myeloma, Waldenstrom macroglobulinemia).
- 24-hour urine protein and creatinine
- Urine protein electrophoresis (UPEP) with immunofixation
Further evaluation for differential diagnoses (guided by clinical features) may include:
- Biochemical evaluation of bone disease (e.g., PTH, vitamin D levels)
- Biochemical evaluation for fatigue and unexplained weight loss (e.g., thyroid function test, diabetes mellitus screening)
- Diagnostic workup for polyneuropathy (e.g., vitamin B12 levels, nerve conduction studies)
- Thrombophilia workup (e.g., testing for hereditary thrombophilia or acquired thrombophilias)
Imaging studies 
Whole-body low-dose CT (WBLDCT)
- First-line test for baseline and follow-up bone surveillance
- More sensitive than x-rays in detecting focal lesions
- Used to guide radiotherapy, biopsies, and surgery
- Detection of osteolysis and osteopenia
- Identification of vertebral instability and fracture risk
- Bone marrow plasma cell infiltration in long bones
Low sensitivity; no longer considered the best initial test
- Multiple lytic lesions ("punched-out" holes), e.g., in the skull
- Inconclusive WBLDCT
- Alternative option for baseline and follow-up bone surveillance
- MRI (whole-body or spine and pelvis): highest sensitivity for diffuse bone marrow involvement
- FDG-PET/CT scan: highest sensitivity for extramedullary disease and active lytic bone lesions
Bone marrow biopsy
- 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
- Mildly organized monoclonal cells
- Perinuclear lucent zone
- Clockface nuclei: Chromatin in the periphery of the nucleus resembles a cartwheel or clock face arrangement.
- Intracytoplasmic crystalline inclusion bodies containing IgG
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|
|I|| || |
|II|| || |
|III|| || |
The R-ISS for multiple myeloma incorporates LDH levels and FISH 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|
β2 microglobulin < 3.5 mg/L AND albumin ≥ 3.5 g/dL
> 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 autologous hematopoietic stem cell transplantation (HSCT)
- 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., ECOG, Karnofsky score) and comorbidities
Process typically includes the following:
- Induction chemotherapy (3–4 cycles)
- Hematopoietic stem cell collection (from peripheral blood)
- Conditioning regimen
- Autologous HSCT
- Maintenance chemotherapy or consolidation therapy (at least 2 cycles) as an alternative
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
- Standard risk: (e.g., R-ISS stage I or II) immunomodulator PLUS proteasome inhibitor PLUS steroid (e.g., VRd)
- High risk (e.g., R-ISS stage III): additional cancer immunotherapy (e.g., D-VRd)
- Conditioning regimen: high-dose melphalan
- Standard risk: lenalidomide monotherapy; bortezomib monotherapy as an alternative
- High risk: proteasome inhibitor with or without lenalidomide
- Induction therapy
- Transplant ineligible patients: immunomodulators and/or proteasome inhibitors PLUS a steroid (e.g., Rd, VRd)
|Overview of chemotherapeutic agents commonly used for multiple myeloma |
|Medication class||Common agents|
|Proteasome inhibitors|| |
|Cancer immunotherapy|| |
|For the mechanism of action and common adverse effects, see “Chemotherapeutic agents.”|
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
- Defined as recurrence or worsening of myeloma-defining events (e.g., CRAB) after clinical improvement 
- Management (i.e., salvage/delayed autologous HSCT and/or chemotherapy) should be individualized.
- After a relapse, therapy may be continued until the disease progresses.
Nearly all patients will relapse; the average time to first relapse is ∼ 3–4 years after initial diagnosis.
Prevention of complications 
Recommended immunizations 
- Recombinant zoster
- Haemophilus influenzae
- Pneumococcal vaccines
- Bacteremia and sepsis prophylaxis during the first two cycles of chemotherapy; e.g., levofloxacin (off label) 
- PCP prophylaxis for patients receiving high-dose corticosteroids; e.g., low‑dose TMP/SMX
- Herpes zoster prophylaxis for patients receiving proteasome inhibitors; e.g., valacyclovir (off label) or acyclovir (off label) 
- Recommended immunizations 
- Prevention of acute kidney injury: e.g., avoid nephrotoxic medications, maintain adequate hydration status
- Indicated for all patients, especially those receiving immunomodulatory agents (e.g., lenalidomide)
- The preferred agent (e.g., aspirin, direct oral anticoagulant, LMWH, warfarin) depends on the patient's individual risk of thrombosis.
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|| |
Treatment of pain (e.g., due to compressive myelopathy or pathological fractures) includes low-dose radiotherapy, high-dose corticosteroids, and invasive therapy (e.g., vertebroplasty, balloon kyphoplasty).
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|
|Solitary plasmacytoma|| |
|Plasma cell leukemia|| |
|POEMS syndrome|| |
|Monoclonal gammopathy of undetermined significance (MGUS)|| |
|Waldenstrom macroglobulinemia || |
POEMS syndrome: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell proliferative disorders, Skin changes
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 
Patients can be stratified into the following categories according to their risk of progression to multiple myeloma or related malignancy.
Low-risk MGUS includes all of the following:
- Nonimmunoglobulin G-type M protein
- M-protein concentration < 1.5 g/dL
- Normal SFLC ratio
- 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.”
- CBC, serum creatinine, and calcium
- SPEP and UPEP with immunofixation
- Quantitative immunoglobulin assessment
- SFLC assay
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) 
- Bone marrow biopsy
- WBLDCT (modality of choice)
- A skeletal survey is indicated if CT is not available.
- Whole-body MRI is indicated in patients with inconclusive CT results.
- Management is usually expectant.
Long-term follow up: Monitor for progression to lymphoplasmacytic malignancy.
- Studies: CBC, serum calcium and creatinine, SPEP, and SFLC assays
- Cadence: 6 months after diagnosis and then every 1–3 years.
Monitor patients with MGUS 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 
A type of non-Hodgkin lymphoma associated with abnormal production of monoclonal IgM antibodies
Mostly occurs in older adults
- Extremities are involved first with progressive, proximal, symmetrical spread
- Presents with paresthesias and weakness (sensory and motor nerve involvement)
- Impaired platelet function → hemorrhagic diathesis with petechial bleeding
- Normochromic anemia
Formation of cold agglutinins (IgM) with hyperviscosity syndrome
- Raynaud phenomenon
- Impaired acral blood flow
- Cerebral venous thrombosis
- Impaired vision (e.g., blurry vision)
- Retinal hemorrhages, engorged retinal veins on fundoscopic exam
- Impaired hearing
- Impaired renal function
- Lymph node enlargement possible
- Constitutional symptoms (e.g., fatigue)
Diagnostic criteria may help establish a diagnosis; see “Diagnostic criteria for plasma cell dyscrasias.”
- CBC, CMP
- Increased ESR, uric acid, LDH, and alkaline phosphatase
- Serum β2 microglobulin level
- SPEP and UPEP with immunofixation
- Quantitative serum immunoglobulin levels
- 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 contrast-enhanced CT scan of the chest, abdomen, and pelvis.
Additional studies for suspected hyperviscosity syndrome
- 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), Bruton tyrosine kinase inhibitors (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:
- Increased production of monoclonal plasma proteins
- Skin changes
The differential diagnoses listed here are not exhaustive.
Dysproteinemia-associated kidney disease 
Myeloma cast nephropathy (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 end-stage renal disease (ESRD)
- Monoclonal immunoglobulin deposition disease (MIDD)
- Light chain deposition disease (LCDD)
- Heavy chain deposition disease (HCDD)
- Light and heavy chain deposition disease (LHCDD)
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
- Myeloma cast nephropathy (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
- AL amyloidosis: Light chains can accumulate as amyloids and may lead to restrictive cardiomyopathy, renal insufficiency, macroglossia, and malabsorption syndromes.
- Increased risk due to immunodeficiency (nonfunctional immunoglobulins) and side effects of medications
- Major cause of death in patients with multiple myeloma
Secondary plasma cell leukemia 
- Leukemic course secondary to multiple myeloma
- Diffuse spreading of abnormal cells and distribution of large amounts of plasma cells into the circulatory system
- Rare; occurs in 2–3% of cases
- 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.
- The course of disease and prognosis are highly variable.
- Therapeutic options have improved significantly. However, complete remission is rare.
- Poor prognostic factors include
- Advanced stage according to the R-ISS staging system
- Advanced age
- ↑ β2 microglobulin
- ↓ Serum albumin
- ↑ CRP
- ↑ LDH