Clonal plasma cell malignancy with monoclonal protein, lytic bone disease, hypercalcemia, anemia, and renal failure (CRAB).
Also known as: MM, multiple myeloma, plasma cell myeloma, myeloma
Overview
Clonal proliferation of malignant plasma cells in the bone marrow, producing a monoclonal immunoglobulin or light chain (M protein) and causing end-organ damage. Diagnostic criteria require ≥10% clonal plasma cells in marrow (or plasmacytoma) PLUS evidence of myeloma-defining events: CRAB features (hyperCalcemia, Renal failure, Anemia, Bone lesions) OR myeloma-defining biomarkers (clonal plasma cells ≥60%, serum free light chain ratio ≥100, >1 focal lesion on MRI).
Epidemiology
Annual US incidence ~7 per 100,000. Median age at diagnosis ~69 years (rare under 40). Twice as common and presents at younger age in Black patients. Slight male predominance. Preceded by monoclonal gammopathy of undetermined significance (MGUS) in nearly all cases; smoldering myeloma is an intermediate state.
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Question 1HematologyMedium
A 72-year-old man presents with several weeks of worsening lower back pain. Laboratory studies show hypercalcemia and a monoclonal (M) spike on serum protein electrophoresis. Urine studies reveal Bence-Jones (monoclonal light-chain) proteinuria, and a bone marrow biopsy shows 30% clonal plasma cells. Which of the following is the most likely diagnosis?
AMultiple myeloma
BMonoclonal gammopathy of undetermined significance
CSolitary plasmacytoma
DWaldenström's macroglobulinemia
Reveal answer & full explanation
Correct answer: A — Multiple myeloma
AMultiple myeloma✓
BMonoclonal gammopathy of undetermined significance
CSolitary plasmacytoma
DWaldenström's macroglobulinemia
Why Multiple myeloma is correct
Multiple myeloma is defined by clonal bone marrow plasma cells (≥10%) plus end-organ damage from the CRAB criteria: hyperCalcemia, Renal insufficiency, Anemia, and lytic Bone lesions
This patient has 30% marrow plasma cells, an M-spike on serum protein electrophoresis, hypercalcemia, bone pain, and Bence-Jones (light-chain) proteinuria — diagnostic of symptomatic myeloma
The combination of a monoclonal protein with myeloma-defining end-organ damage distinguishes it from premalignant plasma cell disorders
Why the others are wrong
Monoclonal gammopathy of undetermined significance — requires <10% marrow plasma cells, an M-protein <3 g/dL, and NO end-organ damage; the 30% plasma cells and hypercalcemia exclude it (premature closure on the M-spike alone)
Solitary plasmacytoma — is a single localized plasma cell mass with a normal marrow and no CRAB features; the diffuse marrow involvement defeats it (confused-with localized plasma cell disease)
Waldenström's macroglobulinemia — is a lymphoplasmacytic lymphoma secreting monoclonal IgM that causes hyperviscosity rather than lytic bone disease or hypercalcemia; the bone/calcium picture defeats it (buzzword-matching a monoclonal protein)
Question 2HematologyMedium
A 68-year-old man presents with 4 months of progressive low back pain, fatigue, and a 6 kg unintentional weight loss. Exam shows pallor and tenderness over the lumbar spine. Labs show Hgb 9.1 g/dL, creatinine 2.3 mg/dL, calcium 11.6 mg/dL, total protein 10.2 g/dL with albumin 3.1 g/dL. Serum protein electrophoresis shows a monoclonal IgG kappa spike of 4.2 g/dL. Skeletal survey reveals multiple lytic lesions in the skull and vertebrae. Which of the following bone marrow findings would best establish the diagnosis?
AReed-Sternberg cells on marrow biopsy
BMarrow infiltration with small mature CD5+ B lymphocytes
CClonal plasma cells comprising 35% of marrow cellularity
DHypercellular marrow with >20% myeloblasts
Reveal answer & full explanation
Correct answer: C — Clonal plasma cells comprising 35% of marrow cellularity
AReed-Sternberg cells on marrow biopsy
BMarrow infiltration with small mature CD5+ B lymphocytes
CClonal plasma cells comprising 35% of marrow cellularity✓
DHypercellular marrow with >20% myeloblasts
Why Clonal plasma cells comprising 35% of marrow cellularity is correct
This patient has classic CRAB features of multiple myeloma: hyperCalcemia (11.6 mg/dL), Renal insufficiency (creatinine 2.3 mg/dL), Anemia (Hgb 9.1 g/dL), and lytic Bone lesions, with a large IgG kappa monoclonal protein spike of 4.2 g/dL
Diagnosis per the International Myeloma Working Group requires clonal bone marrow plasma cells ≥10% (or a biopsy-proven plasmacytoma) PLUS at least one myeloma-defining event
Myeloma-defining events include a CRAB feature or a SLiM criterion: clonal marrow plasma cells ≥60%, involved/uninvolved serum free light chain ratio ≥100, or >1 focal lesion on MRI
Marrow showing 35% clonal plasma cells in a patient with CRAB features establishes the diagnosis
Why the others are wrong
A) Reed-Sternberg cells on marrow biopsy — pathognomonic for Hodgkin lymphoma, which presents with painless lymphadenopathy and B symptoms, not CRAB features or an M-spike
D) Hypercellular marrow with >20% myeloblasts — defines acute myeloid leukemia, which causes pancytopenia and circulating blasts, not lytic bone lesions or a monoclonal IgG spike
B) Marrow infiltration with small mature CD5+ B lymphocytes — defines chronic lymphocytic leukemia, which presents with lymphocytosis and lymphadenopathy, not lytic lesions or hypercalcemia
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Plasma cells in bone marrow undergo somatic hypermutation and class switching during normal differentiation. In myeloma, acquired translocations (often involving IgH locus on chromosome 14 with cyclin D1, MAF, MMSET/FGFR3) and hyperdiploidy drive clonal expansion. Plasma cells produce monoclonal immunoglobulin (intact M protein or free light chains — Bence Jones protein in urine). Bone destruction results from RANKL-driven osteoclast activation; renal failure from light chain deposition (cast nephropathy, light chain deposition disease, AL amyloidosis); anemia from marrow replacement and inflammatory cytokines; hypercalcemia from osteolysis.
Clinical presentation
Symptoms
Bone pain — back, ribs, long bones; worse with movement; pathologic fractures (vertebral compression common)
Fatigue from anemia
Frequent infections (encapsulated organisms — pneumococcus, H. flu; functional hypogammaglobulinemia despite high total protein)
Symptoms of hypercalcemia: confusion, polyuria, polydipsia, nausea, constipation
Symptoms of renal failure: edema, oliguria, uremia
Hyperviscosity (with IgM, IgA, or very high IgG): blurred vision, headaches, confusion, mucosal bleeding
Cord compression — back pain with neurologic deficit; oncologic emergency
Signs of hypercalcemia (dehydration, altered mentation)
Hepatosplenomegaly less common in MM than other plasma cell disorders
Bleeding from coagulopathy or platelet dysfunction
Periorbital ecchymoses ('raccoon eyes'), macroglossia (suggest AL amyloidosis)
Classic findings
Older adult with back pain, anemia, renal failure, hypercalcemia, and 'punched-out' lytic skull lesions on X-ray (Rouleaux formation on smear, M-spike on SPEP).
Differential diagnosis
MGUS — M protein <3 g/dL, marrow plasma cells <10%, NO end-organ damage; ~1%/year progression to MM
Smoldering myeloma — M protein ≥3 g/dL or marrow plasma cells 10-60%, no end-organ damage; intermediate progression risk
Clonal plasma cells ≥10% in marrow (or biopsy-proven plasmacytoma) PLUS ≥1 of: hyperCalcemia (Ca >11 or >1 mg/dL above normal), Renal insufficiency (Cr >2 mg/dL or eGFR <40 attributable to MM), Anemia (Hb <10 or >2 g/dL below normal), Bone lesions (≥1 lytic lesion on imaging), OR myeloma-defining biomarkers (clonal plasma cells ≥60%, FLC ratio ≥100, >1 focal lesion on MRI).
Labs
CBC — normocytic normochromic anemia; Rouleaux formation (stacks of RBCs) on smear
Comprehensive metabolic panel — hypercalcemia, elevated creatinine (renal failure), elevated total protein with normal/low albumin (gamma globulin gap)
Serum protein electrophoresis (SPEP) with immunofixation — identifies and characterizes M protein
• Corticosteroids — dexamethasone (high-dose initially, then weekly)
Autologous stem cell transplant (ASCT) for fit patients <70-75 after induction — improves PFS; tandem ASCT for high-risk
Maintenance: lenalidomide ± bortezomib (for high-risk) until progression
Supportive care: bisphosphonate (zoledronic acid, pamidronate) or denosumab monthly for bone protection (reduces SREs); calcium and vitamin D; VTE prophylaxis with IMiDs (aspirin for standard risk, anticoagulation for high risk); herpes zoster prophylaxis (acyclovir/valacyclovir) with proteasome inhibitors and daratumumab; IVIG for recurrent infections; vaccinations (pneumococcal, influenza, RSV, COVID); avoid live vaccines
Second-line / adjunct
Relapsed/refractory MM: combination therapy with novel agents and previously unused classes; many options including pomalidomide + dexamethasone, carfilzomib + lenalidomide + dexamethasone, daratumumab combinations, selinexor (XPO1 inhibitor)
Cord compression: emergent dexamethasone + radiation therapy or surgical decompression
Hypercalcemia: aggressive IV fluids, calcitonin (quick onset), bisphosphonate, glucocorticoids
Plasmapheresis for hyperviscosity or symptomatic cryoglobulinemia
Renal failure: aggressive hydration, dexamethasone, anti-myeloma therapy (bortezomib-based often used given renal safety); avoid NSAIDs, contrast
Complications
Skeletal-related events (SREs): pathologic fracture (vertebral compression, long bone), spinal cord compression, hypercalcemia, need for radiation or surgery for bone disease
Renal failure — multifactorial: light chain cast nephropathy, hypercalcemia, dehydration, NSAIDs, contrast; up to 50% have renal involvement at diagnosis
Recurrent infections from immune dysfunction — encapsulated organisms; PJP and fungal in heavily treated
AL amyloidosis (~15% of MM) — cardiac, renal, neurologic involvement
Hyperviscosity syndrome with very high M protein
Venous thromboembolism with IMiDs (especially lenalidomide + dexamethasone)
Peripheral neuropathy from bortezomib (use subcutaneous, weekly; switch to ixazomib or carfilzomib), thalidomide
Secondary malignancies: AML/MDS (especially with lenalidomide maintenance and prior alkylator); other solid tumors
CRAB criteria — hyperCalcemia, Renal failure, Anemia, Bone lesions — define active myeloma requiring treatment. Plus updated SLiM-CRAB biomarkers (Sixty percent plasma cells, Light chain ratio ≥100, MRI focal lesions).
MGUS → smoldering myeloma → active myeloma is a continuum. Asymptomatic states are observed; treatment is reserved for active disease (CRAB) or high-risk smoldering.
M-protein on SPEP plus light chains in urine (Bence Jones) plus marrow plasmacytosis is the classic triad.
Whole-body low-dose CT, PET/CT, or whole-body MRI has replaced traditional skeletal survey for bone disease assessment — more sensitive for early lytic lesions.
Quadruplet induction (D-VRd or D-RVd) followed by autologous stem cell transplant followed by lenalidomide maintenance is standard for fit patients.
Bisphosphonates or denosumab are essential to reduce skeletal-related events — give monthly for at least 2 years.
Cord compression is an oncologic EMERGENCY — start dexamethasone immediately, urgent MRI, radiation or surgical decompression.
IMiDs (lenalidomide, pomalidomide, thalidomide) require VTE prophylaxis with aspirin or anticoagulant; teratogenic — REMS program enrollment required.
CAR-T cell therapy (idecabtagene, ciltacabtagene) and bispecific antibodies (teclistamab, talquetamab, elranatamab) have transformed outcomes in relapsed/refractory disease.
AL amyloidosis can coexist with myeloma and is the dominant clinical issue when present — periorbital ecchymoses, macroglossia, restrictive cardiomyopathy, nephrotic syndrome should prompt fat pad biopsy with Congo red staining.
References
IMWG — International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma (Rajkumar et al., Lancet Oncol 2014)
NCCN 2024 — NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma (NCCN.org)
PERSEUS — Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Newly Diagnosed Multiple Myeloma (Sonneveld et al., NEJM 2024)
GRIFFIN — Daratumumab plus VRd in transplant-eligible myeloma (Voorhees et al., Blood 2020)
KarMMa/CARTITUDE — BCMA CAR-T cell therapy in relapsed/refractory multiple myeloma (Munshi et al., NEJM 2021; Berdeja et al., Lancet 2021)
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