Plasma Cell Dyscrasias

Claudia Bale

Background

  • MGUS (monoclonal gammopathy of undetermined significance): pre-malignant and malignant conditions with clonal proliferation of plasma cells or B cells that MAY produce monoclonal Igs detected in serum and/or urine.
  • NOTE: MGUS → SMM → MM represent a disease progression continuum.
  • Malignant plasma cell disorders: Smoldering Multiple Myeloma( SMM), multiple myeloma (MM), plasmacytoma, Waldenström Macroglobulinemia (IgM), AL amyloidosis, POEMS, Castleman disease
  • Complications 2/2 malignant plasma cells (BM infiltration, bone destruction) and/or their Ig product (infiltrative cardiomyopathy, renal toxicity, hyperviscosity, neuropathy).
  • What triggers workup: elevated protein gap (TP – Alb >4), unexplained anemia, renal insufficiency, hypercalcemia, lytic bone lesions, or unexplained proteinuria.
SymptomsSigns
  • Fatigue, weakness, weight loss
  • Bone pain (2/2 lytic lesions/fractures)
  • Paresthesias, neuropathy (2/2 Ig toxicity)
  • Visual disturbances (if hyperviscosity)
  • Lymphadenopathy, fever (uncommon; 2/2 immunosuppression)
  • Anemia (Hgb <10)
  • Renal insufficiency (Cr > 2)
  • Hypercalcemia (Ca > 11.5)
  • Elevated protein gap (Total protein - Alb > 4)
  • Osteolytic bone lesions (typically central)
  • Unexplained heavy proteinuria
  • Rouleux formation on blood smear

Evaluation 

Labs:

  • CBC w/ diff, peripheral blood smear, CMP (Cr, Ca, Alb, TP).
  • M-protein detection: SPEP (detects/quantifies M-protein) + SIF (clonality & type:
    IgG/A/M/D/E, kappa/lambda) + SFLC (abnormal ratio in ~90% of MM) + quantitative Igs (IgG, IgA, IgM).
  • 24hr urine for total protein + UPEP + urine immunofixation (UIF) — detects Bence Jones protein and screens for nephrotic-range proteinuria (AL amyloidosis, LCDD).
  • Pitfall of UA is dipstick detects albumin, NOT light chains. A negative dipstick does NOT rule out myeloma kidney — proteinuria in cast nephropathy is from FLC (Bence Jones), which dipstick misses therefore order UPEP/UIF to detect it.
  • LDH, B2-microglobulin, albumin — these 3 + cytogenetics determine R-ISS stage (I–III), which predicts survival and guides treatment intensity.
  • NT-proBNP/BNP — screens for cardiac involvement (amyloid, volume overload).

Imaging:

  • Whole body FDG-PET/CT (not base-of-skull to thigh as we need to evaluate calvarium for lesions) or low-dose whole body CT — for all suspected MM or solitary plasmacytoma. Imaging findings (lytic lesions, >1 MRI focal lesion) are myeloma-defining events that can establish Dx even without CRAB.
  • If PET/CT or CT negative and no other myeloma-defining events → WB MRI w/o contrast to distinguish SMM from MM (most sensitive for focal BM lesions).
  • Skeletal survey (X-ray) — only if advanced imaging unavailable.

Additional Testing:

  • BMBx — required for all suspected MM:
  • Aspirate + biopsy with IHC and/or flow cytometry.
  • FISH panel: del(13), del(17p13), t(4;14), t(11;14), t(14;16), t(14;20), 1q21 gain/amp, 1p deletion
  • NGS for TP53 mutation (important: del(17p) by FISH misses some TP53 mutations)
  • For MGUS: BMBx recommended for intermediate/high-risk patients; not needed for low-risk MGUS.
  • If amyloidosis suspected:
    • Fat pad biopsy with Congo red staining (preferred initial tissue Dx); if negative (high false negative rate) → biopsy involved organ + mass spectrometry for amyloid subtyping.
    • Cardiac workup: TTE, NT-proBNP (if not already ordered), troponin T, EKG; if amyloid infiltration is suspected – endomyocardial bx to confirm.
    • Full organ involvement: CMP, coags, UPCR/UACR, EMG.
  • If dx of MGUS but renal involvement is suspected (Monoclonal Gammopathy of Renal Significance (MGRS):
    • Consider renal biopsy if: AKI stage 3, eGFR <60 with >2 mL/min/yr decline, proteinuria >1 g/day, or Fanconi syndrome.

Additional Tips for Lab Interpretation

SPEP / UPEP Free light chains (FLC) Urinalysis
Initial screening test to look and quantify M-protein

Serum immunofixation determines clonality (e.g. mono or polyclonal)

Monoclonal spike >1.5 is indicative of underlying dyscrasia

Polyclonal spike suggests infectious, inflammatory, or reactive etiology 		Ratio of kappa/lambda >3 highly suggestive of plasma cell dyscrasia or amyloidosis

Ratio 1.65 to 3 can be due to infectious process or renal insufficiency

Ratio ≥100 + involved FLC ≥10 mg/dL → diagnostic of MM

Useful when SPEP negative (light-chain-only disease) 		Dipstick detects albumin, NOT light chains

Dipstick negative + proteinuria → think cast nephropathy (Bence Jones)

Dipstick positive → think AL amyloid (nephrotic albumin loss)

To detect light chains: order UPEP/UIF or sulfosalicylic acid
MGUSSMMMM
% Plasma Cells in BM<10%10-60%≥10%
Monoclonal Protein IgG, IgA, IgM: 1.5 - 3 g/dL IgG or IgA >3 g/dL (or BJ >500 mg/24h) IgG or IgA >3 (or any level)
SymptomsNoneNone Lytic bone lesions, fatigue, bone pain, infection
Prognosis 1% / year progression to MM 10% / year progression to MM R-ISS staging (see below)
Monitoring and / or Treatment Monitoring only:
CBC, CMP, SPEP, SIF, SFLC at 6 mo
If stable: Q2-3yr or with new Sx 		BMBx and WB low-dose CT or MRI at Dx to exclude MM

CBC, CMP, SPEP, SIF, SFLC at 6mo then annually for life 		Chemotherapy, plus SCT for eligible pts — see below

Monoclonal Gammopathy of Unknown Significance (MGUS)

  • Asymptomatic, premalignant clonal plasma cells in the bone marrow that may produce monoclonal Igs with or without abnormal free light chains. Common in the elderly: prevalence >4% in those over 40 and >10% in those over 80.
  • Subtypes: non-IgM MGUS (may progress to MM), IgM MGUS (may progress to WM), and light chain MGUS (may progress to LC MM). All require M-protein <3 g/dL, BM plasma cells <10%, and no end-organ damage.
  • IgM MGUS also requires no anemia, hyperviscosity, lymphadenopathy, or hepatosplenomegaly. If imaging needed, order CT chest/abdomen for lymphadenopathy/organomegaly (WM workup), not bone imaging. Light chain MGUS: abnormal FLC ratio with increased involved light chain but no monoclonal heavy chain.
  • Watch for MGCS (monoclonal gammopathy of clinical significance): paraprotein causes organ damage (skin, nerves, kidneys) despite low tumor burden — treat the Ig-mediated disease, not the clone.
  • How to risk stratify (Mayo model):
    • 3 risk factors: 
      • 1. M-protein ≥1.5 g/dL, 
      • 2. non-IgG isotype (IgA or IgM), 
      • 3. abnormal FLC ratio (<0.26 or >1.65).
  • 20-year progression rates: low risk (0 factors) = 5%, intermediate (1–2) = 21–37%, high risk (all 3) = 58%
  • PANGEA model (2025): adds dynamic measures to track lab trends overtime (Hgb decline, renal function change) for more refined risk assessment (but not yet prospectively validated).
  • Important: progression risk is highest in the first year after diagnosis and increases with rising Mprotein (this is why initial 6-month follow-up is recommended before extending intervals).

Smoldering Multiple Myeloma (SMM)

  • Intermediate stage between MGUS and active MM, with approximately 10% risk of progression to MM per year.
  • Diagnostic criteria: M-protein ≥3 g/dL and/or BM plasma cells 10–60%, but NO CRAB criteria or SLiM biomarkers.
  • Risk stratify with Mayo 2018 “2/20/20” model: high risk = ≥2 of: M-protein >2 g/dL, FLC ratio >20, BM plasma cells >20%.
  • Rising parameters (increasing M-protein, worsening cytopenias, rising Ca/Cr) = high risk regardless of baseline --> closer monitoring, consider repeat BMBx + imaging. 
  • Screen for AL amyloidosis: if abnormal FLC ratio with rising involved FLC, check NT-proBNP and urine albumin.

What to Do — MGUS & SMM Monitoring by Risk:

Category Labs Imaging BMBx What to Do
MGUS — Low Risk
(0 risk factors) 		CBC, CMP,
SPEP, SIF,
SFLC at 6 months

If stable: Q2–3yr or with new symptoms 		Not recommended Not recommended Primary care can monitor
No heme referral needed
Educate on red flags (bone pain, fatigue, infections, fractures)
MGUS — Int/High Risk
(1–3 risk factors) 		CBC, CMP,
SPEP, SIF,
SFLC at 6 months

Then annually for life
24hr urine (UPEP/UIF) as indicated 		WB low-dose CT or MRI at Dx to exclude MM

Repeat only if symptoms or rising M-protein 		At Dx to exclude SMM/MM Heme referral at Dx
Monitor for rising M-protein

(highest predictor of progression)
Consider PANGEA model for dynamic risk
SMM — Low Risk
(<2 of 2/20/20) 		CBC, CMP,
SPEP, SIF,
SFLC Q3–6 months
24hr UPEP/UIF as indicated 		WB MRI (preferred) or PET/CT annually × 5yr minimum
Same technique each time 		As clinically indicated
(rising labs, new Sx) 		Observation is standard (NCCN Cat 1)
Clinical trial encouraged
Monitor for SLiM criteria (>60% PC, FLCr ≥100, >1 MRI lesion)
SMM — High Risk
(≥2 of 2/20/20) 		CBC, CMP,
SPEP, SIF,
SFLC Q3 months
24hr UPEP/UIF as indicated 		WB MRI or PET/CT annually or as needed
Consider alternating CT/MRI in very high-risk 		As clinically indicated Clinical trial preferred
OR daratumumab mono (NCCN Cat 1, AQUILA: 5yr PFS 59% vs 37%, HR 0.49; OS benefit HR 0.52)
OR active monitoring Q3 months
Shared decision-making

Multiple Myeloma (MM)

  • Neoplastic proliferation of plasma cells producing monoclonal Ig (“M protein”). Median age at diagnosis 65–74; more common in males (1.4:1) and Black patients (2–3× higher incidence).
  • Symptoms arise from the plasma cells (bone pain, fractures, hypercalcemia, anemia) and/or from the Ig product (renal impairment, paresthesias, protein gap, recurrent infections from hypogammaglobulinemia). Other symptoms are nonspecific: weakness and weight loss.

Why this happens (pathophysiology): 

  • Progression from MGUS → SMM → MM: translocation during class switching places an oncogene (Cyclin D1/3, FGFR-3, C-MAF) next to IgH on chromosome 14. Additional hits (MYC, RAS/MAPK, TP53 deletion) drive proliferation.
  • Bone: myeloma cells activate osteoclasts (↑RANKL, ↓OPG) and inhibit osteoblasts (DKK1) → lytic lesions and hypercalcemia.
  • Kidney: light chains bind uromodulin in the ascending loop of Henle → obstructing casts (cast nephropathy). Hypercalcemia → vasoconstriction. Proximal tubule LC accumulation→ proximal RTA.
  • Anemia: BM replacement by plasma cells, CKD-related low EPO, dilution (M-protein ↑ plasma volume), +/- folate/B12 deficiency, warm AIHA.
  • Infection: functional hypogammaglobulinemia and impaired lymphocyte function — leading cause of early death in MM.

How to diagnose (IMWG criteria):

  • BM plasma cells ≥10% OR biopsy-proven plasmacytoma, AND ≥1 myeloma-defining event: 
    • CRAB: Ca >11, Cr >2 (or CrCl <40), Hb <10, lytic lesions ≥5 mm
    • SLiM: ≥60% clonal BM plasma cells, FLC ratio ≥100 (or <0.01), >1 focal lesion ≥5 mm on MRI.
  • Less common variants: non-secretory/oligo-secretory (~10%) and light chain only (~20%)

Emergencies — recognize and act immediately:

  • Cord compression: back pain + LE weakness or bowel/bladder dysfunction → emergent MRI whole spine → if confirmed call NSGY and discuss tx with high dose steroids.
  • Hyperviscosity (IgM, rare with IgG/IgA): blurred vision, AMS, oronasal bleeding → emergent plasmapheresis (does not work well for IgG/IgA as these extrude into tissues).
  • Severe hypercalcemia: AMS, AKI → aggressive IVF, calcitonin, bisphosphonates.
  • AKI: hydration, avoid nephrotoxins/contrast; urgent heme consult for chemo initiation.

What treatment looks like (2026 NCCN/ASCO):

  • Note: regimens are attending/institution-specific
  • Risk stratify first: R-ISS stage (B2-microglobulin, albumin, LDH, cytogenetics). High risk = del(17p), t(4;14), t(14;16), t(14;20), 1q21 gain/amp; very high LDH; plasma cell leukemia (≥5% circulating).
  • Transplant eligible → quadruplet induction (Cat 1): anti-CD38 (dara or isatuximab) + bortezomib + lenalidomide + dex. CyBorD if renal failure at Dx. Then autoSCT → maintenance (lenalidomide +/- bortezomib if high-risk). MRD-guided consolidation emerging (MIDAS trial).
  • Transplant ineligible → if <80 and not frail: quadruplet also preferred. Otherwise: VRd-lite or DRd (dara + lenalidomide + dex) → lenalidomide maintenance.
  • Relapsed/refractory → good prior response: repeat PI/IMiD/dara +/- autoSCT. Poor response: bispecific Abs (teclistamab, elranatamab, talquetamab, linvoseltamab), BCMA. CAR-T (cilta-cel after 1 line, ide-cel after 2), belantamab mafodotin + BorDex after 2 lines, venetoclax if t(11;14). Sequential BCMA-targeting → lower response rates — sequencing is critical.

Supportive care you should know:

  • Pain: radiation for focal bone disease; bisphosphonates or denosumab for bone protection; surgical fixation if fracture/impending.
  • DVT prophylaxis required on IMiDs (lenalidomide): ASA vs DOAC vs LMWH based on VTE risk.
  • VZV prophylaxis on proteasome inhibitors; PJP prophylaxis if prolonged steroids.
  • Infection: hypogammaglobulinemia common (especially with bispecifics/CAR-T) → consider IVIG if recurrent infections. Prophylactic tocilizumab may reduce CRS with bispecifics.

Plasmacytoma 

  • Clonal plasma cell mass, either in bone (solitary bone plasmacytoma, SBP) or soft tissue (solitary extramedullary plasmacytoma, SEP); found in ~7% of MM at diagnosis on PET/CT, sometimesas purple subQ masses.
  • Workup: full MM labs (SPEP/SIF, SFLC, UPEP/UIF, CBC, CMP) + biopsy of lesion + PET/CT or MRI (must exclude other lesions).
  • Criteria for solitary plasmacytoma: biopsy-proven clonal plasma cells, BMBx with <10% plasma cells, no CRAB criteria, no additional lesions on cross-sectional imaging.
  • Tx: radiation to lesion +/- surgical resection for SEP; monitor long-term for progression to MM.

Waldenstrom Macroglobulinemia (WM)/ Lymphoplasmacytic Lymphoma

What it is: lymphoplasmacytic lymphoma (LPL) in bone marrow + IgM monoclonal gammopathy in blood. MYD88 L265P mutation found in >90% of WM (vs <5% of IgM myeloma — this helps distinguish the two).

How it presents:

  • Hyperviscosity syndrome: massive IgM increases serum viscosity → blurry vision, retinal hemorrhage, papilledema, headache, dizziness, altered mental status, bleeding (epistaxis). Symptoms unlikely if viscosity <4 cP, likely if >6 cP.
  • Cytopenias: B cell infiltration of marrow → anemia, thrombocytopenia, neutropenia.
  • Autoimmune hemolytic anemia: IgM directed against RBC antigens → Coombs-positive warm or cold AIHA.
  • Cryoglobulinemia: IgM precipitates at cold temperatures → Raynaud’s, acral cyanosis, tissue necrosis.
  • Peripheral neuropathy: IgM against myelin-associated glycoprotein (MAG) → distal, symmetric, sensorimotor neuropathy.
  • Lymphadenopathy / hepatosplenomegaly: B cell infiltration of lymph nodes, liver, spleen.
  • Renal: IgM deposits in glomerular basement membrane; cryoglobulin-associated glomerulonephritis.

What to order:

  • CMP (protein gap), CBC (anemia), peripheral smear (rouleaux).
  • BMBx: look for lymphoplasmacytic cells with intranuclear IgM vacuoles; molecular studies for MYD88 L265P.
  • SPEP/IFE (monoclonal IgM), quantitative Igs (IgM very high, IgG/IgA often suppressed), SFLC.
  • Serum viscosity: order if hyperviscosity suspected.
  • LDH, B2-microglobulin; CT chest/abdomen/pelvis (lymphadenopathy,
    hepatosplenomegaly; should NOT have lytic bone lesions — if lytic lesions present, think IgM myeloma instead).

How to diagnose:

  • Criteria: IgM monoclonal gammopathy in serum + BMBx >10% lymphocytes with plasmacytoid differentiation.
  • Smoldering WM: meets criteria but no symptoms — no hyperviscosity, no anemia, no lymphadenopathy, no hepatosplenomegaly.
  • WM vs IgM myeloma: WM has LPL morphology, MYD88+ (>90%), NO lytic lesions. IgM MM has plasma cell morphology, MYD88 rare (<5%), lytic lesions, often t(11;14).

Management:

  • Asymptomatic: observe Q4-6mo. Higher progression risk if IgM >4500, B2-microglobulin >4, albumin <3.5, BMBx lymphoplasmacytic population >70%.
  • Symptomatic (hyperviscosity or end-organ damage): start with plasmapheresis to rapidly lower IgM, then definitive Tx: bendamustine + rituximab (fit patients) vs BTK inhibitor (unfit). Caution: rituximab can cause IgM flare → worsen hyperviscosity; avoid as monotherapy if viscosity borderline.

Other Plasma Cell Dyscrasias

Light Chain (AL) Amyloidosis

  • Monoclonal plasma cells produce light chains that misfold and deposit as beta-pleated sheet (amyloid) fibrils in tissues, causing progressive organ damage.
  • Organ involvement — what to look for: 
    • Kidneys: amyloid deposits in glomerular basement membrane --> proteinuria, often nephrotic range. Unlike myeloma kidney (cast nephropathy), UA dipstick is POSITIVE (albumin loss).
    • Heart: inter-myocyte deposition, especially septum --> restrictive cardiomyopathy (diastolic > systolic dysfunction). Look for low voltage on EKG + thickened walls on ECHO = classic.
    • Nerves: peripheral nerve sheath deposits --> small fiber neuropathy (numbness, paresthesias), autonomic dysfunction (orthostasis, GI dysmotility), carpal tunnel syndrome.
    • Blood vessels: vessel wall amyloid → fragility → easy bruising, periorbital purpura (classic exam finding), GI bleeding.
    • Liver/spleen/tongue: hepatosplenomegaly, macroglossia 2/2 direct infiltration.
  • How to distinguish from MM: 
    • AL amyloidosis usually has <20% BMBx plasma cells, no lytic bone lesions, modest Bence Jones proteinuria, and nephrotic syndrome (not cast nephropathy). Can coexist with MM.
  • How to diagnose (all 4 required): 
    • Amyloid-related organ syndrome (nephrotic syndrome, restrictive CMP, neuropathy, etc).
    • Congo red-positive tissue biopsy (start with abdominal fat pad + BMBx; if negative, biopsy involved organ).
    • Confirm amyloid is light chain (mass spectrometry or immunoelectron microscopy).
    • Evidence of monoclonal plasma cell disorder (SPEP/IFE, SFLC, UPEP/IFE).
  • Organ damage workup to order: 
    • CMP, coags (light chains cause functional factor X deficiency), UPCR/UACR (nephrotic), troponin + NT-proBNP (cardiac staging), EKG (low voltage), TTE (thickened septum), EMG/NCS (neuropathy).
  • Treatment: 
    • Dara-CyBorD (daratumumab + cyclophosphamide + bortezomib + dex) is standard firstline; consider consolidation with autoSCT in select candidates (usually younger, limited organ involvement). Organ response can take months — serial biomarkers (NT-proBNP, proteinuria) guide response.
  • Advanced amyloidosis with severe organ dysfunction (cardiac, hepatic, GI) takes months of therapy to restore organ function – consider palliative care consult to help manage patient expectations.

POEMS Syndrome

  • Mnemonic — "POEMS PEST": Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes, Papilledema, Extravascular volume overload, Sclerotic bone lesions, Thrombocytosis.
  • Chronic overproduction of inflammatory cytokines (IL-1, IL-6, TNF-α) and VEGF by clonal plasma cells → multi-system damage.
  • How to distinguish from MM: 
    • POEMS has polyneuropathy (mandatory, rare in MM), osteosclerotic (not lytic) lesions, elevated VEGF, and typically NO anemia, hypercalcemia, renal failure, or high % bone marrow plasma cells.
  • What to order: 
    • CBC (expect ↑Hb and ↑platelets, NOT anemia), CMP, SPEP/IFE, UPEP/IFE, VEGF (usually markedly elevated), BMBx.
    • Endocrine workup: glucose/A1c, AM cortisol, TSH, prolactin, testosterone/estrogen, other hormones as indicated. 
    • CT skeletal survey (look for sclerotic, not lytic, lesions), dilated fundoscopic exam (papilledema). 
  • Diagnostic criteria: 
    • Mandatory (need both): peripheral polyneuropathy + monoclonal plasma cell disorder (usually lambda light chain).
    • Major (need 1 of 3): osteosclerotic bone lesions, elevated VEGF, Castleman disease.
    • Minor (need 1 of 6): organomegaly, extravascular volume overload, endocrinopathy (excluding DM/hypothyroidism alone), skin changes, papilledema, thrombocytosis/polycythemia.
  • Treatment: 
    • Limited bone disease (1-3 lesions) → radiation; disseminated → systemic chemo (dara, lenalidomide, bortezomib, dex) +/- autoSCT. Also treat volume overload (diuretics), endocrine deficiencies (hormone replacement), DVT prophylaxis.

Castleman Disease

  • Angiofollicular lymph node hyperplasia — NOT a plasma cell neoplasm per se, but frequently associated with plasma cell dyscrasias (especially POEMS).
  • Types: unicentric (lymph nodes in single region, usually curable) vs multicentric (multiple regions, systemic inflammation). Multicentric subdivided by HHV-8 status.
  • Why it happens: 
    • HHV-8-associated → virus drives uncontrolled IL-6 release → systemic inflammation. 
    • HHV-8-negative (iMCD) → poorly understood, may involve autoimmune mechanisms.
  • How it presents: 
    • Lymphadenopathy, hepatosplenomegaly, fevers, night sweats, fatigue, fluid accumulation (effusions, edema, anasarca), cytopenias, violaceous skin papules.
  • How to diagnose: 
    • Imaging: lymphadenopathy (unicentric = single station; multicentric = widespread).
    • Pathology: excisional LN biopsy showing characteristic inflammatory/angiofollicular changes (+/- HHV-8 staining). 
    • Clinical: signs of systemic inflammation (fevers, night sweats, hepatosplenomegaly) or HHV-8 features (violaceous papules, Kaposi-like). 
    • Labs: elevated ESR/CRP, cytopenias, AKI, hypoalbuminemia, elevated IL-6. 
  • Important: must rule out autoimmune disease, lymphoma, and other malignancies before diagnosing Castleman. 
  • What to do: 
    • If associated with POEMS → treat the POEMS (see above).
    • Unicentric: surgical resection (often curative); if not resectable --> observation or rituximab.
    • Multicentric: anti-IL-6 therapy (siltuximab preferred, tocilizumab alternative) or rituximab +/- chemotherapy. If HHV-8+/HIV+ --> ART is essential.
Last updated on