Monoclonal Gammopathy

Background:

• Disorders characterized by the presence of a Monoclonal Ig (M protein) or its components, produced by:

  • Clonal population of plasma cells:

    • Monoclonal Gammopathy of Undetermined Significance (MGUS)

      • IgG >> IgA , IgM

    • Smoldering Multiple Myeloma (SMM)

      • IgG >> IgA

    • Multiple Myeloma (MM)

      • IgG >> IgA

    • AL amyloidosis

    • POEMS syndrome

  • Clonal population of B-lineage/lymphoplasmacytic cells:

    • Waldenström Macroglobulinemia (WM)

      • IgM

• Monoclonal Gammopathy of Clinical Significance (MGCS) is an umbrella term for conditions in which a small B-cell or plasma-cell clone produces a monoclonal protein that causes clinically significant organ damage despite NOT otherwise meeting criteria for overt malignancy.

Diagnosis and Management of Monoclonal Gammopathy of Undetermined Significance.

JAMA Intern Med. March 31, 2025.

Diagnosis:

• Myeloma-defining events (MDE):

  • CRAB-SLiM

    • Calcium >11 or >1 above ULN

    • Renal insufficiency: Cr >2 or CrCl <40 

    • Anemia: Hb <10 or 2< below LLN

    • Bone: ≥1 osteolytic lesion

    • ≥Sixty/60% clonal plasma cells in BM

    • Free Light chains (FLC): involved/uninvolved FLC ratio ≥100 + involved FLC ≥100 mg/L

    • MRI >1 focal lesion, each ≥5 mm

	M protein/ FLC	Clonal BM plasma cells	CRAB-SLiM
Light Chain MGUS	Abnormal serum FLC ratio and ↑ involved light chain	<10%	None
Ig MGUS	Serum M protein <3 g/dL	<10%	None
SMM	Serum M protein ≥3 g/dL and/or Urine M protein ≥500 mg/24 h	≥10% and <60%	None
MM	Not required	≥10% or Biopsy-proven plasmacytoma	≥1

Table 1. Diagnostic criteria of MGUS, SMM and MM

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Diagnosis:

  • See Table 1 for diagnostic criteria.

• Mayo risk stratification is based on:

  • M protein: ≥1.5 g/dL

  • K/L ratio: Abnormal

  • Ig subtype: non-IgG

• Risk of progression to MM:

  • 0/3 factors: Low risk

    • Risk of progression in 20 years: %5

    • Repeat CBC, Cr and SPEP q6 months, no additional testing is required

  • 1/3 factor: Low-intermediate risk

    • Risk of progression in 20 years: %21

  • 2/3 factors: High-intermediate risk

    • Risk of progression in 20 years: %37

  • 3/3 factors: High risk

    • Risk of progression in 20 years: %58

Smoldering Multiple Myeloma (SMM)

• Diagnosis:

  • See Table 1 for diagnostic criteria.Treatment:

• Standard of care: observation

  • PETHEMA-GEM study: OS benefit of treatment for high risk Smoldering MM with lenalidomide/Dexamethasone

  • High risk SMM: if 2 out of 3 criteria:

  • >20% BM plasmacytosis

  • >20 K/L ratio

  • >2 g/dl M protein

Multiple Myeloma (MM)

• Multiple Myeloma is discussed in a separate lecture.

Waldenstrom Macroglobulinemia (WM)

• Malignancy of mature plasmacytoid lymphocytes that secrete IgM

• Categorized as a lymphoplasmacytic lymphoma

• No treatment if patient is asymptomatic

Indications for treatment: 

• Disease related Hb <10 and plt <100, hepatosplenomegaly, bulky LAP, Hyperviscosity syndrome, neuropathy, amyloidosis, B symptoms, cold agglutinin hemolytic anemia

Treatment:

• Preferred regimens:

• Bendamustine + Rituximab

• Dexa + Rituximab + Bortezomib

• Dexa + Rituximab + Cyclophosphamide

• Ibrutinib ± Rituximab 

• Zanubrutinib

• Patients with hyperviscosity syndrome and patients undergoing treatment with Rituximab-containing regimen, plasmapheresis should be considered to lower IgM level to <4000 mg/dl (Rituximab can cause flare in the level of IgM)

Plasmacytoma

• Solitary or multiple osseous or soft tissue plasma cell tumors

• They may have M spikes

• Treatment: Radiation 

• They may progress to multiple myeloma

Plasma Cell Leukemia

• Highly aggressive, OS <12 months

• Immunophenotype is different from myeloma

• ≥5% plasma cells in peripheral blood

POEMS Syndrome

Paraneoplastic syndrome of plasma cell disorder

• Demyelinating Polyneuropathy (Major criteria)

• Organomegaly

• Endocrinopathy

• Monoclonal gammopathy (Major criteria)

• Skin changes