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Plasma Cell Disorders¶

Part 4: Oncology and Hematology · Part 4 – Oncology: Hematologic Malignancies · Part 4 – Oncology: Hematologic Malignancies · Chapter 116

Key Clinical Points¶

Multiple myeloma (MM) is defined by clonal bone marrow plasmacytosis (>10%), a serum/urine M component, and at least one myeloma-defining event (CRAB: Hypercalcemia, Renal insufficiency, Anemia, Bone lesions).
MGUS has a 1% annual progression rate to myeloma; high-risk features include M protein >30 g/L, marrow plasma cells >10%, and abnormal free light chain ratio.
The International Staging System (ISS) uses serum beta-2 microglobulin and albumin: Stage I (62 months survival), Stage II (44 months), Stage III (29 months).
Bone lesions in MM are purely osteolytic due to osteoclast activation (RANKL) and osteoblast suppression (DKK-1); plain radiography is preferred over radioisotopic scans.
Hyperviscosity syndrome occurs at serum viscosity >4 centipoises, typically with IgM (>40 g/L), IgG3 (>50 g/L), or IgA (>70 g/L).
Renal failure (25% of patients) results from light chain cast nephropathy and amyloidosis; hypercalcemia is a common driver.
Common cytogenetic abnormalities include hyperdiploidy, del(17p), t(4;14), t(14;16), and t(11;14).
Solitary bone plasmacytoma involves a single lytic lesion without marrow plasmacytosis.
POEMS syndrome requires polyneuropathy, monoclonal plasma cell disorder, and two of: sclerotic bone lesions/VEG elevation, or organomegaly/edema/endocrinopathy/skin changes.
Infection risk is high (75%) due to hypogammaglobulinemia and T-cell dysfunction; common pathogens include S. pneumoniae, S. aureus, and E. coli.

1. DEFINITION & CLASSIFICATION¶

• Overview: Plasma cell disorders are monoclonal neoplasms arising from late B-lymphocyte lineage progenitors. • Key Entities: Multiple myeloma (MM), Waldenström's macroglobulinemia, primary amyloidosis, and heavy chain diseases.

Definition (Harrison's 22e): Multiple myeloma is defined by clonal bone marrow plasmacytosis (>10%), a serum/urine M component, and at least one myeloma-defining event (CRAB: Hypercalcemia, Renal insufficiency, Anemia, Bone lesions).

• Monoclonal Proteins: May occur in non-neoplastic conditions (e.g., cirrhosis) or other lymphoid malignancies. • MGUS Progression: Approximately 10% of MGUS progress to myeloma annually.

1.1 Immunoglobulin Structure & Genetics¶

• Structure: Antibody molecules consist of two heavy chains (~50,000 mol wt) and two light chains (~25,000 mol wt), linked by disulfide bonds. • Regions: Variable regions form antigen recognition sites (idiotypes); constant regions define isotypes (IgG, IgA, etc.) and allotypes. • Genetics: VDJ (heavy) and VJ (light) rearrangements ensure allelic exclusion → single light chain isotype per clone. • Bence Jones Proteins: In ~20% of myelomas, only light chains are produced.

• Figure 116-1: Illustrates the genetic basis of antibody diversity and how specific genomic segments (V, D, J) correspond to protein domains.

2. EPIDEMIOLOGY¶

• Incidence: 35,780 new MM cases estimated in the U.S. (2024); median age at diagnosis is 69 years. • Demographics: - White men: 8.1/100,000 - Black men: 17.1/100,000 (nearly double the rate of whites). - Higher rates observed in Pacific Islanders and native Hawaiians. • Global Impact: Myeloma accounts for 1.8% of all malignancies globally.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

• Etiology: No single known cause; associated with radiation, occupational hazards (farming), and chromosomal abnormalities. • Cytogenetics: - Common: hyperdiploidy (trisomies 3, 5, 7, 9, 11, 15, 19, 21), del(17p), t(4;14), t(14;16), t(11;14). - Additional markers: t(14;20), amp1q34, del1p. • Mutational Landscape: KRAS/NRAS (~20% each), TP53, DIS3, FAM46C, BRAF (5–10%). • Bone Marrow Microenvironment: - Interaction with stromal cells → production of IL-6, IGF-1, and VEGF. - Signaling Pathways: - Ras/Raf/MAPK → growth - PI3K/Akt → drug resistance - PKC → migration - Immune Suppression: Mediated by plasmacytoid dendritic cells, MDSCs, and T17 cells.

• Renal Pathophysiology: - Light chain excretion → tubular damage (Fanconi syndrome) and light chain cast nephropathy. - Hypercalcemia is the most common cause of renal failure in myeloma. - Other factors: Amyloid deposition, hyperuricemia, and bisphosphonate use.

3.1 Bone Marrow Microenvironment¶

• Mechanism: MM cells interact with stromal cells via adhesion molecules (VLA-4, ICAM-1) → trigger cytokine-mediated signaling. - JAK → STAT3 → Bcl-xL, Mcl-1 (drug resistance/anti-apoptosis). - MAPK pathway: Raf → MEK → p42/44 MAPK (proliferation). - PI3K Pathway: PI3K → Akt → Bad, NF-\kappaB, FKHR (cell cycle) and PKC (migration).

• Figure 116-4: Illustrates these interactions and the resulting promotion of tumor growth and survival.

4. CLINICAL FEATURES¶

• Bone Pain: Affects 70% of patients; caused by osteolytic lesions (RANKL activation, DKK-1 mediated osteoblast suppression). • Hyperviscosity Syndrome: - Trigger: Serum viscosity >4 cP. - Specific Thresholds: - IgM: >40 g/L - IgG3: >50 g/L - IgA: >70 g/L • Renal Failure: Affects 25% of patients; caused by light chain nephropathy and amyloidosis. • Infection: 75% develop serious infections (S. pneumoniae, S. aureus, E. coli) due to hypogammaglobulinemia and T-cell dysfunction.

• Anemia & Clotting: - Normocytic anemia (80%) from marrow infiltration and erythropoietin deficiency. - Thrombocytopenia/clotting issues due to M component interaction with factors.

• Neuropathy: - IgM-associated: >50% involve anti-MAG antibodies. - Other causes: Treatment (thalidomide, bortezomib) or amyloid infiltration.

4.1 Bone & Skeletal Manifestations¶

• Imaging: Plain radiography is preferred for identifying 'punched-out' lytic lesions (Figure 116-5). • Complications: Spinal cord compression from vertebral collapse; hypercalcemia leading to lethargy and confusion.

5. DIFFERENTIAL DIAGNOSIS¶

• MGUS vs. Smoldering Myeloma (SMM): - MGUS: M protein <30 g/L, marrow plasma cells <10%. - SMM: M protein ≥30 g/L or urine ≥500 mg/24h; marrow plasma cells 10–60%. • Waldenström's Macroglobulinemia: IgM monoclonal gammopathy with lymphoplasmacytic infiltration. • Amyloidosis: Systemic organ involvement from amyloid fibrils. • Heavy Chain Diseases: Absence of light chains in serum and urine.

6. INVESTIGATIONS & DIAGNOSIS¶

Initial Screening:
Serum/urine protein electrophoresis (SPEP) and immunofixation (IFE) to identify M component.
Quantification of serum Ig levels (IgG, IgA, IgM).
Serum free light chain and ratio calculation.
Bone Marrow Assessment:
Biopsy/aspirate for histology.
Clonality testing via kappa/lambda immunostaining or flow cytometry.
Imaging Studies:
Plain radiography: Identify lytic lesions (skull, vertebrae).
MRI: Evaluate spinal cord compression and vertebral collapse.
PET/CT: Used for extramedullary plasmacytomas or if smoldering MM is suspected.
Risk Stratification & Specialized Tests:
Serum β-microglobulin and albumin (ISS staging).
DNA sequencing/FISH for mutations: del(17p), t(4;14), t(11;14), t(14;16), t(14;20), amp1q34, del1p, p53.
Serum viscosity (if IgM >40 g/L or IgA >70 g/L or M component >7 g/dL).
Myd88 and CXCR4 mutation analysis (if IgM component present).

Laboratory Criteria (Table 1)¶

• MGUS: M protein <30 g/L; Plasma cells <10%; No MDE. • Smoldering: M protein ≥30 g/L or Urine ≥500 mg/24h; Plasma cells 10–60%; No MDE. • Symptomatic MM: Plasma cells ≥10% OR plasmacytoma AND any one of: - Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) above normal or >2.75 mmol/L (>11 mg/dL). - Renal insufficiency: creatinine clearance <40 mL/min or serum creatinine >177 μmol/L (>2 mg/dL). - Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin value <100 g/L. - Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT. - Biomarkers of malignancy: - Clonal bone marrow plasma cell percentage ≥60%. - Involved:uninvolved serum free light chain ratio ≥100. - >1 focal lesion on MRI studies. • Nonsecretory Myeloma: No M protein in serum/urine; Marrow ≥10% or plasmacytoma; End-organ damage present. • Solitary Plasmacytoma: Biopsy-proven single lesion; Normal marrow; Normal skeletal survey (except primary site); No CRAB. • POEMS Syndrome: Must meet all 4: - 1. Polyneuropathy - 2. Monoclonal plasma cell disorder - 3. Any one of: (a) sclerotic bone lesions; (b) Castleman's disease; (c) elevated levels of vascular endothelial growth factor (VEG). - 4. Any one of: (a) organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy); (b) extravascular volume overload (edema, pleural effusion, or ascites); (c) endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, and pancreatic); (d) skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, and white nails); (e) papilledema; (f) thrombocytosis/polycythemiag.

7. MANAGEMENT & TREATMENT¶

Initial Assessment: Determine MDE status and transplant eligibility.
Smoldering Myeloma Management: Observation only; no treatment unless progression to myeloma (emergence of MDE).
Induction Therapy (Symptomatic MM):
VRd: Bortezomib (1.3 mg/m²), Lenalidomide (25 mg), Dexamethasone (40 mg).
KRd: Carfilzomib (20–56 mg/m²), Lenalidomide (25 mg), Dexamethasone (40 mg).
Consolidation & Maintenance:
Transplant eligible → High-dose therapy with ASCT.
Maintenance: Lenalidomide or Ixazomib.
Targeted/Specialized Therapies:
CAR-T (BCMA-targeting), Bispecific antibodies (Teclistamab, Elranatamab).
Supportive Care:
Bisphosphonates for bone disease.
Plasma exchange for hyperviscosity (IgM >40 g/L or IgA/IgG3 >70 g/L).

Treatment Algorithm Logic (Figure 116-6): • Path A (Smoldering): No MDE → Smoldering myeloma → No therapy except on clinical study/high-risk follow-up. • Path B (Transplant Eligible - Responsive): Yes (MDE) → Transplant eligible → Induction → Response → HDT with ASCT/consolidation → Maintenance → Relapse → 4th and beyond alternate regimen. • Path C (Transplant Eligible - Non-responsive): Yes (MDE) → Transplant eligible → Induction → No response → Alternate regimen → [Response/No response loop] → Relapse → 4th and beyond alternate regimen. • Path D (Transplant Ineligible - Responsive): Yes (MDE) → Transplant ineligible → Induction → Response → Maintenance → Relapse → 5th and beyond alternate regimen. • Path E (Transplant Ineligible - Non-responsive): Yes (MDE) → Transplant ineligible → Induction → No response → Alternate regimen → [Response/No response loop] → Relapse → 5th and beyond alternate regimen. • Path F (Emergent MDE): Smoldering → Appearance of MDE → Yes (MDE) → Proceed to Transplant eligibility determination.

Standard Therapeutic Agents (Table 4)¶

• Immunomodulatory drugs (IMiD): - Thalidomide: 50–200 mg qd. - Lenalidomide: 5–25 mg daily imes 21 days q 4 weeks. - Pomalidomide: 2–4 mg daily imes 21 days q 4 weeks. • Proteasome Inhibitors: - Bortezomib: 1.3 mg/m² (various schedules). - Carfilzomib: 20–56 mg/m². - Ixazomib: 4 mg days 1, 8, 15. • Antibodies: - Daratumumab: 16 mg/kg (various schedules). - Elotuzumab: 10 mg/kg. - Isatuximab: 10 mg/kg. - Belantamab mafodotin: 2.5 mg/kg. • Other Agents: - Selinexor: 80 mg days 1, 3. - Panobinostat: 20 mg every other day for 3 doses/week for 2 weeks every 21 days. - Melphalan (M): 0.25 mg/kg per day for 4 days (with P). - Cyclophosphamide (C): 300–500 mg/m² weekly imes 2 q 4 weeks (IV) or 50 mg qd imes 21 days (Oral). - Bendamustine (B): 70–90 mg days 1, 2 OR days 1, 8. - Melflufen (Me): 40 mg day 1 (with D 40 mg on days 1, 8, 15, and 22) q 28 days. - Dexamethasone (D) / Prednisone (P): 10–40 mg q week / 1 mg/kg. - Idecabtagene vicleucel (Ide-cel): 450 imes 10^6 cells. - Ciltacabtagene autoleucel (Cilta-cel). - Bispecifics: Teclistamab, Elranatamab, Talquetamab.

PROGNOSIS & COMPLICATIONS¶

• ISS Staging (Table 3): - Stage I: β-microglobulin <3.5, Albumin ≥3.5 → Median survival: 62 months. - Stage II: β-microglobulin <3.5, [Intermediate] → Median survival: 44 months. - Stage III: β-microglobulin >5.5 or (β-microglobulin <3.5 and Albumin <3.5) → Median survival: 29 months.

• Complications: - Renal failure (25%). - Infections (75%). - Pathologic fractures. - Amyloidosis.

SPECIAL CONSIDERATIONS¶

• POEMS Syndrome: Requires polyneuropathy, monoclonal plasma cell disorder, and 2 of: - Sclerotic bone lesions or elevated VEGF. - Organomegaly, edema, endocrinopathy, or skin changes. • Solitary Plasmacytoma: Single lytic lesion without marrow involvement; extramedullary variants in nasopharynx.

KEY PEARLS & CLINICAL TRAPS¶

• MGUS vs. Myeloma: Differentiation is based on M protein size (<30 g/L) and marrow percentage (<10%). • ISS Staging: Useful for prognosis but not curative; newer systems (e.g., R-ISS) include LDH. • Light Chain Myeloma: May lack serum M component but show Bence Jones proteins in urine. • Hyperviscosity: Requires urgent intervention even if asymptomatic, especially with IgM >40 g/L or IgA >70 g/L; check for M component >7 g/dL. • Imaging Choice: Plain radiography is the standard for identifying lytic bone lesions; MRI is preferred for spinal cord compression.

Reference Tables¶

TABLE 116-1 Diagnostic Criteria for Multiple Myeloma, Myeloma Variants, and Monoclonal Gammopathy of Undetermined…¶

Harrison's 22e, p.888

Monoclonal Gammopathy of Undetermined Significance (MGUS)
Serum monoclonal protein (non-IgM type) <30 g/L
Clonal bone marrow plasma cells <10%a
Absence of myeloma-defining events or amyloidosis that can be attributed to the plasma cell proliferative disorder
Smoldering Multiple Myeloma (Asymptomatic Myeloma)
Both criteria must be met:
• Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10–60%
• Absence of myeloma-defining events or amyloidosis
Symptomatic Multiple Myeloma
Clonal bone marrow plasma cells or biopsy-proven bony or extramedullary plasmacytomaa and any one or more of the following myeloma-defining events:
• Evidence of one or more indicators of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
• Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
• Renal insufficiency: creatinine clearance <40 mL/minb or serum creatinine >177 μmol/L (>2 mg/dL)
• Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin value <100 g/L
• Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CTc
• Any one or more of the following biomarkers of malignancy:
• Clonal bone marrow plasma cell percentagea ≥60%
• Involved: uninvolved serum free light chain ratiod ≥100
• >1 focal lesion on MRI studiese
Nonsecretory Myeloma
No M protein in serum and/or urine with immunofixationf
Bone marrow clonal plasmacytosis ≥10% or plasmacytomaa
Myeloma-related organ or tissue impairment (end-organ damage, as described above)
Solitary Plasmacytoma
Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
Normal bone marrow with no evidence of clonal plasma cellsa
Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lymphoplasma cell proliferative
disorder
POEMS Syndrome
All of the following four criteria must be met:
1. Polyneuropathy
2. Monoclonal plasma cell proliferative disorder
3. Any one of the following: (a) sclerotic bone lesions; (b) Castleman’s disease; (c) elevated levels of vascular endothelial growth factor (VEGF)
4. Any one of the following: (a) organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy); (b) extravascular volume overload (edema, pleural effusion, or
ascites); (c) endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, and pancreatic); (d) skin changes (hyperpigmentation, hypertrichosis, glomeruloid
hemangiomata, plethora, acrocyanosis, flushing, and white nails); (e) papilledema; (f) thrombocytosis/polycythemiag

TABLE 116-2 Standard Investigative Workup in Multiple Myeloma (MM) Investigations to Evaluate for Clonal Plasma Cells…¶

Harrison's 22e, p.889

Investigations to Evaluate for Clonal Plasma Cells
Bone marrow aspirate and biopsy (fine-needle aspiration of plasmacytoma if
indicated)
• Histology
• Clonality by kappa/lambda immunostaining by flow cytometry or
immunohistochemistry
Investigations to Evaluate Clonal Paraprotein
Serum protein electrophoresis and immunofixation
Quantitative serum immunoglobulin levels (IgG, IgA, and IgM)
24-h urine protein electrophoresis and immunofixation
Serum free light chain and ratio
Immunofixation for IgD or IgE in select cases
Investigation to Evaluate End-Organ Damage
Hemogram to assess for anemia.
Chemistry panel for renal function and calcium
Skeletal survey or PET/CT scan to evaluate bone lesions
PET/CT or MRI if smoldering MM or solitary plasmacytoma
Investigation for Risk Stratification
β-Microglobulin and serum albumin for ISS stage
2
DNA-sequencing or if not available Fluorescent in situ hybridization for
hyperdipoidy, del17p, t(4;14); t(11;14), t(14;16), t(14;20), amp1q34, and del1p and
p53 mutation on bone marrow sample
LDH
Specialized Investigation in Selected Cases
Abdominal fat pad for amyloid
Serum viscosity if IgM component or high IgA levels or serum M component >7
g/dL
Myd88 and CXCR4 mutation analysis if IgM component

TABLE 116-3 Risk Stratification in Myeloma

METHOD	STANDARD RISK (75–80%) (EXPECTED SURVIVAL 8–10+ YEARS)	HIGH RISK (20–25%) (EXPECTED SURVIVAL 3–4 YEARS)
DNA sequencing or FISH if sequencing not available	t(11;14)	del(17p) (20% cutoff) and/ or TP53 mut
	del(13)	t(4;14)/t(14;16)/t(14;20) with 1q gain and/or 1p del
	Hyperdiploidy	Del 1p + 1q gain or biallelic del 1p

TABLE 116-3 Risk Stratification in Myeloma¶

Harrison's 22e, p.889

INTERNATIONAL STAGING SYSTEM (ISS)
INTERNATIONAL STAGING SYSTEM (ISS)	STAGE	MEDIAN SURVIVAL, MONTHS
βM <3.5, ALB ≥3.5 2	I (28%)	62
	II (39%)
βM >5.5 or βM <3.5, 2 2 ALB <3.5 or βM = 3.5–5.5 2	III (33%)	29

TABLE 116-4 Standard Therapeutic Agents in Myeloma CLASS Immunomodulatory drugs (IMiD)¶

Harrison's 22e, p.890

CLASS	AGENT	STANDARD DOSAGE AND ADMINISTRATION	COMBINATION	MYELOMA INDICATION
Immunomodulatory drugs (IMiD)	Thalidomide (T)	Oral 50–200 mg qd	TD, VTD	Newly diagnosed and relapsed
	Lenalidomide (R)	Oral 5–25 mg daily × 21 days q 4 weeks	RD, RVD, DaRD, ERD, KRD, IRD, DaRVD	Newly diagnosed, maintenance, and relapsed
	Pomalidomide (P)	Oral 2–4 mg daily × 21 days q 4 weeks	PD, KPD, DaPD	Relapsed
	Bortezomib (V)	IV or SC 1.3 mg/m2 days 1, 4, 8, 11 OR days 1, 8, 15	VD, VTD, VRD, DaVD, VCD DaRVD
	Carfilzomib (K)	IV 20–56 mg/m2 days 1, 2, 8, 9, 15, 16 q 4 weeks	KD, KRD, KPD, Da KD, Da KRD, IsaKD
	Ixazomib (I)	Oral 4 mg days 1, 8, 15	IRD
Antibodies	Daratumumab (Da)	IV or SC 16 mg/kg per week for 8 weeks then every 2 weeks for 16 weeks and then every 4 weeks thereafter	Dara, DaRD, DaVD, DaPD, DaKD	Newly diagnosed, maintenance, and relapsed
	Elotuzumab (E)	IV 10 mg/kg days 1, 8, 15, and 22 for first two cycles, then on days 1 and 15; along with RD	ERD, EPD	Relapsed
	Isatuximab (Isa)	IV 10 mg/kg weekly for 4 weeks and then every 2 weeks	IsaPD, IsaKD	Relapsed
	Belantamab mafodotin	IV 2.5 mg/kg once every 3 weeks		Relapsed or refractory—4 prior lines of therapy
	Selinexor (S)	Oral 80 mg on days 1 and 3 of each week	SVD
Histone deacetylase inhibitor	Panobinostat (Pa)	Oral 20 mg once every other day for 3 doses/week for 2 weeks every 21 days	PaVD	Relapsed
	Melphalan (M)	Oral 0.25 mg/kg per day for 4 days (with P) every 4–6 weeks	MP, MPT, MPR, MPV, DaMPV, high-dose M
	Cyclophosphamide	IV—300–500 mg/m2 weekly × 2 q 4 weeks Oral—50 mg qd × 21 days	VCD
	Bendamustine (B)	IV 70–90 mg days 1, 2 OR days 1, 8 q 4 weeks	BD or BVD
	Melflufen (Me)	IV 40 mg day 1 (with D 40 mg on days 1, 8, 15, and 22) q 28 days	MeD
Glucocorticoid	Dexamethasone (D) Prednisone (P)	Oral 10–40 mg q week Oral 1 mg/kg		All stages
	Idecabtagene vicleucel (Ide-cel)	IV 450 × 106 cells	None
	Ciltacabtagene autoleucel (Cilta-cel)	IV	None
Bispecific antibodies	Teclistamab Anti-BCMA–anti-CD3	Step-up doses of 0.06 mg and 0.3 mg per kilogram SC days 1, 4 and 1.5 mg per kilogram of body weight day 8 and q week	None	Relapsed or refractory—4 prior lines of therapy with prior exposure to PI, IMiD, and anti-CD38 antibody
	Elranatamab Anti-BCMA–anti-CD3	Step-up doses of 12 and 32 mg on days 1, 4 and 76 mg SC day 8 and then q week for 25 weeks and then q 2 weeks	None
	Talquetamab Anti-GPRC5D–anti-CD3	Two step-up doses during first week and then every week or every other week regimen	None