48 Plasma Cell Disorders

Key Points

MGUS: M-protein <3 g/dL, PC <10%, no CRAB/SLiM; ~1%/yr progression
SMM: M-protein ≥3 or PC 10-59%, no CRAB/SLiM; ~10%/yr progression
MM dx: PC ≥10% + ≥1 CRAB or SLiM
- CRAB: ↑Ca, renal, anemia, bone
- SLiM: PC ≥60%, FLC ratio ≥100, MRI ≥1 focal lesion
Staging: ISS (biochemistry) & FISH (cytogenetics) guide intensity
High-risk: t(4;14), del(17p), TP53 mutations, high LDH
Induction: Triplet (VRd, VTD) × 4-6 cycles
Consolidation: ASCT for eligible (age <65-70, good PS)
Maintenance: Lenalidomide 10-15 mg indefinite
MRD: Flow ≥10^-4 or NGS ≥10^-6; MRD-neg = better OS
Relapse: CAR-T, BCMA×CD3 inhibitors, re-challenge w/ prior agents

48.1 Overview & Epidemiology

Spectrum: MGUS → SMM → MM w/ clonal evolution & progressive risk

Incidence: ~6/100,000/yr; median age 71 yr
African Americans: 2× ↑ incidence
Common cause: hypercalcemia (hospitalized), anemia (elderly)

48.2 Pathogenesis & Genomic Abnormalities

Early drivers: 1q gains, chr 13 loss, IgH translocations (45% MM)

48.2.1 IgH Translocations (FISH-detected)

Standard-risk: t(11;14) → CCND1; favorable
High-risk:
- t(4;14) → MMSET/NSD2, FGFR3; 15% MM
- t(14;16) → MAF; very aggressive
- t(14;20) → MAFB; rare, aggressive
- t(6;14) → CYCLIN D3; intermediate

48.2.2 Chromosome Gains & Losses

Favorable: Hyperdiploidy (trisomy 3, 5, 7, 9, 11, 15, 19, 21)

Unfavorable: - del(13p) → CDKN2A; 50% MM, shorter OS - del(1p) → independent adverse factor - del(17p) → TP53; rarest (5-10%), OS <2 yr

48.2.3 Mutations (WGS)

KRAS/NRAS: 40% MM; define outcomes
TP53: 10-15%; ↑ w/ progression
BRAF: rare; treatable w/ inhibitors

48.3 Clinical Presentation & Diagnosis

48.3.1 Presentation

CRAB (any 1 = symptomatic MM): - Ca >11 mg/dL - Renal: Cr >2 or eGFR <40 - Anemia: Hb <10 g/dL - Bone: Lytic lesions ± fractures

SLiM: - PC ≥60% - FLC ratio ≥100 - MRI ≥1 focal lesion

Common: Bone pain (70%), anemia (70%), renal dysfn (20-30%), infections (10-20%)

48.3.2 Diagnostic Workup

SPEP w/ immunofixation → M-spike, light chain type
24-hr urine UPEP w/ immunofixation → Bence Jones
Quantitative Ig → suppressed normal Ig
Serum FLC → κ/λ ratio
β2-M, LDH, Ca, Cr, albumin → staging
CBC, chemistries, LFTs
BM aspiration/biopsy:
- ≥10% clonal PC = diagnostic
- FISH: t(4;14), del(17p), del(1p)
Imaging:
- CT → lytic lesions
- MRI → gold standard for BM, EMD
- PET-CT → optional prognostication

48.4 MGUS, SMM & MM

48.4.1 MGUS

Def: M-protein <3 g/dL, PC <10%, no CRAB/SLiM
Prev: ~3% age ≥50, ~5-10% age >70
Progression: ~1%/yr (cumulative 30% @ 30 yr)
Risk (Rajkumar):
- Low: M-protein <1.5, IgG, normal FLC → 0.5%/yr
- Int: M-protein 1.5-2.5 or abnormal FLC → 1%/yr
- High: M-protein ≥2.5 or IgM/IgA or abnormal FLC → 3%/yr
Mgmt: Low-risk = observe; Int/high = f/u 6 mo then annually

48.4.2 SMM

Def: M-protein ≥3 or PC 10-59% or FLC ratio ≥100, no CRAB/SLiM
Progression: ~10%/yr to MM (first 5 yr)
Risk:
- Low: PC <60%, slow M-protein rise → PFS >10 yr
- High: PC ≥60% or fast M-protein rise → PFS <2 yr
- Genomic high-risk: del(17p), t(4;14), >3 MRI lesions
Mgmt: Low = observe (3-6 mo f/u); high = consider lenalidomide ± induction

48.4.3 MM (Symptomatic)

Def: PC ≥10% + ≥1 CRAB or SLiM

48.5 Staging & Prognostic Factors

48.5.1 Revised ISS (RISS)

Stage	Criteria	5-yr PFS	5-yr OS
I	β2-M <3.5, alb ≥3.5, standard-risk	82%	82%
II	Not I or III	62%	62%
III	β2-M ≥5.5, high-risk	40%	40%

48.5.2 Cytogenetics (FISH)

Standard-risk: No del(17p), t(4;14), del(1p)

High-risk: ≥1 of del(17p), t(4;14) → OS ~3-4 yr w/o novel agents

Very-high: Complex karyotype (≥3 abnormalities) → historically OS <2 yr, improving w/ combos

48.5.3 Additional Risk Factors

Adverse: - High LDH, high β2-M - High PC labeling index - MRD+ after induction - Advanced age, poor PS

48.5.4 Minimal Residual Disease (MRD)

Critical prognostic marker: MRD-neg post-ASCT → improved OS

Methods: - Flow: ≥10^-4 sensitivity (practical) - NGS: ≥10^-6 sensitivity (VDJ clonotype)

Timing: Post-induction, post-ASCT, at relapse

48.6 Treatment: Initial (Eligible for ASCT)

Pathway: Induction × 4-6 cycles → ASCT → Maintenance

48.6.1 Induction Regimens (Triplets)

VRd (preferred): - Bortezomib 1.3 mg/m² IV d 1, 4, 8, 11 - Lenalidomide 25 mg d 1-14 - Dex 40 mg weekly × 4 cycles - ≥VGPR ~50%; median PFS ~30+ mo post-ASCT

VTD: - Bortezomib, thalidomide 100 mg qd, dex - CR ~45%, ≥VGPR ~70%; median OS >10 yr - PN risk 20% grade ≥2

Daratumumab combos: - DVD (daratumumab-bortezomib-dex) - ↑ ≥VGPR, faster kinetics

48.6.2 ASCT

Indications: Age <65-70, good PS, adequate organ fn
Preparatory: High-dose melphalan 200 mg/m²
Target: ≥2 × 10^6 CD34+/kg
Outcomes: TRM ~2-3%, ≥VGPR ~80-90%

48.6.3 Maintenance (Post-ASCT)

Lenalidomide (standard): - 10-15 mg daily indefinite - PFS +7 mo, improves OS - Manageable toxicity

Bortezomib: - 1.3 mg/m² SC q 3 weeks - Median PFS 36 mo

Response (IMWG):

Response	Criteria
CR	No M-protein (IF), <5% BM PC, normal FLC
≥VGPR	M-protein by IF only or <5% BM PC
PR	≥50% ↓ M-protein, ≥90% ↓ urine
sCR	CR + normal FLC, no BM PC
MRD-	No clonal PC (NGS/flow ≥10^-5)
PD	≥25% ↑ M-protein or ≥200 mg/24h urine

48.7 Treatment: Initial (Ineligible for ASCT)

48.7.1 Lenalidomide & Dex (Rd)

Lenalidomide 25 mg d 1-21, dex 40 mg weekly
≥VGPR ~55%, median PFS 22 mo
VTE risk 10-15% → aspirin prophylaxis
Continue indefinite or to progression

48.7.2 Bortezomib-based (VD, VRd)

Vd (bortezomib-dex): ≥VGPR ~50%, OS ~4.8 yr (elderly)
Preferred if renal impairment
PN risk, infusion requirement

48.7.3 Daratumumab Combos

DVD (daratumumab-bortezomib-dex)
ALCYONE (dara-VMP): PFS 24 mo vs. 19 mo (VMP alone)
Improved efficacy, consider cost/infusion burden

48.8 Treatment: Relapsed/Refractory MM

48.8.1 Risk Assessment @ Relapse

TTP <6 mo = early relapse (poor prognosis)
TTP >1 yr = late relapse (rechallengeprior agents)
Prior therapy resistance, del(17p), TP53 mutations = very poor
MRD status at relapse prognostic

48.8.2 Anti-CD38 Monoclonal Antibodies

Daratumumab: - Monotherapy: ~35% response (early relapse) - w/ Len/Dex: ~80% ≥PR

Isatuximab: - Similar mechanism, outcomes to daratumumab

Elotuzumab (anti-SLAMF7): - w/ Len/Dex: ↑ PFS vs. Len/Dex alone

48.8.3 Proteasome Inhibitors

Carfilzomib (next-gen): - 27 mg/m² IV d 1, 2, 8, 9, 15, 16 - ~55-65% response (PI-naive) - Lower PN risk than bortezomib - Monitor cardiac toxicity

Ixazomib (oral): - 4 mg weekly w/ Len/Dex - ~68-72% ≥PR (relapsed) - Lower PN risk

Bortezomib re-challenge: - If >1 yr from last exposure

48.8.4 IMiDs

Pomalidomide: - 4 mg d 1-21 w/ dex or bortezomib - ~45-50% response (len-refractory)

Lenalidomide: - 10-15 mg qd indefinite - PFS ~12-18 mo w/ combos - VTE prophylaxis: aspirin

48.8.5 High-Risk Approach

Quad induction (triplet + daratumumab or PI): - Goal: MRD-neg, low residual burden - Consider early 2nd ASCT if eligible

MRD-driven: - MRD-neg: Lenalidomide monotherapy - MRD+: Intensified duplet/triplet

48.9 Supportive Care

48.9.1 Bone Disease

Bisphosphonates: - Zoledronic acid 4 mg IV monthly × 12 mo (hold if eGFR <30) - Pamidronate 90 mg IV monthly - Effect: ↓ bone resorption, prevents SRE - ONJ risk 1-5%; monitor w/ prolonged use

Denosumab (RANKL inhibitor): - SC monthly; no renal adjustment - ↓ SRE vs. zoledronic acid - Preferred in renal impairment

Supportive: Ca & Vit D, weight-bearing exercise, avoid NSAIDs, PPI if high-dose dex, radiation for focal pain

48.9.2 Anemia

ESA if Hb <10; target 10-12 g/dL
Iron if deficient
Transfusion for symptomatic (target Hb >7)
G-CSF for chemotherapy-induced neutropenia

48.9.3 Renal Dysfunction

Prevention: - Adequate hydration - Avoid NSAIDs, nephrotoxins - Alkalize urine (sodium bicarbonate)

Management: - Bortezomib preferred (not renally excreted) - Adjust lenalidomide/pomalidomide for eGFR - Dialysis for ESRD; may recover renal fn

48.9.4 Infections

Prophylaxis: - IVIG 0.4 g/kg monthly (hypogammaglobulinemia + recurrent infections) - Prophylactic antibiotics (levofloxacin) for high-risk neutropenia - Vaccines: PCV13, PPSV23, influenza, COVID-19

Management: Empiric broad-spectrum antibiotics for fever

48.9.5 Peripheral Neuropathy

Agents: Bortezomib (dose-dependent), lenalidomide, thalidomide, ixazomib

Prevention: Minimize cumulative bortezomib

Grading: NCI-CTCAEv5

Management: Dose reduction if grade 2-3; gabapentin/pregabalin; substitute if grade ≥3

48.9.6 Other Complications

Hyperviscosity (1-2%): - Plasmapheresis for acute relief - Chemotherapy for underlying disease

Cord compression (~10%): - MRI spine (dx) - High-dose dex 10-16 mg IV qd × 3-5 d - Radiation, surgery if unstable

Hypercalcemia (10-20%): - IV hydration, loop diuretics - Bisphosphonates, dex 40 mg/d × 4 d - Calcitonin for immediate effect (onset <4 h)

AL amyloidosis (~5%): - Light chain deposition; biopsy confirmation - Consider if neuropathy, proteinuria, cardiomyopathy

48.10 Other Plasma Cell Disorders

48.10.1 Solitary Plasmacytoma of Bone

Single clonal PC focus, no MM; 10% progress
Dx: Biopsy, imaging to exclude lesions
Tx: Radiation 40-50 Gy → CR >75%
F/u: Monitor for MM progression

48.10.2 Solitary Extramedullary Plasmacytoma

Rare: PC tumor outside BM (ENT, sinuses, orbit, lung, GI, skin)
>50% develop MM
Tx: Radiation ± chemotherapy if disseminated
Prognosis: Median OS 5-10 yr

48.10.3 Nonsecretory MM (3-5%)

Clonal BM PC ≥10% w/o M-protein
Challenge: No M-protein for monitoring
Dx: PC morphology, immunophenotyping, FISH
Monitor: FLC ratio, imaging (MRI, PET-CT)

48.10.4 Plasma Cell Leukemia

Circulating PC ≥2,000/μL (>5% WBC)
Aggressive: Median age 55 yr, median OS 7-12 mo
Risk factors: TP53 mutations, hepatomegaly, ↑ LDH
Tx: Intensive induction (quad combos), ASCT if eligible
Consider: Clinical trial enrollment

48.11 Key Clinical Pearls

MRD-neg = strongest prognostic marker; assess post-induction & post-ASCT (flow ≥10^-4 or NGS ≥10^-6)
High-risk cytogenetics (del(17p), t(4;14), del(1p)) → intensive induction & early ASCT
Maintenance post-ASCT prolongs PFS (+7 mo) & OS; lenalidomide standard; intensify if MRD+ or high-risk

48.12 Bibliography

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Chim CS, Kumar S, Tan D, et al. International Myeloma Working Group consensus statement and guidelines for the management of smoldering multiple myeloma. Leukemia. 2017;31(3):573-586.

Dimopoulos MA, Kastritis E, Rosinol L, et al. Pathogenesis and treatment of renal failure in multiple myeloma. Leukemia. 2008;22(8):1485-1493.

Dispenzieri A, Rajkumar SV. Role of novel agents in treatment of newly diagnosed multiple myeloma. Best Pract Res Clin Haematol. 2005;18(4):563-580.

Fonseca R, Abramson J, Rajkumar SV, et al. Multiple myeloma: review on how to manage newly diagnosed patients. Am J Hematol. 2011;86(12):964-976.

Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412-3420.

Kumar SK, Dimopoulos MA, Kastritis E, et al. Natural history of relapsed myeloma, refractory myeloma, and second-line disease outcomes from the PANORAMA1 and IFM2005-01 trials. Blood. 2017;130(21):2260-2266.

Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621-631.

Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91(7):719-734.

Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548.

Richardson PG, Lonial S, Jakubowiak AJ, et al. Ixazomib-based regimens for newly diagnosed patients with relapsed/refractory MM. Lancet Oncol. 2015;16(16):1619-1629.

San Miguel JS, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906-917.

Terpos E, Kleber M, Engelhardt M, et al. European Myeloma Network guidelines for the management of multiple myeloma-related complications. Haematologica. 2015;100(10):1254-1266.