7.7 Lymphomas & Plasma Cell Disorders

1. Lymphomas: Hodgkin vs. Non-Hodgkin

Hodgkin Lymphoma (HL)

• Histopathology: Clonal giant multinucleated Reed-Sternberg (RS) cells (classic "owl's eye" appearance) or mononuclear Hodgkin cells expressing CD15 and CD30 (negative for CD20 and CD45), surrounded by a reactive inflammatory background of lymphocytes, eosinophils, and plasma cells.
• Epidemiology & Presentation: Bimodal age distribution (peaks in 20s and 60s). Painless, rubbery cervical or supraclavicular lymphadenopathy (60–80%) and mediastinal widening. Constitutional B symptoms (fever > 38°C, drenching night sweats, unexplained weight loss > 10% in 6 months), severe generalized pruritus, and alcohol-induced lymph node pain (pathognomonic).
• Staging & Therapy: Staged using the Ann Arbor system with whole-body $^{18}\text{F}$-FDG PET-CT.
  • First-line regimen: ABVD (Adriamycin [Doxorubicin], Bleomycin, Vinblastine, Dacarbazine) or Brentuximab vedotin + AVD (A+AVD).
  • Drug Toxicities: Bleomycin causes dose-dependent pulmonary toxicity and interstitial fibrosis (monitor DLCO; avoid high-flow O2); Doxorubicin causes cumulative cardiotoxicity (monitor LVEF); Vinblastine causes peripheral neuropathy and paralytic ileus.

Non-Hodgkin Lymphomas (NHL)

2. Plasma Cell Dyscrasias

Plasma cell neoplasms are characterized by the clonal proliferation of post-germinal center B-lineage plasma cells producing a monoclonal immunoglobulin (M-protein) or free light chains (kappa or lambda).

Spectrum of Monoclonal Gammopathies

Diagnostic Criteria for Active Multiple Myeloma

Diagnosis requires clonal bone marrow plasma cells $\ge 10%$ (or tissue plasmacytoma) PLUS at least one of the following:

Classic CRAB Criteria:

• C — Hypercalcemia: Serum calcium > 11.0 mg/dL (> 2.75 mmol/L) or > 1.0 mg/dL above normal.
• R — Renal Insufficiency: Serum creatinine > 2.0 mg/dL (> 177 mcmol/L) or measured/estimated CrCl < 40 mL/min attributable to myeloma cast nephropathy (light chain deposition in distal tubules forming obstructive casts).
• A — Anemia: Hemoglobin < 10.0 g/dL or > 2.0 g/dL below lower limit of normal.
• B — Bone Lesions: $\ge 1$ osteolytic bone destruction on skeletal radiography, whole-body low-dose CT, or $^{18}\text{F}$-FDG PET-CT.

SLiM Biomarkers of Malignancy (≥ 80% risk of progression to symptomatic disease within 2 years):

• S: $\ge$ 60% Clonal Bone Marrow Plasma Cells.
• Li: Involved-to-Uninvolved Serum Free Light Chain (FLC) ratio $\ge$ 100 (with involved light chain $\ge 100$ mg/L).
• M: > 1 Focal Lesion on Whole-Body MRI (lesions $\ge 5$ mm in size).

Comprehensive Management of Multiple Myeloma

1. Induction Chemotherapy: Quadruplet therapy is current standard of care for transplant-eligible patients: Daratumumab (anti-CD38 monoclonal antibody) + Bortezomib (proteasome inhibitor) + Lenalidomide (immunomodulatory drug / IMiD) + Dexamethasone (D-VRd).
2. High-Dose Chemotherapy & Consolidation: High-dose Melphalan followed by Autologous Stem Cell Transplantation (ASCT) for eligible patients (age < 75–80 without severe prohibitive comorbidities).
3. Maintenance Therapy: Continuous Lenalidomide maintenance until disease progression.
4. Bone Disease & Skeletal-Related Events: All patients with active MM requiring therapy should receive monthly bone-targeted antiresorptive therapy: IV Zoledronic Acid (4 mg) or Subcutaneous Denosumab (120 mg) (preferred in severe renal failure) for at least 2 years. Monitor for osteonecrosis of the jaw and hypocalcemia.

Related Plasma Cell Disorders

• AL (Primary) Amyloidosis: Deposition of monoclonal immunoglobulin light chain fibrils (lambda > kappa) in tissues exhibiting apple-green birefringence under polarized light with Congo red stain. Manifestations: restrictive cardiomyopathy (low voltage ECG with thickened LV walls), nephrotic syndrome (heavy albuminuria), hepatomegaly, periorbital purpura ("raccoon eyes"), and macroglossia. Treatment: Daratumumab + CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone) $\pm$ ASCT.
• Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma): Clonal lymphoplasmacytic proliferation producing an IgM monoclonal gammopathy, strongly associated with somatic MYD88 L265P mutation (> 90%).
  • Clinical hallmarks: Anemia, lymphadenopathy, hepatosplenomegaly, and Hyperviscosity Syndrome (caused by large pentameric IgM molecules): epistaxis, retinal hemorrhages ("sausage-link" veins), blurry vision, dizziness, ataxia, headache, and stupor.
  • Emergency Management for Hyperviscosity: Immediate Therapeutic Plasmapheresis to rapidly lower IgM levels, followed by definitive systemic therapy (Bendamustine + Rituximab or BTK inhibitors [Zanubrutinib / Ibrutinib]). Rituximab can trigger a transient "IgM flare"; do not give single-agent rituximab if baseline IgM > 4,000 mg/dL without pre-treatment plasmapheresis.