daratumumab

**Mechanism of action** - Binds CD38, a transmembrane glycoprotein/ectoenzyme that is overexpressed on malignant plasma cells. - Kills tumor cells through several mechanisms: - Complement-dependent cytotoxicity (CDC) - Antibody-dependent cell-mediated cytotoxicity (ADCC) - Antibody-dependent cellular phagocytosis (ADCP) - Direct apoptosis via cross-linking - Immunomodulation: depletes CD38+ regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells, which may boost T-cell responses.

**Clinical use** - Multiple myeloma (plasma cell neoplasm; CRAB features: hypercalcemia, renal failure, anemia, bone lesions). - Newly diagnosed disease: combined with lenalidomide + dexamethasone ± bortezomib (for example D-VRd, DRd, VMP). - Relapsed/refractory disease: combined with pomalidomide or carfilzomib + dexamethasone, and also used as monotherapy. - Subcutaneous formulation (with hyaluronidase) is available and has a lower infusion-reaction rate than IV. - Also used in AL amyloidosis (with cyclophosphamide, bortezomib, dexamethasone). - Related anti-CD38 agent: isatuximab. Other myeloma targets: elotuzumab (SLAMF7), and bispecific T-cell engagers/CAR-T against BCMA.

**Adverse effects** - Infusion-related reactions (most common with the first dose): bronchospasm, dyspnea, cough, rhinitis, hypertension. Premedicate with steroids, antihistamines, and acetaminophen. - Cytopenias (neutropenia, thrombocytopenia, lymphopenia) and increased infections. - Hepatitis B reactivation, so screen before starting. - Herpes zoster, so give antiviral prophylaxis.

**Key high-yield interference** - CD38 is weakly expressed on RBCs. Daratumumab binds them and causes a **pan-reactive positive indirect antiglobulin (Coombs) test** and a positive antibody screen. This can mask clinically significant alloantibodies. - Tell the blood bank before therapy, and obtain type and screen/phenotype beforehand. - Mitigation: treat reagent RBCs with DTT, or use anti-CD38-neutralizing methods. - Direct Coombs may also be positive, but hemolysis is usually absent. - Daratumumab is an IgG-kappa antibody and can be detected on serum protein electrophoresis/immunofixation. This may falsely suggest persistent M-protein in patients with IgG-kappa myeloma and hinder assessment of complete response.

**Related pearls** - Name: "-mab" = monoclonal antibody; "-umab" = fully human; "-tumu-" (older nomenclature) = tumor target. - Myeloma pathology: monoclonal plasma cell proliferation with M-spike on SPEP, Bence-Jones proteins (free light chains) in urine, rouleaux formation on smear, "punched-out" lytic lesions on skull X-ray, and >10% clonal plasma cells in marrow. - Immunophenotype: CD38+, CD138+ (syndecan-1), and usually CD56+, whereas CD20 is typically negative. This is why rituximab is not used in myeloma.