C42-01 A Two-hit Theory: Eosinophilic Pneumonitis With Daratumumab and Carfilzomib

Abstract Introduction Combination therapy with daratumumab, carfilzomib, pomalidomide, and dexamethasone (Dara-KPd) has shown promising response rates in early-phase studies for relapsed or refractory multiple myeloma. While the pulmonary effects of daratumumab are rarely reported beyond case reports, carfilzomib has been associated with ∼0.4% of pneumonitis cases, with eosinophilic pneumonitis being even rarer. When such combinations cause overlapping symptoms, diagnosis and attribution to a specific medication becomes challenging. Our case describes a “two-hit” immune injury: eosinophilic pneumonitis developing soon after carfilzomib was added to long-term daratumumab. Case Presentation A 76-year-old woman with IgA kappa multiple myeloma, status post autologous stem cell transplant (2018), had remained stable for two years on Dara-KPd. After a relapse with complex cytogenetics, low-dose carfilzomib was added to her regimen. Following the seventh dose, she developed acute dyspnea requiring 2-3 L/min of oxygen. Chest CT revealed new bilateral micronodular and patchy ground-glass opacities. Laboratory tests showed peripheral eosinophilia of 20% and bronchoscopy revealed >25% eosinophils. Infectious workup (viral panel, blood, and sputum cultures) was negative. Cardiogenic pulmonary edema was unlikely, given a recent ejection fraction of 74% and normal BNP levels. Hypersensitivity pneumonitis was ruled out due to no recent exposure to allergens or medication changes. Drug-induced eosinophilic pneumonitis was diagnosed. Prednisone 40 mg daily was initiated with rapid symptomatic improvement and reduction in peripheral eosinophilia to 5% within two weeks. A three-week steroid taper resulted in radiographic resolution. Due to her advanced myeloma, carfilzomib was continued at a reduced dose with steroid cover after multidisciplinary discussion, while the daratumumab backbone was maintained. She remained clinically stable without recurrent symptoms. Discussion Daratumumab works by targeting CD38 on myeloma cells, whereas carfilzomib is a proteasome inhibitor. In combination therapy, eosinophilic pneumonitis can result from the immune response triggered by daratumumab and cellular stress induced by carfilzomib. Long-term use of daratumumab may alter the immune response, making the lungs more susceptible to further damage. When used alongside medications like carfilzomib, which is known to cause pneumonitis, the overall risk of adverse effects increases. This case adds to the growing literature on drug-induced eosinophilic pneumonitis. We highlight the rarity of this toxicity, the need for heightened awareness, and careful treatment modification to prevent acute respiratory failure. As the use of these regimens expands, further studies are needed to fully understand the associated risks and to guide appropriate prescribing practices. This abstract is funded by: None