Severe Diffuse Alveolar Hemorrhage Associated with Bortezomib Administration in Patients with Multiple Myeloma

Background: Bortezomib, a proteasome inhibitor, is frequently used in treatment of patients with multiple myeloma (MM). Bortezomib is generally well tolerated with gastrointestinal symptoms and peripheral neuropathy being the most common adverse effects. Here we report cases of severe diffuse alveolar hemorrhage (DAH) associated with bortezomib administration. Methods and Results: We identified 3 cases of severe DAH that were associated with bortezomib administration in MM patients treated at our institution between 2010 and 2014 (Table 1). All 3 patients presented with fever and worsening hypoxia shortly after initiation of bortezomib therapy and later developed progressive respiratory failure due to DAH. None of 3 patients had any respiratory symptoms or preexisting pulmonary conditions prior to bortezomib initiation. In one patient respiratory symptoms developed after 4 doses of bortezomib, improved off therapy, however rapidly progressed to a respiratory failure with a subsequent bortezomib treatment. Imaging studies showed diffuse areas of ground-glass opacities, apparent prominence of segmental and subsegmental bronchi and interlobular septal thickening. Infectious workup, which included bronchoscopy with bronchoalveolar lavage and respiratory viral studies, was completely negative in all 3 patients. All patients received supportive care, empiric broad-spectrum antimicrobial therapy and high-dose glucocorticoids, which were started within 4 days of hospital admission. Two patients died from complications of DAH and 1 patient recovered without pulmonary sequelae. Conclusion: Bortezomib-associated DAH is a rare, but serious and potentially fatal adverse event. Pathogenesis remains unclear and is likely related to impaired regulation of the inflammatory response. Early recognition of bortezomib associated DAH is essential for immediate discontinuation of the drug and prompt initiation of high dose steroids. More reports are needed to provide further insights about the pathogenesis and most optimal management of bortezomib induced DAH. | Pt | Age/ Gender/Race | Smoker | Sx | Bor dose | Bor schedule | # of Bor doses | Time of onset after last bor dose (days) | Platelet count at the onset (103/mm3) | Imaging/BAL findings | Time to initiation of high dose steroids | Outcome | | -- | ------------------------ | ------ | ------------- | --------- | ------------ | -------------- | ---------------------------------------- | ------------------------------------- | -------------------------------------- | ---------------------------------------- | -------- | | 1 | 67/M/C | Never | SOB, fever | 1.3 mg/m2 | IV/2Xwk | 8 | 5 | 157 | Bilateral infiltrates and GGO/DAH | 2 | Death | | 2 | 72/M/C | Yes | Fever, cough | 1.3 mg/m2 | IV/2Xwk | 2 | 3 | 108 | Bilateral infiltrates/DAH | 4 | Recovery | | 3 | 55/M/C | Yes | Fever, chills | 1.5 mg/m2 | IV/2Xwk | 1 | 2 | 144 | Bilateral diffuse airspace disease/DAH | 4 | Death | Abstract 5761. Table 1: Patients who developed DAH after bortezomib administration Abbreviations: Pt, patient; M, male; C, Caucasian; Sx, symptoms; Bor, bortezomib; BAL, broncho-alveolar lavage; GGO, ground-glass opacities. Disclosures No relevant conflicts of interest to declare.