Sarcoid-like drug reaction is a granulomatous inflammation having clinical and morphological similarity with sarcoidosis and developing as a rule on chemo/immunotherapy. An important characteristic of the drug-induced sarcoid-like reaction consists in its time relationship with a drug assignment and also with a regression upon its withdrawal. Sarcoid-like reactions are known to occur on therapy with immune checkpoint inhibitors, interferons, tumor necrosis factor-alpha antagonists, antiretroviral drugs, BRAF inhibitors, and rituximab. However, no reports have been published on a sarcoid-like reaction associated with the monoclonal anti-CD38 therapy despite a wide experience in their use for treating plasma cell neoplasms. This paper reports the first case of sarcoid-like reaction characterized by pulmonary lesions with confluent large-nodular areas that developed on daratumumab maintenance therapy in a female patient with multiple myeloma and systemic AL amyloidosis. This case report proves the probability of a sarcoid-like reaction on daratumumab therapy. Further studies are necessary to understand the pathogenesis of similar reversible damage.