Dear Editor,

Leukoencephalopathy is a term given to any disorder that affects the white matter in the CNS [1]. There are only a limited number of case reports on leukoencephalopathy after daratumumab exposure, showing daratumumab-related leukoencephalopathy (DRL) as a late and likely irreversible adverse event (AE) [2,3,4]. Here, we report a case with early develo** but highly reversible DRL during daratumumab treatment.

A 56-year-old woman was diagnosed with relapsed IgG-κ multiple myeloma (MM). Five years ago, she had been diagnosed as MM, received prior treatment (including VCD, VTD, ASCT, and Rd), and achieved sCR and MRD-negative. On July 19, 2022, she was initiated on D-VPd [daratumumab (16 mg/kg d1, 8, 15, 22) [2], bortezomib, pomalidomide, and dexamethasone], which was discontinued after the third dose of daratumumab due to fever and neutropenia. Blood tests showed no other remarkable abnormalities. Her COVID-19 test was negative.

On August 16, she reported transient numbness and weakness in her left limbs, which later became more severe and bilateral, along with dysarthria and salivation. However, the brain MRI revealed no remarkable changes (Fig. 1A). Neurological examinations showed limited tongue movement, bilateral adduction, and abduction of eye movements. The strength of her right upper limb was 3/5, with a positive Babinski sign on the right side. A lumbar puncture showed no abnormalities in cerebrospinal fluid (CSF), including CSF pressure, total protein, Pandy’s reaction, WBC, chloride, glucose, tumor cells, pathogenic microorganisms like John Cunningham virus [3], and autoimmune encephalitis-related neuronal autoantibodies. On August 19, the brain MRI revealed patchy T2/fluid-attenuated inversion recovery (FLAIR) hyperintense signal in bilateral frontal and parietal white matter, centrum semiovale, and corona radiate (Fig. 1A). She then received 1 mg/kg methylprednisolone every 12 h [5], after which she had a rapid improvement of the neurological symptoms within 24 h. With consecutive methylprednisolone treatment for 10 days, virtually all neurological symptoms and signs disappeared. However, the alterations on MRI continued to progress and expand until a substantial improvement was noted on November 4, 2022 (Fig. 1A). Since then, she has been re-treated with VPd for MM, with her disease well controlled without any notable neurological symptoms thus far. Based on the concern that this agent was most likely associated with leukoencephalopathy, we decided not to include daratumumab for the re-treatment of MM in this case. The timeline for clinical changes and management is summarized in Fig. 1B.

Fig. 1
figure 1

Clinical and neuroimaging changes during the course of daratumumab-related leukoencephalopathy. A After the last (third) dose of daratumumab, the brain MRI was taken at the indicated timepoints. B Timeline of the patient with daratumumab-related leukoencephalopathy. Dx, diagnosis; Tx, treatment; LT, line of treatment; VTD, Velcade + thalidomide + dexamethasone; ASCT, autologous stem-cell transplantation; Rd, Revlimid + dexamethasone; MRD, minimal residue disease; D-VPd, daratumumab + Velcade + pomalidomide + dexamethasone; Dara, daratumumab; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; MP, methylprednisolone; VPd, Velcade + pomalidomide + dexamethasone

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Daratumumab is a human IgG-κ monoclonal antibody targeting human CD38, with substantial efficacy against newly diagnosed and relapsed/refractory MM, and other plasma cell diseases [6, 7]. Because CD38 is also expressed in various brain cells [8], along with the capability of daratumumab to cross the blood–brain barrier [9], this anti-CD38 antibody may directly attack cells responsible for myelin formation, resulting in demyelination [10]. Whereas daratumumab-associated AEs involving CNS are relatively rare (e.g., only one case of progressive multifocal leukoencephalopathy reported thus far in the trials involving daratumumab) [2], DRL has been reported in at least three cases [3, 4], showing DRL as a late AE after long-term use of daratumumab (Supplemental Table S1). However, we observed that DRL could occur early and progress rapidly after daratumumab administration. Of note, with timely and appropriate management (e.g., daratumumab discontinuation and corticosteroid administration), DRL could quickly and fully recover, although the neuroimaging improvement might lag behind.