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Progressive multifocal leukoencephalopathy during bispecific
antibody therapy in multiple myeloma: from immune
dysfunction to early recognition. Comment on: “Progressive
multifocal leukoencephalopathy and BK virus-nephropathy
with bispecific antibody therapy in multiple myeloma”
by Davide Facchinelli and Livio Pagano
Received: August 30, 2026.
Accepted: September 3, 2026.
Citation: Davide Facchinelli and Livio Pagano. Progressive multifocal leukoencephalopathy during
bispecific antibody therapy in multiple myeloma: from immune dysfunction to early recognition.
Comment on: “Progressive multifocal leukoencephalopathy and BK virus-nephropathy with bispecific
antibody therapy in multiple myeloma”.
Haematologica. 2026 Sept 10. doi: 10.3324/haematol.2026.301888 [Epub ahead of print]
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Progressive multifocal leukoencephalopathy during bispecific antibody therapy in multiple
myeloma: from immune dysfunction to early recognition. Comment on: “Progressive
multifocal leukoencephalopathy and BK virus-nephropathy with bispecific antibody therapy
in multiple myeloma”
Davide Facchinelli1, Livio Pagano2,3
1Hematology Unit, Department of Clinical Oncology, San Bortolo, Vicenza, Italy
2Section of Hematology, Department of Radiological and Hematological Sciences, Catholic
University, Rome, Italy
3Department of Laboratory and Hematological Sciences, Fondazione Policlinico Gemelli IRCCS,
Rome, Italy
Running head: PML during bispecific antibody therapy.
Corresponding author:
Davide Facchinelli
Hematology Unit, Department of Clinical Oncology, San Bortolo, Vicenza, Italy
Email: davide.facchinelli@aulss8.veneto.it
Acknowledgments: None.
Funding: No specific funding was received for this work.
Conflicts of interest: Nothing to declare.
Data-sharing statement: Not applicable.
Author contributions: DF wrote the initial draft of the manuscript. LP contributed to the critical
review and editing of the text.
The recent study by Siegel et al.1 provides important insights into the severe immune dysfunction
associated with therapy using bispecific antibodies that redirect T cells in multiple myeloma (MM).
The authors describe a patient treated sequentially with bispecific antibodies targeting BCMA and
GPRC5D, who developed BK virus-associated nephropathy followed by rapidly fatal progressive
multifocal leukoencephalopathy (PML). It is important to emphasise that longitudinal analysis of
the immune profile revealed impairment of both humoral and cellular immunity, including the loss
of JC virus (JCV)-specific CD8+ T-cell responses, which preceded the clinical onset of PML1.
These findings provide a biological framework for an increasingly recognized clinical concern:
PML during prolonged exposure to bispecific antibodies.
PML has historically been regarded as a rare complication of MM and its treatment. Prior to the
widespread use of T-cell-redirecting therapies, Koutsavlis identified 16 well-documented cases of
PML in MM and suggested that this complication might be underdiagnosed2. Subsequently,
Hoeynck et al. described six patients with MM who developed PML, including a patient exposed to
teclistamab, providing an early signal in the era of BCMA-directed therapies3. More recently,
individual cases have been reported with both teclistamab and elranatamab, including two patients
receiving elranatamab reported by Tomkins et al. and a further elranatamab-associated case
described by Çetiner et al4,5.
This emerging association is now supported by larger contemporary cohorts. Gadoth et al. recently
reported five patients who developed PML following treatment with bispecific antibodies; all were
receiving a bispecific antibody directed against BCMA at the time of PML diagnosis. The median
interval between the start of bispecific antibody therapy and the onset of PML was 12 months
(range, 6–24), and all patients had lymphopenia and hypogammaglobulinaemia prior to diagnosis6.
Importantly, one patient developed PML after only two prior lines of therapy, suggesting that
cumulative pretreatment alone may not fully explain susceptibility6. Furthermore, Le Henaff et al.
identified 14 definite cases of PML among patients with MM exposed to bispecific antibodies, all
involving BCMA-targeting agents, with a median exposure of 22 months. Their pharmacovigilance
analysis identified a significant disproportionality signal for PML with bispecific antibodies
compared with other MM therapies (reporting odds ratio, 17.7; 95% CI, 12.1–26.1)7. Although
these observations do not allow us to establish a causal link or to estimate the incidence, they
reinforce the emerging association between prolonged exposure to the bispecific antibody directed
against BCMA and PML.
Our recent multicenter SEIFEM study provides complementary real-world evidence8. Among 35
patients with hematologic malignancies diagnosed with PML across 16 Italian centers, seven (20%)
had MM and two developed PML after bispecific antibody therapy, including one receiving
elranatamab. Overall prognosis was poor, with a median survival from PML diagnosis of 2.17
months and 80% mortality. Importantly, the median interval between neurological symptom onset
and PML diagnosis was 28 days (range, 2–110), highlighting the considerable diagnostic challenge
posed by this disease8.
The patient treated with elranatamab represented the upper extreme of this diagnostic interval. This
62-year-old woman had previously received daratumumab, bortezomib, thalidomide and
dexamethasone followed by autologous stem-cell transplantation. At relapse, she received
elranatamab and developed motor and speech impairment after 11 months of treatment. Brain
magnetic resonance imaging showed a single frontal lesion, and PML was ultimately diagnosed by
detection of JCV DNA in cerebrospinal fluid (CSF) 110 days after neurological symptom onset. At
diagnosis, neutropenia, lymphopenia and hypogammaglobulinemia were present.
The 11-month exposure in our patient is remarkably consistent with the temporal pattern emerging
from recent reports. Gadoth et al. observed a median exposure of 12 months6, while Chizzoniti et al.
recently described late-onset PML after approximately nine months of teclistamab therapy9.
Collectively, these observations suggest that PML may represent a delayed complication of
sustained immune dysfunction rather than an early toxicity of bispecific antibody therapy.
The immunological findings are equally important. Severe hypogammaglobulinaemia is a well-
known complication of BCMA-targeted therapy, but the preservation or replacement of
immunoglobulins may not fully restore antiviral immune surveillance. Chizzoniti et al. reported
cases of PML despite regular immunoglobulin replacement therapy, in a context of marked CD4+
lymphopenia9. Similarly, Gadoth et al. demonstrated a reduction in the populations of naïve CD4+
and CD8+ T lymphocytes and a phenotypic shift towards terminally differentiated, activated and
exhausted cells6. It is interesting to note that JCV/BKV-specific T-cell responses remained
detectable in two of the four patients assessed, suggesting that qualitative T-cell dysfunction may be
as significant as their quantitative depletion6. These observations complement the longitudinal
findings of Siegel et al.1 and support a potential role for sustained cellular immune dysfunction in
PML susceptibility.
Early diagnosis is therefore crucial. Neurological symptoms may initially be attributed to
cerebrovascular disorders, metabolic abnormalities, treatment-related neurotoxicity or other
infections. Furthermore, a negative PCR result for JCV in cerebrospinal fluid does not rule out
PML: in the SEIFEM and Gadoth series, some selected patients required a brain biopsy despite a
negative cerebrospinal fluid test result6,8. New, otherwise unexplained progressive neurological
symptoms during bispecific antibody therapy should therefore prompt early brain MRI and CSF
JCV testing, with repeat testing or brain biopsy considered when clinical and radiological suspicion
persists.
As bispecific antibodies move into earlier treatment lines and exposure becomes increasingly
prolonged, PML deserves greater attention as a rare but potentially fatal complication. Current
evidence does not justify routine JCV screening, and the absolute risk remains undefined.
Nevertheless, the convergence of clinical series, pharmacovigilance data and emerging
immunological evidence suggests that duration of exposure, lymphopenia and qualitative T-cell
dysfunction warrant prospective investigation as potential risk markers. Increased awareness and
timely diagnostic evaluation may currently represent our most effective tools for reducing the
devastating consequences of delayed PML recognition.
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