Mauro Passucci, Francesca Fazio and Maria Teresa Petrucci.
Department of Translational and Precision Medicine, Policlinico Umberto I, La Sapienza University of Rome, Italy.
Published: January 1, 2023
Received: November 11, 2022
Accepted: December 21, 2022
Mediterr J Hematol Infect Dis 2023, 15(1): e2023012 DOI
10.4084/MJHID.2023.012
This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0),
which permits unrestricted use, distribution, and reproduction in any
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To the editor
We
want to comment on a rare and life-threatening neurologic complication
of Multiple Myeloma called hyperammonemia encephalopathy.
Despite improved prognosis due to the greater availability of novel
agents like proteasome inhibitors, immunomodulatory drugs, and
anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains
incurable; it is associated with a more aggressive course in about
20-30% of the cases. Disease features related to bone marrow
infiltration or paraproteinemia include hypercalcemia, renal
insufficiency, anemia and osteolytic bone lesions. Neurologic symptoms
like altered mental status, depression/euphoria, and seizures are
usually associated with hypercalcemia, renal insufficiency, or
hyperviscosity. Hyperammonemia is a rare MM-related condition which may
cause a neurologic syndrome in MM patients.
Here we report a case of hyperammonaemic encephalopathy (HE) in advanced relapsed/refractory non-secretory multiple myeloma.
In May 2020, a 61-year-old female came to our hematologic Emergency
Department for lower back pain that had progressively worsened for
several months. She presented with mild anemia (Hb 10.1 g/dl),
hypercalcemia, and hyperuricemia with acute renal failure (calcium 19
mg/dl, uricemia 10.6 mg/dl, creatinine 3.0 mg/dl). A spine magnetic
resonance imaging (MRI) showed several osteolytic lesions in the
dorsal-lumbar region. A full MM workup was pursued. Serum protein
electrophoresis revealed hypogammaglobulinemia; no monoclonal protein
was detected; serum free light chain kappa/lambda ratio was 1.34;
24-hour proteinuria was < 200 mg/24h, and urine immunofixation was
negative. A bone marrow aspirate revealed 37% of clonal plasma cells;
4% of plasma cells were also identified in the peripheral blood.
Fluorescence in situ hybridization (FISH) performed on bone marrow
plasma cells showed t(11;14), defining MM as a standard risk by
cytogenetics. According to the 2016 International Myeloma Working Group
(IMWG) diagnostic criteria, we diagnosed ISS III – R-ISS II
non-secretory MM. In June 2020, we started induction treatment
bortezomib (1.3 mg/m2 on days 1, 4, 8
and 11), thalidomide (200 mg/die), and dexamethasone (40 mg on days 1-4
and 8-11) every three weeks – VTd regimen. During the fourth cycle, she
developed right lower limb deep vein thrombosis requiring
anticoagulants and, according to this condition, she performed the last
two cycles without thalidomide. At the end of induction, stem cells
were collected by leukapheresis following chemo-mobilization with
cyclophosphamide (2.4 mg/m2), granulocyte colony-stimulating factor, and plerixafor. In January 2021, high-dose melphalan conditioning at 200 mg/m2
was administered in two separate doses, followed by peripheral blood
autologous stem cell transplantation after two days. Based on the
International Myeloma Working Group (IMWG) response criteria, the
patient obtained a complete response (CR). In July 2021, complete blood
counts revealed a progressive increase of peripheral large unstained
cells (LUC). Cytomorphological peripheral blood examination showed 21%
of plasma cells, diagnostic for end-stage multiple myeloma (secondary
plasma cell leukemia). The patient started second-line therapy with a
DRd regimen (daratumumab, lenalidomide, dexamethasone). After the first
dose of intravenous daratumumab, the patient progressively developed
altered mental status, and she came to our Emergency Department (ED).
Physical examination showed poor general conditions: the patient was
disoriented in space and time with severe lethargy and diffuse muscle
hypotonia but no focal deficits. Blood exams showed severe anemia,
thrombocytopenia (Hb 9.8 g/dl, PLT 2.000/mm3),
and hyperuricemia (blood uric acid 11.9 mg/dl) with normal liver/renal
function and no electrolytic abnormalities. Serum B12 and thyroid
hormones were normal. Brain computed tomography (CT) and magnetic
resonance imaging (MRI) were negative for intracranial bleeding or
space-occupying lesions; there were no radiological features of brain
metabolic or vascular distress. Cytological, chemical-physical and
microbiological analyses of cerebrospinal fluid were negative for MM
localization or signs of bacterial, viral, or fungal infections
(cultural and molecular exams were performed). Considering
hyperammonemia in the diagnostic workup, we performed blood ammonium
detecting it at a high concentration (179 µmol/l, normal range 11-51
µmol/l). We immediately started antibiotic therapy with vancomycin and
evacuation therapy with enemas. Unfortunately, blood ammonium remained
stable at > 100 µmol/l, and the patient's neurological condition
worsened until coma and death within a few days.
This case shows a rare manifestation of end-stage multiple myeloma
presenting with severe hyperammonaemic encephalopathy. Neurologic
manifestations in MM often correlate to high calcium levels, drug side
effects, hyperviscosity, or infections. Hyperammonaemia is much more
frequent in acute or chronic liver failure; uncommonly, high levels of
ammonia leading to encephalopathy have been described in multiple
myeloma. MM-related hyperammonemia is often associated with advanced
disease (International Staging System stage III) and with high risk
features such as the presence of plasma cells in the peripheral blood,
unfavorable cytogenetics abnormalities, and extra-medullary
localization.[1]
The pathogenesis of increased ammonia blood levels in MM has yet to be
fully understood. However, it is probably related to MM infiltration of
the liver leading to hepatic failure and portosystemic shunts. This
hypothesis is in line with the evidence from the case series of
increased HE risk in patients with MM and the presence of plasma cells
in peripheral blood.[2] In addition, a review of 27 HE cases showed a higher frequency of IgA MM.[3]
Secondary plasma cell leukemia (PCL), nearly 40% of all cases of PCL,
is associated with end-stage disease and a worse patient outcome,[4]
as in our patient. In the absence of liver failure, recent studies
suggest that either aggressive plasma cell clone can produce ammonia or
myeloma-related humoral factors can influence amino acid metabolism
leading to an increase in blood ammonium. Brain toxicity derives from
converting excess ammonium into glutamine by astrocytes, leading to an
osmotic transmembrane gradient and subsequent cerebral edema. Moreover,
glutamine can negatively regulate lysosomal proteolysis and activate
intracellular proteasome activation; this could explain the possible
therapeutic effect of proteasome inhibitors in HE.[5]
Amino acids L -ornithine- L –aspartate (LOLA) supplementation (together
with specific anti-myeloma treatment) could support the hepatic
production of urea, reducing ammonia blood levels.[6]
Symptoms of HE are progressive and start with confusion, dizziness, and
tremor, leading to irreversible coma in the absence of specific
treatment, with a mortality rate of about 40%.[7]
First, a proper diagnostic workup of HE requires the exclusion of
infective or disease-associated causes of encephalopathy and a blood
ammonium measurement. Central nervous system localization of plasma
cells is rare both at diagnosis and relapse (1%), but it is associated
with a worse prognosis. HE treatment is primarily directed to the cause
of increased ammonia production and so in an aggressive therapeutic
approach to the underlying MM. Symptomatic treatment tends to reduce
pathological ammonia production or to increase its clearance through
enemas, osmotic laxatives, and antibiotic therapy acting on the gut
microbial environment.
Our patient presented MM end-stage progression in secondary plasma cell
leukemia and started a specific treatment with anti-CD38 and
lenalidomide-based triplet. There is no clear association between
specific treatments and the onset of “iatrogenic” HE. A case of HE
after the first dose of daratumumab is reported by Murtaza et al. in a
patient with MM.[8] However, there is no clear pathogenic association between the drug and this condition.
Sharma et al. reported a patient with kappa light chain MM developing
HE at disease onset and not at progression (or after treatment for
progression); the clear evidence is that also in this case the clinical
picture was rapidly worsening (the patient required support in
Intensive Care Unit), and HE was substantially a diagnosis of
exclusion.[9] The authors reported the efficacy of
cyclophosphamide combined with new drugs (the so-called VCd regimen,
bortezomib/cyclophosphamide/dexamethasone). An aggressive approach that
comprises chemotherapy has demonstrated variable efficacy in rapidly
reducing disease burden and neurologic symptoms. Also in other case
series, VCd is often reported.[10] Nevertheless, the prognosis of this condition in MM remains poor despite chemotherapy.
Our report underlines the importance of considering HE in the
differential diagnosis of neurologic symptoms in patients with MM both
at diagnosis and at relapse. Despite its rarity, this condition has to
be promptly recognized and clinicians should keep MM in the
differentials in case of hyperammonaemia.
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