Central Neurotoxicity of Immunomodulatory Drugs in Multiple Myeloma

Patel, Urmeel; Mir, Mohammad Amin; Sivik, Jeffrey; Raheja, Divisha; Pandey, Manoj K.; Talamo, Giampaolo

doi:10.4081/hr.2015.5704

Cited by 26 publications

(14 citation statements)

References 21 publications

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“…17 We and others reported single-agent activity of lenalidomide in refractory secondary CNS diffuse large B-cell lymphoma (DLBCL) as well as mantle cell lymphoma involving the CNS. 18,19 Given reports of neurotoxicity associated with lenalidomide and other immunomodulatory drugs in the setting of myeloma and other lymphoid malignancies, 20,21 that the direct binding protein and mediator of cellular activity of lenalidomide, cereblon, is highly expressed in neurons in the brain, 22,23 and that it is well-established that CNS lymphoma patients are at high risk for neurocognitive deficits and neurotoxicity, we designed a phase 1 investigation to determine a safe, maximum tolerated dose (MTD) of lenalidomide for this patient population. The rationale for this approach is also supported by the fact that CNS lymphoma patients often have a poor performance status and are particularly vulnerable because of immune suppression.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma

et al. 2018

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There is an unmet need for effective biological therapies for relapsed central nervous system (CNS) lymphoma. Lenalidomide is active in activated B-cell type diffuse large B-cell lymphoma and rituximab is effective in CNS lymphoma. These observations are the basis for this first trial of an immunomodulatory drug as monotherapy in CNS lymphoma, and, in patients with inadequate responses to lenalidomide, with rituximab. In an independent cohort, we evaluated lenalidomide maintenance after salvage with high-dose methotrexate or focal irradiation in relapsed primary CNS lymphoma (PCNSL). We determined safety, efficacy, and cerebrospinal fluid (CSF) penetration of lenalidomide at 10-, 15-, and 20-mg dose levels in 14 patients with refractory CD20 CNS lymphoma. Nine subjects with relapsed, refractory CNS lymphoma achieved better than partial response with lenalidomide monotherapy, 6 maintained response ≥9 months, and 4 maintained response ≥18 months. Median progression-free survival for lenalidomide/rituximab was 6 months. In the independent cohort, response duration with lenalidomide maintenance after complete responses 2 through 5 were significantly longer than response durations after standard therapy. The CSF/plasma partition coefficient of lenalidomide was ≥20% at 15- and 20-mg dose levels. Change in CSF interleukin-10 at 1 month correlated with clinical response and response duration to lenalidomide. Metabolomic profiling of CSF identified novel biomarkers, including lactate, and implicated indoleamine-2,3 dioxygenase activity with CNS lymphoma progression on lenalidomide. We conclude that lenalidomide penetrates ventricular CSF and is active as monotherapy in relapsed CNS lymphomas. We provide evidence that maintenance lenalidomide potentiates response duration after salvage in relapsed PCNSL and delays whole brain radiotherapy (WBRT). This trial was registered at www.clinicaltrials.gov as #NCT01542918.

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Section: Introductionmentioning

confidence: 99%

Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma

et al. 2018

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“…PN of grades 1–2 has been observed in 18%–24% cases, considering also that the majority of these patients had a prior history of PN 87–89. Rare cases of central neurotoxicity with IMiDs have been reported 90. New IMiD pomalidomide causes very few incidences of PN; <5% 91,92…”

Section: Treatment-related Pnmentioning

confidence: 99%

Managing treatment-related peripheral neuropathy in patients with multiple myeloma

Grammatico¹,

Cesini²,

Petrucci³

2016

BLCTT

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Peripheral neuropathy is one of the most important complications of multiple myeloma treatment. Neurological damage can be observed at the onset of the disease, due to the effect of monoclonal protein or radicular compression, but more often is treatment related. Vinca alkaloids in the past era, and more recently, thalidomide and bortezomib are mainly responsible. Degeneration of dorsal root ganglion is common, prevalently related to angiogene sis inhibition and cytokine modulation in the case of thalidomide and inhibition of the ubiquitin proteasome system in the case of bortezomib. Sensory neuropathy and neuropathic pain are more common; motor neuropathy and autonomic damage are less frequently observed. Neurotoxicity often affects patient's quality of life and requires dose modification or withdrawal of therapy, with a possible effect on the overall response. A prompt recognition of predisposing factors (such as diabetes mellitus, alcohol abuse, vitamin deficiencies, or viral infections) and appearance of signs and symptoms, through a periodic neurological assessment with appropriate scales, is extremely important. Effective management of treatment at the emergence of peripheral neuropathy can minimize the incidence and severity of this complication and preserve therapeutic efficacy. Dose adjustment could be necessary during treatment; moreover, gabapentin or pregabalin, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, carbamazepine, and opioid-type analgesics are suggested according to the pain severity. Some authors reported that patients who develop peripheral neuropathy during their multiple myeloma treatments presented a particular gene expression profile; therefore, future studies could be helpful for a better understanding of possible biological pathways underlying neurotoxicity.

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“…After the use of Thalidomide, with typical doses ranging from 50 mg to 300 mg/day, the onset of a dose-dependent peripheral sensory neuropathy has been reported, which symmetrically begins from the distal extremities (hands and feet), and which clinically manifests with paresthesia of the extremities [ 113 , 114 , 115 ]. Further studies confirmed that the sensory neuropathy is length-dependent [ 20 , 116 ].…”

Section: Thalidomidementioning

confidence: 99%

“…Since Thalidomide induces a dose-dependent neuropathy, the clinical recommendation is to use the lowest effective dose, with a careful monitoring of electrophysiological parameters which represent the first neuropathic sign, such as the reduction of SNAPs amplitude, to evaluate the drug dose reduction or even the treatment temporary or permanent withdrawal. In addition, preventive strategies such as anti-oxidant or growth factors administration are currently under evaluation [ 117 , 118 ], as well as the use of derivatives with a very low neurotoxic profile, such as Lenalidomide and Pomalidomide [ 113 ].…”

Section: Thalidomidementioning

confidence: 99%

Axonal Transport Impairment in Chemotherapy-Induced Peripheral Neuropathy

Nicolini

Monfrini

Scuteri

2015

Toxics

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Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a dose-limiting side effect of several antineoplastic drugs which significantly reduces patients’ quality of life. Although different molecular mechanisms have been investigated, CIPN pathobiology has not been clarified yet. It has largely been recognized that Dorsal Root Ganglia are the main targets of chemotherapy and that the longest nerves are the most damaged, together with fast axonal transport. Indeed, this bidirectional cargo-specific transport has a pivotal role in neuronal function and its impairment is involved in several neurodegenerative and neurodevelopmental diseases. Literature data demonstrate that, despite different mechanisms of action, all antineoplastic agents impair the axonal trafficking to some extent and the severity of the neuropathy correlates with the degree of damage on this bidirectional transport. In this paper, we will examine the effect of the main old and new chemotherapeutic drug categories on axonal transport, with the aim of clarifying their potential mechanisms of action, and, if possible, of identifying neuroprotective strategies, based on the knowledge of the alterations induced by each drugs.

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Central Neurotoxicity of Immunomodulatory Drugs in Multiple Myeloma

Cited by 26 publications

References 21 publications

Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma

Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma

Managing treatment-related peripheral neuropathy in patients with multiple myeloma

Axonal Transport Impairment in Chemotherapy-Induced Peripheral Neuropathy

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