Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose

Amro M. Stino; Naresh Bumma; Rachel Smith; Long Davalos; Jeff Allen; Jing Christine Ye; Matthew Pianko; Erica Campagnaro; Cassandra Fierro; Abdelrahman Awad; Ben Murdock; Maciej Pietrzak; Gerard Loszanski; David M. Kline; Yvonne Efebera; Bakri Elsheikh

doi:10.1111/ene.16164

Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose

Amro M. Stino, Naresh Bumma, Rachel Smith, Long Davalos, Jeff Allen, Jing Christine Ye, Matthew Pianko, Erica Campagnaro, Cassandra Fierro, Abdelrahman Awad, Ben Murdock, Maciej Pietrzak, Gerard Loszanski, David M. Kline, Yvonne Efebera, Bakri Elsheikh

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy. Methods: This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. Results: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58–77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1–40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (−0.95, 95% CI −1.81 to −0.09) and total IgM (−162 mg/dL, 95% CI −298 to −26) showed signs of improvement by month 12. Conclusions: Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. Trial Registration: Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.

Original language	English (US)
Article number	e16164
Journal	European Journal of Neurology
Volume	31
Issue number	3
DOIs	https://doi.org/10.1111/ene.16164
State	Published - Mar 2024
Externally published	Yes

Keywords

anti-MAG neuropathy
drug safety
drug trial
lenalidomide
outcome measures

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1111/ene.16164

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Stino, A. M., Bumma, N., Smith, R., Davalos, L., Allen, J., Ye, J. C., Pianko, M., Campagnaro, E., Fierro, C., Awad, A., Murdock, B., Pietrzak, M., Loszanski, G., Kline, D. M., Efebera, Y., & Elsheikh, B. (2024). Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose. European Journal of Neurology, 31(3), Article e16164. https://doi.org/10.1111/ene.16164

Stino, AM, Bumma, N, Smith, R, Davalos, L, Allen, J, Ye, JC, Pianko, M, Campagnaro, E, Fierro, C, Awad, A, Murdock, B, Pietrzak, M, Loszanski, G, Kline, DM, Efebera, Y & Elsheikh, B 2024, 'Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose', European Journal of Neurology, vol. 31, no. 3, e16164. https://doi.org/10.1111/ene.16164

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title = "Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose",

abstract = "Background: Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy. Methods: This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. Results: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58–77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1–40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (−0.95, 95% CI −1.81 to −0.09) and total IgM (−162 mg/dL, 95% CI −298 to −26) showed signs of improvement by month 12. Conclusions: Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. Trial Registration: Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.",

keywords = "anti-MAG neuropathy, drug safety, drug trial, lenalidomide, outcome measures",

author = "Stino, {Amro M.} and Naresh Bumma and Rachel Smith and Long Davalos and Jeff Allen and Ye, {Jing Christine} and Matthew Pianko and Erica Campagnaro and Cassandra Fierro and Abdelrahman Awad and Ben Murdock and Maciej Pietrzak and Gerard Loszanski and Kline, {David M.} and Yvonne Efebera and Bakri Elsheikh",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.",

year = "2024",

month = mar,

doi = "10.1111/ene.16164",

language = "English (US)",

volume = "31",

journal = "European Journal of Neurology",

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T1 - Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy

T2 - A phase 1 study to identify the maximum tolerated dose

AU - Stino, Amro M.

AU - Bumma, Naresh

AU - Smith, Rachel

AU - Davalos, Long

AU - Allen, Jeff

AU - Ye, Jing Christine

AU - Pianko, Matthew

AU - Campagnaro, Erica

AU - Fierro, Cassandra

AU - Awad, Abdelrahman

AU - Murdock, Ben

AU - Pietrzak, Maciej

AU - Loszanski, Gerard

AU - Kline, David M.

AU - Efebera, Yvonne

AU - Elsheikh, Bakri

PY - 2024/3

Y1 - 2024/3

N2 - Background: Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy. Methods: This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. Results: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58–77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1–40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (−0.95, 95% CI −1.81 to −0.09) and total IgM (−162 mg/dL, 95% CI −298 to −26) showed signs of improvement by month 12. Conclusions: Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. Trial Registration: Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.

AB - Background: Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy. Methods: This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. Results: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58–77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1–40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (−0.95, 95% CI −1.81 to −0.09) and total IgM (−162 mg/dL, 95% CI −298 to −26) showed signs of improvement by month 12. Conclusions: Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. Trial Registration: Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.

KW - anti-MAG neuropathy

KW - drug safety

KW - drug trial

KW - lenalidomide

KW - outcome measures

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Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose

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