Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 1593-1599 ◽  
Author(s):  
Andreas A. Argyriou ◽  
Gregoris Iconomou ◽  
Haralabos P. Kalofonos
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Treatment Plan ◽  
Symptomatic Treatment ◽  
Future Research ◽  
Significant Activity ◽  
Significant Toxicity ◽  
Incidence Risk ◽  
Schedule Change

AbstractBortezomib has demonstrated significant activity in clinical trials, mainly against recurrent or newly diagnosed multiple myeloma (MM). Peripheral neuropathy is a significant toxicity of bortezomib, requiring dose modification and potential changes in the treatment plan when it occurs. The mechanism underlying bortezomib-induced peripheral neuropathy (BIPN) is unknown. Metabolic changes resulting from the accumulation of bor-tezomib in the dorsal root ganglia cells, mitochondrial-mediated disregulation of Ca++ homeostasis, and disregulation of neurotrophins may contribute to the pathogenesis of BIPN. It is increasingly recognized that BIPN may be a proteasome inhibitor class effect, producing primarily a small fiber and painful, axonal, sensory distal neuropathy. Incidence of BIPN is mainly related to various risk factors, including cumulative dose and evidence of preexisting neuropathy. Assessment of BIPN is based primarily on neurologic clinical examination and neurophysiologic methods. To date, apart from the use of dose reduction and schedule change algorithm, there is no effective treatment with neuroprotective agents for BIPN. Analgesics, tricyclic antidepressants, anticonvulsants, and vitamin supplements have been used as symptomatic treatment against bortezomib-associated neuropathic pain with some success. This review looks critically at the pathogenesis, incidence, risk factors, diagnosis, characteristics, and management of BIPN, and highlights areas for future research.

scholarly journals Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients

2006 ◽  
Vol 134 (6) ◽  
pp. 620-623 ◽  
Author(s):  
Kostas Zervas ◽  
Evgenia Verrou ◽  
Zisis Teleioudis ◽  
Konstantinos Vahtsevanos ◽  
Anastasia Banti ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Osteonecrosis Of The Jaw ◽  
Single Centre ◽  
Single Centre Experience ◽  
Incidence Risk

A Phase II Study With Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) For Newly Diagnosed Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 685-685 ◽  
Author(s):  
Sara Bringhen ◽  
Chiara Cerrato ◽  
Maria Teresa Petrucci ◽  
Mariella Genuardi ◽  
Fabiana Gentilini ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Complete Response ◽  
Current Treatment ◽  
Drug Discontinuation ◽  
Significant Activity ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Gastrointestinal Complications ◽  
Co Morbidity

Abstract Background The current treatment for newly diagnosed elderly multiple myeloma (MM) patients, not eligible for transplant, induces approximately 30% near-complete response/complete response (nCR/CR). Carfilzomib is a novel, irreversible proteasome-inhibitor with significant activity and favourable toxicity profile, including very low rates of peripheral neuropathy and neutropenia. We evaluated efficacy and safety of the combination carfilzomib-cyclophosphamide-dexamethasone (CCd) in elderly newly diagnosed MM patients. Methods The Bryant and Day two-stage design was used to evaluate both efficacy and safety. Patients received oral cyclophosphamide (300 mg/m2 on days 1,8,15), oral dexamethasone (40 mg on days 1, 8, 15, 22) and iv carfilzomib administered over 30 minutes (20 mg/m2 on days 1, 2, and 36 mg/m2 on days 8, 9, 15, 16, cycle 1; 36 mg/m2 on days 1, 2, 8, 9, 15, 16, cycles 2-9) every 28 days for 9 cycles, followed by maintenance with iv carfilzomib (36 mg/m2 on days 1, 2, 15, 16) every 28 days until progression or intolerance. Results Enrollment is complete (58 pts): median age was 71 years, 28% of patients were older than 75 years, 40% had ISS stage III, 35% had unfavorable FISH profile [t(4;14) or t (14;16) or del17p] and 31% are frail, defined according to Charlson co-morbidity index (≥2), geriatric assessment score ADL (<4) and IADL (<5) and age with cut-off setting at 80 years. Twenty-five patients completed induction. After 9 induction cycles, 96% of patients achieved at least PR, 76% VGPR, 64% CR/nCR, including 24% stringent-CR. The 1-year PFS was 86% and the 1-year OS was 87%. Grade (G) 4 hematologic AE included neutropenia (3 pts, 5%). G3-4 non-hematologic AEs were infections (4 pts, 7%), cardiac (3 pts, 5%), constitutional (2 pts, 4%), renal (2 pts, 4%) and gastrointestinal complications (1 pt, 2%). Peripheral neuropathy was experienced by 11% of patients and was limited in severity to grade 1 or 2. Overall, the CCd regimen was well tolerated, 20% of patients required dose reduction and only 11% of patients required drug discontinuation during induction due to AEs. Twenty-five patients were assessable for maintenance treatment. After a median duration of maintenance of 6 months, the PR rate was 100%, including 68% CR/nCR (Table). The most frequent toxicity (all grades) during maintenance was fever (G1-2 in 6 pts [24%], G3 in 2 pts [8%]), occurring during the evening following the Carfilzomib infusion and not associated with chills, rigors, dyspnea and/or creatinine increase. There was only 1 (4%) G3 neutropenia and 1 (4%) G2 pericardial effusion. Peripheral neuropathy remained limited (2 pts [8%], all G 1-2). Conclusions The CCd regimen is highly active, showing rapid and deep responses, reaching after 9 cycles, 64% (at least nCR) and 24% sCR, further improving approximately 10-15% during maintenance. These responses compare favorably with the best frontline regimens, showing a doubling in nCR rate. It is well tolerated with limited grade 3-4 AEs, only 11% of patients required drug discontinuation due to AEs. An update will be presented at the meeting. Disclosures: Bringhen: Onyx: Consultancy. Sonneveld:Onyx: Honoraria, Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Features and Risk Factors of Peripheral Neuropathy During Treatment with Bortezomib for Advanced Multiple Myeloma

2008 ◽  
Vol 8 (3) ◽  
pp. 146-152 ◽  
Author(s):  
Jean El-Cheikh ◽  
Anne-Marie Stoppa ◽  
Réda Bouabdallah ◽  
Hugues de Lavallade ◽  
Diane Coso ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Peripheral Neuropathy

scholarly journals Successful Transition from Bortezomib Subcutaneous (SubQ) to Generic Intravenous (IV) Bortezomib: Cost Savings Initiative with Global Economic Impact

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4758-4758 ◽  
Author(s):  
Radhika Jhaveri ◽  
Vaishali Sanchorawala ◽  
John Mark Sloan ◽  
Adam Lerner ◽  
Shayna Sarosiek ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Patient Satisfaction ◽  
Peripheral Neuropathy ◽  
Cost Containment ◽  
Research Funding ◽  
Medical Center ◽  
Treatment Plan ◽  
Al Amyloidosis ◽  
Data Set ◽  
Satisfaction Surveys

Background: It is estimated that the U.S. will spend $370 billion in 2019 on pharmaceuticals and by 2020 the cost of cancer care will be approximately 158 billion. Cost containment strategies for high cost drugs are needed. In 2019 global sales from subcutaneous (SubQ) bortezomib manufactured by Takeda® will exceed $1 billion. There exists an opportunity to decrease overall cost related to bortezomib by $300-400 million across the globe by switching patients to bortezomib intravenous (IV) (manufactured by Fresenius Kabi®). Generic bortezomib was first approved by the FDA in January 2018 but it can only be administered intravenously. A phase 3 randomized controlled trial of twice weekly SubQ vs IV bortezomib showed no difference in time to progression or 1 year overall survival, however rate of Grade 3 peripheral neuropathy doubled in the IV arm compared to SubQ (Moreau et al, 2011). Although twice weekly bortezomib has fallen out of favor and there are retrospective data suggesting that neuropathy from weekly subQ and weekly IV bortezomib may be similar, there exist no prospective data to date to confirm this. Bortezomib induced peripheral neuropathy (BIPN) typically occurs by cycle 4 of twice weekly therapy, and the majority of cases are partially reversible (Dimopolous et al, 2011). We hypothesized that patients who have not developed neuropathy after or during 4 cycles of subcutaneous bortezomib could be switched to IV bortezomib without greatly increasing neuropathy. Methods: Boston Medical Center Health System is a 500 plus bed integrated delivery network which not only functions as payer but also as a provider. A protocol was implemented to switch patients from SubQ to IV bortezomib. Patients had to complete 4 cycles of SubQ bortezomib and have either Grade 1 or no BIPN to qualify to switch to IV bortezomib generic formulation. Patients were eligible to be switched regardless of indication or dose, if other criteria were met. After approval from the hematology/oncology providers and nursing department, this protocol was implemented to start accrual in November 2018. Patients eligible for the switch were identified primarily by pharmacists. After provider approval, pharmacists would update the treatment plan orders and also notify nursing and patients of the change. Nursing and patient satisfaction surveys were also administered to obtain input from all stakeholders. Results: Eleven patients have received at least 1 cycle of IV generic bortezomib for various indications from Nov 2018 to June 2019, with minimum of 2 doses and maximum of 16 doses. The diseases for which bortezomib was being used included multiple myeloma (n= 6) and AL amyloidosis (n= 2), renal transplant rejection and thrombotic thrombocytopenic purpura (TTP). One of the 11 patients had Grade 1 BIPN prior to switching, while all others reported no neuropathy prior to the switch. None of the patients have developed new neuropathy after making the switch from subQ to IV bortezomib. Results of the nursing and patient satisfaction surveys are being collected and will be presented. Conclusion: We describe a method to switch from subcutaneous bortezomib to generic IV bortezomib instituted at a large academic medical center as a cost containment strategy. This has resulted in no new cases of neuropathy in our growing data set. Global adoption of this protocol has the potential to substantially reduce drug costs related to multiple myeloma. Disclosures Sanchorawala: Celgene: Research Funding; Takeda: Research Funding; Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding. Sloan:Merck: Other: endpoint review commitee; Abbvie: Other: Endpoint Review Committee; Stemline: Consultancy. Sarosiek:Acrotech: Research Funding. Shah:Rigel Pharmaceutical: Consultancy, Speakers Bureau.

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