General Aspects and Mechanisms of Peripheral Neuropathy Associated With Bortezomib in Patients With Newly Diagnosed Multiple Myeloma

Broyl, Annemiek; Jongen, Joost L.M.; Sonneveld, Pieter

doi:10.1053/j.seminhematol.2012.04.001

Cited by 21 publications

(16 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This lengthy recovery period is also paralleled by what is seen in patients treated with bortezomib, who may take months to recover from neuropathy by at least one grade (Cavaletti and Jakubowiak, 2010; Broyl, Jongen, Sonneveld, 2012). There must be a persistent signal cascade following bortezomib's activity on its primary targets to produce an effect on this scale, as normal proteasomal activity is restored 48 to 72 hours following treatment (Adams, 2002).…”

Section: Discussionmentioning

confidence: 73%

“…This parallels the symptoms seen in patients. Treatment-emergent CIPN occurs in 37% of patients within the first five cycles of bortezomib treatment, but frequency plateaus at this point with regard to further treatment cycles (Kane et al, 2006; Richardson et al, 2006; Cavaletti and Jakubowiak, 2010; Broyl, Jongen, Sonneveld, 2012). Dose reduction of bortezomib at the first sign of neuropathy was reported to reduce the severity and risk of further CIPN (Richardson et al, 2006), so it is possible that chemotherapy cycles spread out over a longer period would allow identification of low levels of neuropathy before the threshold is fully reached.…”

Section: Discussionmentioning

confidence: 99%

“…This appears in a stocking and glove distribution with patients reporting the most severe neuropathic symptoms in the glabrous skin of their toes and fingers (Cata et al, 2007). CIPN frequently becomes so severe that patients are given a lower dose than maximally effective or forced off of chemotherapy entirely (Cata et al, 2007; Broyl, Jongen, Sonneveld., 2012). Understanding the mechanisms of chemotherapy-induced peripheral neuropathy so that it may be alleviated or prevented is therefore critical if patients are to have a higher quality of life and benefit fully from chemotherapy treatment.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Altered discharges of spinal neurons parallel the behavioral phenotype shown by rats with bortezomib related chemotherapy induced peripheral neuropathy

2014

View full text Add to dashboard Cite

Bortezomib is a first generation proteasome inhibitor that is the frontline chemotherapy for multiple myeloma with the chief dose-limiting side effect of painful peripheral neuropathy. The goal of this study was to define the behavioral phenotype in a preclinical model of bortezomib chemotherapy-induced peripheral neuropathy (CIPN) and to test whether this is matched by changes in the physiological responses of spinal wide dynamic range neurons. Sprague-Dawley rats were treated with four injections of bortezomib at four doses, 0.05mg/kg, 0.10 mg/kg, 0.15 mg/kg, 0.20 mg/kg, or equal volume of saline. All doses of bortezomib above 0.05mg/kg produced showed significant dose-dependent mechanical hyperalgesia that was fully established at 30 days after treatment and that recovered to baseline levels by day 69 after treatment. Thermal, cold, and motor testing were all unaffected by treatment with bortezomib. Spinal wide dynamic range (WDR) neurons in rats with confirmed bortzomib-related CIPN showed an increase in number of evoked discharges to mechanical stimuli and exaggerated after-discharges in rats with bortezomib CIPN.

show abstract

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Altered discharges of spinal neurons parallel the behavioral phenotype shown by rats with bortezomib related chemotherapy induced peripheral neuropathy

2014

View full text Add to dashboard Cite

show abstract

“…Recovery may not be complete; leaving patients with chronic PN and neuropathic pain. [6,8–10] The pathogenesis of neuropathy is not entirely clear, although it has been proposed that BTZ causes direct dorsal root ganglion toxicity through various mechanisms,[11,12] including tubulin polymerization[13] and disturbances in calcium homeostasis. [14] The initial standard administration schedule for BTZ has been twice a week intravenously (IV) with at least 72 hours between doses, which results in a high incidence of new or worsening of pre-existing neuropathy.…”

Section: Introductionmentioning

confidence: 99%

Neuropathy and efficacy of once weekly subcutaneous bortezomib in multiple myeloma and light chain (AL) amyloidosis

et al. 2017

View full text Add to dashboard Cite

IntroductionRandomized studies have shown that bortezomib (BTZ) can be given weekly via intravenous (IV) route or twice weekly via subcutaneous (SC) route with lower neuropathy risk and no loss of anti-myeloma efficacy compared to original standard IV twice weekly schedule. Weekly SC should therefore yield the best therapeutic index and is widely used but has not been compared to established administration schedules in the context of a clinical trial.MethodsComprehensive electronic medical record review was done for disease control and neuropathy symptoms of 344 consecutive patients who received their first BTZ-containing regimen for myeloma or AL amyloidosis before or after we changed to SC weekly in December 2010. Univariate and multivariable analyses were carried out that adjusted for age, underlying disease, concurrently used anticancer agents, underlying conditions predisposing to neuropathy, and number of prior regimens compared SC weekly to other schedules.ResultsFifty-three patients received BTZ SC weekly, 17 SC twice weekly, 127 IV weekly and 147 IV twice weekly. Risk for neuropathy of any grade was higher with other schedules compared to SC weekly (44.3% vs. 26.9%, p = 0.001) while response rate was similar (72.1% vs. 76.6%, respectively, p = 0.15). Multivariable analyses upheld higher neuropathy risk (Odds ratio 2.45, 95% CI 1.26–4.76, p = 0.008) while the likelihood of not achieving a response (= partial response or better) was comparable (Odds ratio 1.25, 95% CI 0.58–2.71, p = 0.56) for other schedules compared to SC weekly, respectively. Lower neuropathy risk translated into longer treatment duration when BTZ was started SC weekly (p = 0.001).ConclusionsWeekly SC BTZ has activity comparable to other schedules and causes low rates of neuropathy.

show abstract

“…BIPN has been reported in at least 37% of patients treated with BTZ at maximum tolerated dose (MTD) 1.3 mg/m 2 [31]. In early clinical trials, MLN9708 shows a lower incidence of peripheral neuropathy than BTZ controls.…”

Section: Discussionmentioning

confidence: 99%

MLN2238, a proteasome inhibitor, induces caspase-dependent cell death, cell cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy-sensitive or rituximab-chemotherapy-resistant B-cell lymphoma preclinical models

Gu¹,

Hernandez‐Ilizaliturri²,

Mavis³

et al. 2013

Anti-Cancer Drugs

View full text Add to dashboard Cite

To further develop therapeutic strategies targeting the proteasome system, we studied the antitumor activity and mechanisms of action of MLN2238, a reversible proteasome inhibitor, in preclinical lymphoma models. Experiments were conducted in rituximab-chemotherapy-sensitive cell lines, rituximab-chemotherapy-resistant cell lines (RRCL), and primary B-cell lymphoma cells. Cells were exposed to MLN2238 or caspase-dependent inhibitors, and differences in cell viability, alterations in apoptotic protein levels, effects on cell cycle, and the possibility of synergy when combined with chemotherapeutic agents were evaluated. MLN2238 showed more potent dose-dependent and time-dependent cytotoxicity and inhibition of cell proliferation in lymphoma cells than bortezomib. Our data suggest that MLN2238 can induce caspase-independent cell death in RRCL. MLN2238 (and to a much lesser degree bortezomib) reduced RRCL S phase and induced cell cycle arrest in the G2/M phase. Exposure of rituximab-chemotherapy-sensitive cell lines and RRCL to MLN2238 potentiated the cytotoxic effects of gemcitabine, doxorubicin, and paclitaxel and overcame resistance to chemotherapy in RRCL. MLN2238 is a potent proteasome inhibitor active in rituximab-chemotherapy-sensitive and rituximab-chemotherapy-resistant cell models and potentiates the antitumor activity of chemotherapy agents and has the potential of becoming an effective therapeutic agent in the treatment of therapy-resistant B-cell lymphoma.

show abstract

General Aspects and Mechanisms of Peripheral Neuropathy Associated With Bortezomib in Patients With Newly Diagnosed Multiple Myeloma

Cited by 21 publications

References 44 publications

Altered discharges of spinal neurons parallel the behavioral phenotype shown by rats with bortezomib related chemotherapy induced peripheral neuropathy

Altered discharges of spinal neurons parallel the behavioral phenotype shown by rats with bortezomib related chemotherapy induced peripheral neuropathy

Neuropathy and efficacy of once weekly subcutaneous bortezomib in multiple myeloma and light chain (AL) amyloidosis

MLN2238, a proteasome inhibitor, induces caspase-dependent cell death, cell cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy-sensitive or rituximab-chemotherapy-resistant B-cell lymphoma preclinical models

Contact Info

Product

Resources

About