Treatment-related Peripheral Neuropathy Research Articles

Perifosine Plus Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients Previously Treated with Bortezomib: Final Results of a Phase I/II Trial

Perifosine Plus Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients Previously Treated with Bortezomib: Final Results of a Phase I/II Trial

Towards a better understanding of treatment-related peripheral neuropathy in multiple myeloma

In this issue of The Lancet Oncology, Annemeik Broyl and colleagues1 assessed the genetic susceptibility to treatment-emergent neuropathy in patients who were in a prospective, phase 3 trial of bortezomib-based therapy (bortezomib, doxorubicin, and dexamethasone) versus vincristine-based induction treatment (vincristine, doxorubicin, and dexamethasone). The comparison between vincristine-induced peripheral neuropathy and bortezomib-induced peripheral neuropathy using gene expression profiling suggests that the factors involved in the development of peripheral neuropathy are distinct and involve different molecular mechanisms.

Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues

Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved outcomes for patients with multiple myeloma. As a result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological side-effect associated with thalidomide and bortezomib. Maximising treatment benefit while preserving quality of life therefore requires a careful balance between achieving optimum activity and minimising toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib.

Complications of Multiple Myeloma Therapy, Part 1: Risk Reduction and Management of Peripheral Neuropathy and Asthenia

Peripheral neuropathy (PN) and asthenia (fatigue) occur as both disease- and treatment-related complications in patients with multiple myeloma (MM). Risk factors for treatment-related PN, which has an estimated incidence of 37% to 83% among patients with MM, include therapy duration, dose intensity, cumulative dose, and the presence of preexisting neuropathy. Asthenia is the most common adverse effect of treatment, occurring in approximately 76% to 96% of patients receiving therapy. The severity of PN and asthenia can range from mild to potentially debilitating. These conditions can be dose limiting; they may interfere with optimizing duration of therapy and may also substantially affect patient quality of life. Regular screening and monitoring, combined with patient education and effective management strategies, can reduce the risk of these treatment-related complications, as well as their consequences.

Bortezomib, Bendamustine, and Rituximab in Patients with Relapsed or Refractory Follicular Lymphoma: Encouraging Activity in the Phase 2 VERTICAL Study.

Bortezomib, Bendamustine, and Rituximab in Patients with Relapsed or Refractory Follicular Lymphoma: Encouraging Activity in the Phase 2 VERTICAL Study.

Bortezomib and Thalidomide, a Steroid Free Regimen in Newly Diagnosed Patients with Multiple Myeloma.

Abstract 2867Poster Board II-843Corticosteroids have historically been the backbone of most myeloma targeted therapies. However, they are often the major cause of toxicities, especially in elderly patients. In recent years, novel agents such as bortezomib and thalidomide have demonstrated significant anti-myeloma activity with increased overall response rates. We thus designed a study combining these two agents in a steroid-free regimen. Bortezomib (B) and thalidomide (T) were examined as first line treatment in 27 patients with symptomatic multiple myeloma between September 2004 and September 2006. Patients received B 1.3 mg/m2 on days 1, 4, 8 and 11 every 21 days and T 150 mg daily for a maximum of 8 cycles. The overall response rate was 81.5%, with a near CR or greater of 25.8% and a CR (immunofixation negative) of 11%. A major response identified by greater than 90% reduction in the paraprotein was seen in 33% of the patients. Responses were rapid: median time to first response was 36.5 days (range, 14-101 days) and median time to best response was 61 days (range, 16-171 days). The most common grade 3 toxicities were peripheral neuropathy (22%), pneumonia (15%) and fatigue (7%). The only grade 3 hematologic toxicity was anemia (7%). No grade 4 toxicities were seen. 3 patients had mild peripheral neuropathy (PN) at baseline. PN was the most common reason for dose reduction with an average B dose of 1.1mg/m2 and T of 110mg daily. The major cause of discontinuation of treatment was PN. The PN completely resolved in 80% of the patients upon completion of therapy. No venous thromboembolic events (VTE) were observed even in the absence of prophylactic anticoagulation. It should be noted that upon completion of the study all patients received either B or T maintenance and no patients proceeded onto stem cell transplant immediately. The median progression free survival (PFS) was 16.8 months (95% CI 8.7-21.6 months). Median overall survival has not yet been reached at a median follow up of 39 months. The 3 year overall survival is 74%. This study demonstrates: 1) the excellent efficacy of a steroid-free regimen; 2) good PFS in the absence of stem cell transplantation; and 3) that most treatment-related PN resolves. Disclosures:Huff:Celgene: Consultancy. Borrello:Celgene: Speakers Bureau; Mellenium: Consultancy.

Bortezomib in Combination with Melphalan in the Treatment of Relapsed or Refractory Multiple Myeloma: A Phase I/II Study.

Introduction: Bortezomib (VELCADE®) is a proteasome inhibitor that has demonstrated durable responses as monotherapy for the treatment of pts with relapsed and refractory multiple myeloma. In vitro, bortezomib has been shown to restore melphalan sensitivity to melphalan-resistant cell lines (U266-LR7) and to synergize with melphalan in killing myeloma cells, thereby allowing the use of lower concentrations of melphalan (Ma et al, Clin Cancer Res. 2003; 9:1136). The objective of this dose-escalation phase I/II study was to determine an optimal dose of combination bortezomib + melphalan, starting with doses below those usually recommended for each agent for pts with refractory or relapsed multiple myeloma. Dose limiting toxicities, safety, tolerability, and activity were assesed in a dose-escalation study.Methods : Bortezomib 0.7 mg/m2 was administered by IV push on days 1, 4, 8, and 11 in combination with oral melphalan (0.025, 0.05, 0.1, 0.15, 0.25 mg/kg) on days 1–4 every 4 weeks for up to 8 cycles to 3-pt cohorts with active progressive disease. In the absence of dose-limiting toxicity (DLT), bortezomib was increased to 1.0 mg/m2 and melphalan co-administered using the original 5 escalating doses to subsequent cohorts.Results : Twenty six pts (50% male, median age 55 years, range 33–90 years) have been accrued to the study. The myeloma subtypes include IgG (16/26), IgA (4/26), IgM (2/26) and light chain only (4/26). The median ß2 microglobulin level was 5.0 mg/L (range 2.2–14 mg/L). In this heavily pretreated population (range 2–7 prior therapies), 12 patients received prior melphalan, 12 prior thalidomide, 7 prior CC-5013, 13 prior VAD, 2 prior bortezomib, and 8 prior autologous stem cell transplantation. Dose escalation has proceeded into the bortezomib 1.0 mg/m2 + melphalan 0.10 mg/kg cohort. Toxicities have been manageable. One DLT, grade 4 anemia, was observed at bortezomib 1.0 mg/m2 + melphalan 0.025 mg/kg, requiring expansion of that specific cohort. Grade 3 events were predominantly associated with myelosuppression (anemia, neutropenia, and thrombocytopenia) and were observed only among pts with baseline cytopenia. Among the 12 pts with baseline peripheral neuropathy (PN), symptoms worsened transiently in 1 pt, resolved in 1 pt, and remained stable in the other pts. Treatment-related PN (grade 1) developed de novo in 2 pts. Responses were observed in 67% (16/24 evaluable) of pts: 1 CR, 1 near CR, 6 PR, and 8 MR. The CR and near CR occurred in pts receiving bortezomib 1.0 mg/m2 in combination with melphalan .025 mg/kg. PR or better was independent of prior type of therapy and was also observed among pts who had previously received melphalan or bortezomib. Median time to progression was 1-18 mo. Six active pts out of 26 total pts remain progression-free for 2-8+ mo.Conclusion : Combination bortezomib plus oral melphalan is a promising regimen for the treatment of relapsed, refractory myeloma. The responses that were observed in pts who had previously received either drug serve as preliminary confirmation of preclinical evidence that the combination of low-dose bortezomib and melphalan has the capacity for chemosensitization and suggest possible synergy. Dose escalation with melphalan plus a fixed dose of bortezomib 1.0 mg/m2 is continuing in order to explore the full potential of this combination.