Subcutaneous administration of bortezomib significantly decreased and delayed the development of peripheral neuropathy in patients with newly diagnosed multiple myeloma

The discovery of the ubiquitin–proteasome pathway first, and the proteasome inhibitors thereafter were not made in the hope of improving the treatment of malignant diseases. However, bortezomib, the first in class proteasome inhibitor introduced in the clinical practice has contributed to improve the outcome of patients with multiple myeloma, at relapse or disease progression as well as upfront. The results observed in a large randomized trial (APEX) comparing bortezomib and high-dose dexamethasone demonstrated a significant benefit for bortezomib in terms of response rate, progression-free and overall survival. These results led to bortezomib being approved for use in relapsed and/or refractory myeloma patients. Subsequent studies demonstrated that its activity could be enhanced in combination with other drugs; and the next step was to move to the newly diagnosed patient population; in fact, bortezomib–melphalan–prednisone (VMP) is approved as a standard of care for newly diagnosed elderly patients. However, toxicity, especially peripheral neuropathy, as well as the intravenous route required for its administration are the two most significant bortezomib-related issues. To try to reduce the peripheral neuropathy, new guidelines for its management and the introduction of weekly schedules of administration have contributed to significantly decrease its incidence and the subcutaneous administration has been recently introduce to avoid the intravenous (IV) route. Results obtained in phase I/II and III studies have confirmed that subcutaneous administration is feasible and represents an additional step towards the optimization of bortezomib use, resulting in a probably more convenient method than the IV route that is at least as effective.

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Subcutaneous Administration of Bortezomib in Combination with Thalidomide and Dexamethasone for Treatment of Newly Diagnosed Multiple Myeloma Patients

BioMed Research International ◽

10.1155/2015/927105 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 8

Author(s):

Shenghao Wu ◽

Cuiping Zheng ◽

Songyan Chen ◽

Xiaoping Cai ◽

Yuejian Shi ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Adverse Events ◽

Subcutaneous Administration ◽

Progression Free Survival ◽

The Other ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Free Survival ◽

Grade 3

Objective. To investigate the efficacy and safety of the treatment of the newly diagnosed multiple myeloma (MM) patients with the therapy of subcutaneous (subQ) administration of bortezomib and dexamethasone plus thalidomide (VTD) regimen.Methods. A total of 60 newly diagnosed MM patients were analyzed. 30 patients received improved VTD regimen (improved VTD group) with the subQ injection of bortezomib and the other 30 patients received conventional VTD regimen (VTD group).The efficacy and safety of two groups were analyzed retrospectively.Results. The overall remission (OR) after eight cycles of treatment was 73.3% in the VTD group and 76.7% in the improved VTD group (P>0.05). No significant differences in time to 1-year estimate of overall survival (72% versus 75%,P=0.848) and progression-free survival (median 22 months versus 25 months;P=0.725) between two groups. The main toxicities related to therapy were leukopenia, neutropenia, thrombocytopenia, asthenia, fatigue, and renal and urinary disorders. Grade 3 and higher adverse events were significantly less common in the improved VTD group (50%) than VTD group (80%,P=0.015).Conclusions. The improved VTD regimen by changing bortezomib from intravenous administration to subcutaneous injection has noninferior efficacy to standard VTD regimen, with an improved safety profile and reduced adverse events.

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A Phase II Study of PS-341 for Patients with High Risk, Newly Diagnosed Multiple Myeloma: A Trial of the Eastern Cooperative Oncology Group (E2A02).

Blood ◽

10.1182/blood.v106.11.2546.2546 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2546-2546 ◽

Cited By ~ 2

Author(s):

Angela Dispenzieri ◽

Emily Blood ◽

David Vesole ◽

Rafael Fonseca ◽

Natalie Callander ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Peripheral Neuropathy ◽

High Risk ◽

Partial Response ◽

Progressive Disease ◽

Response Rate ◽

Cell Labeling ◽

Newly Diagnosed ◽

Grade 3

Abstract Background: Multiple myeloma (MM) is an incurable disease with a anticipated overall survival (OS) ranging from months to decades. Modest improvements in OS have been made with high-dose chemotherapy with peripheral blood stem cell transplant (PBSCT), but to date prognostic factors have a greater impact on OS than do individual therapies. Patients with adverse risk factors such as elevated beta-2 microglobulin (B2M), plasma cell labeling index, deletions of the long arm of chromosome 13 by metaphase cytogenetics (del 13q) require innovative new treatment strategies. Bortezomib has significant activity in patients with both newly diagnosed and relapsed/refractory MM, but its specific role in patients with adverse features has not yet been defined. Methods: Patients with newly diagnosed “high-risk” myeloma (B2M ≥ 5.5., PCLI ≥ 1, or del 13q) and adequate organ and functional status were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients were scheduled to receive bortezomib 1.3 mg/m2 every other week indefinitely. Elective peripheral stem cell mobilization (growth factor alone) was allowed after 4 cycles of bortezomib. Patients relapsing on maintenance schedule were to have the full induction schedule resumed. Responses were by the EBMT criteria but a very good partial response category was included. The primary end-point was the response rate in these high-risk patients (90% power to detect a response rate of 50% or higher). The study decision rule requires that 16 or more responses, among 39 eligible patients, are seen in order to declare this treatment effective. Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled on study. Among the 43 eligible patients, median age was 63; 51% were male. All patients had high risk disease: del 13q (6/41); plasma cell labeling index ≥1% (16/34); and B2M≥5.5 (34/43). Preliminary response data are available for 18 of the 44 cases enrolled, of which 7 had partial response, 1 had minimal response, 1 had no response, 2 had progressive disease, and 5 were unevaluable. Among those patients completing induction therapy and with response information, the median number of cycles of therapy administered is 5, range (0,8). The most common non-hematologic adverse events (AEs) of grade 3 or higher included hyponatremia (9 patients) and diarrhea (6 patients). Mild sensory peripheral neuropathy was common: grade 1, 16 patients; grade 2, 2 patients. Only 1 patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses bortezomib due to heart block and asystole. Two patients had a grade 4, 25 patients had grade 3, and 13 had grade 1 or 2 as the worst grade non-hematologic adverse event. Based on data received by August 1, 2005, 18 patients have gone off study: AEs (2); death (1); progressive disease (9); and other reasons (6). Updated results on the full study population along with FISH data for IgH translocations and deletions of 13q and 17p will be presented at the meeting. Conclusions: Preliminary results suggest that upfront bortezomib has activity in patients with high-risk MM, but further follow-up is required.

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Phase 2 Trial of Concurrent Monosialotetrahexosylganglioside in the Prophylactic Treatment of Bortezomib-Induced Peripheral Neuropathy in Patients of Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.5399.5399 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5399-5399

Author(s):

Liang Wang ◽

Zhongjun Xia ◽

Xiaoqin Chen

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Partial Response ◽

Subcutaneous Injection ◽

Complete Response ◽

Phase 2 ◽

Newly Diagnosed ◽

Female Ratio ◽

Phase 2 Trial

Abstract Backgrounds Bortezomib is an important drug in the treatment of multiple myeloma (MM), and peripheral neuropathy (PN) is a significant dose-limiting toxicity of bortezomib. No effective prophylaxis has been defined for PN. Monosialotetrahexosylganglioside (GM), a nerve-protecting drug, is often used to promote growth of nerve and function restoration of damaged nerve. The role of GM in the prophylaxis of bortezomib-induced PN in MM patients has never been investigated. Methods A phase 2 clinical trial was conducted in newly diagnosed MM patients to evaluate the value of GM in the prophylaxis of bortezomib-induced PN. All eligible patients were treated with VD (bortezomib 1.3mg/㎡,subcutaneous injection, d1 ,8,15,22, and dexamethasone 40mg, po,d1 ,8,15,22, 4 weeks a cycle) or CyBorD (cyclophosphamide 300mg/㎡,po,d1 ,8,15, bortezomib 1.3mg/㎡,subcutaneous injection, d1 ,8,1 5,22, and dexamethasone 40mg, po,d1 ,8,15,22, 4 weeks a cycle) for at least 4 cycles. GM was used at a dosage of 100mg/day intravenously at d1 -2, 8-9, 15-16, 22-23. No other nerve-protective drugs or thalidomide-containing regimens were allowed. The primary endpoint was overall incidence rate of PN (the grade of PN was recorded according to CTCAE v3.0). The secondary endpoints included duration of PN, complete response rate after 4 cycles of treatment, 1-year PFS and OS rate. (This trial was registered in ClinicalTrial.gov, NCT02093910). Results From February 2014 to February 2015, 25 patients of newly diagnosed MM were enrolled. The median age was 55 years old (37-75), and male to female ratio was 19:6. 5 patients had ISS stage I disease, 6 patients with stage II, and the remaining 14 patients with stage III. All patients received a median of 4 cycles (range 2-9) of Bortezomibcontaining regimens. At the time of data analysis, 84% of patients had at least partial response, 48% had at least very good partial response, and 24% had complete response. 7 patients experienced PN after a median of 2 cycles (range 1-4) of treatment, resulting in the overall PN rate of 28%. Among these 7 patients, only 1 patient (4%) had grade 2 PN, leading to dose reduction of bortezomib, and all other patients had grade 1 PN. During treatment, 1 patient (4%) had grade 2 diarrhea, and another 1 patient (4%) had herpes zoster infection. The concurrent use of GM did not introduce new side effects and seemed not compromise the efficacy of bortezomib. At a median follow up time of 8 months, 1-year PFS rate and OS rate were speculated to be 69.8% and 100%, respectively. Conclusions The early-term analysis of this phase 2 trial found it feasible to concurrently use GM and bortezomib-containing regimens, and GM had the potential role of reducing bortezomib-induced PN rate and severity without compromising efficacy. This needs to be validated in future phase 3 randomized clinical trials. Disclosures No relevant conflicts of interest to declare.

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Peripheral neuropathy induced by subcutaneous bortezomib-based induction therapy for newly diagnosed multiple myeloma

Haematologica ◽

10.3324/haematol.2014.110221 ◽

2014 ◽

Vol 99 (11) ◽

pp. e242-e243 ◽

Cited By ~ 5

Author(s):

A. Brioli ◽

B. A. Zannetti ◽

E. Zamagni ◽

P. Tacchetti ◽

L. Pantani ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Induction Therapy ◽

Newly Diagnosed

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Combination therapy based on bortezomib for 102 patients with newly-diagnosed multiple myeloma: a Chinese experience

Blood ◽

10.1182/blood.v118.21.5116.5116 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5116-5116

Author(s):

Jingsong He ◽

Li Yang ◽

Xiaoyan Han ◽

Gaofeng Zheng ◽

Xiaojian Meng ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Peripheral Neuropathy ◽

Combination Therapy ◽

Adverse Events ◽

Chinese Population ◽

Median Overall Survival ◽

Chinese Patients ◽

Newly Diagnosed ◽

Significant Difference

Abstract Abstract 5116 Multiple myeloma (MM) is a malignant neoplasm of plasma. The rates of complete remission (CR) or very good partial remission (VGPR) for patients received conventional chemotherapy are still low with median overall survival about 3 years. Here we report our results with combination therapy based on bortezomib in the Chinese population and investigat the efficacy and safety of Bortezomib-based therapies in previously untreated MM patients. Metohds: Between 1st Feb. 2006 and 31st Dec. 2010, 102 consecutive newly-diagnosed patients with symptomatic MM were treated with combination therapies based on bortezomib. Sixty-four patients were male and 38 were female. Median age was 59 years (range 31–86 years). Forty-two patients were stage 3 according to the International Staging System, 36 patients were stage 2 and 24 patients were stage 1. The combinations included dexamethasone (BD group ), dexamethasone plus subsequent thalidomide (BDT group ) and dexamethasone plus cyclophosphamide (BDC group ) or epirubicin (BDA group ) based on bortezomib. Thirty-five patients were in BDT group, 19 in BD group, 32 in BDC group and 16 in BDA. All patients received a median of three cycles of therapy (range 1–5 ). The IMWG criteria was used for response evaluation and toxicities were evluated according to the NCI Common Toxicity Criteria version 3. Results: The efficacy of the triplet combination therapy based on bortezomib including BDT, BCD and BAD were better than BD group, with response rate greater than or equal to partial remission(≥PR) 85.7%, 90.6%, 93.7% and 68.4%, respectively. The efficacy of BDA and BDC group were significantly superior to BD group (P=0.048,0.050). Bortezomib in combination with chemotherapy was highly effective as treatment for symptomatic multiple myeloma, even only after one cycle. The efficacy for patients received one cycle of BDT, BD, BCD and BAD was 65.7%, 42.1%, 65.6% and 62.5%, respectively. Patients treated with BD had suboptimal responses to those received BDT, BCD and BAD treatment and one cycle of BCD was superior to one cycle of BD (P=0.019).The median follow-up time was 17m (1–60m), including 31m (1–60m) for 35 patients in BDT group and 16m (2–29m) for the remaining 67 patients. The median progression-free survival (PFS ) of BDT group was 15m (9.8–20.2m ) while BD group was 12m (8.1–15.8m), BCD group was 13m (5.9–20.1m ), and BAD group was 12m (7.8–16.2m ), without significant difference. The median overall survival (OS ) of BDT group was 35m (13.2–56.8m ) while BD, BCD and BAD groups was not reached yet. There was no significant difference in OS among groups, but BCD and BAD were superior to BD group (P=0.104, 0.142 ). The frequent treatment-emergent adverse events includes hematologic adverse events such as neutropenia, anemia, thrombocytopenia and the non-hematologic adverse events like fatigue, infection, constipation, diarrhea, pleural effusion and ascites, herpes zoster and peripheral neuropathy. Patients treated with BDT were more likely to show peripheral neuropathy than those treated with BD, BCD and BAD (91.4% vs 73.6%, 68.7%, 74.9% ), but there is no statistical significant difference (P = 0.131), Grade 2 or 3 peripheral neuropathy was occurred in 45.7% of BDT group significantly higher than BD, BCD and BAD groups. (21.0%, 15.7% and 18.7%, P = 0.028 ). Other related adverse events in all the groups had no significant difference. Routine anticoagulation or anti-thrombsis were not used. Only 1 patient suffered from DVT/PE but did well with treatment. Conclusions: Our preliminary experience in Chinese patients indicated that combination chemotherapy based on bortezomib is highly effective in newly-diagnosed multiple myeloma and BDC, BDA or BDT regimens may be more superior to BD in Chinese population. There were relative lower rates of DVT/PE in the Chinese patients with MM received combination chemotherapy based on bortezomib. Disclosures: No relevant conflicts of interest to declare.

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Subcutaneous Injection Of Bortezomib, Combined With Doxorubicin and Dexamethasone (sPAD) Is Effective and Safety Induction Therapy For Untreated Multiple Myeloma Patients

Blood ◽

10.1182/blood.v122.21.5391.5391 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5391-5391 ◽

Cited By ~ 1

Author(s):

Naoki Takezako ◽

Naohiro Sekiguchi ◽

Akihisa Nagata ◽

Tsuyoshi Hagino ◽

Satoshi Noto ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Induction Therapy ◽

Intravenous Administration ◽

Subcutaneous Injection ◽

Plasma Concentrations ◽

Subcutaneous Administration ◽

Phase Iii ◽

Maximum Plasma ◽

Grade 3

Abstract Background Bortezomib is the first generation proteasome inhibitor which is used as induction therapy for multiple myeloma (MM) patients. Recently, triplet therapies including bortezomib are recommended by several committees. Among various triplet therapies, PAD (bortezomib, doxorubicin, and dexamethasone), which was reported in the analysis of randomized phase III HOVON-65/ GMMG-HD4 trial, is an effective therapy. Complete response (CR), including near CR, was superior after PAD induction to VAD induction (15% vs. 31%; P < .001) (Sonneveld P et al.). However, peripheral neuropathy (PN) was observed in 37% of PAD induction arm (grade 3 or 4 Peripheral neuropathy (PN) was 24%). Recently, some investigators reported that subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with an improved safety profile (Moreau P et al.). PN was significantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated. Therefore, we performed a phase 2 PAD study using subcutaneous bortezomib (sPAD) in Japanese MM patients. Materials and Methods Eligible patients were aged 20 years and older from whom was obtained written informed consent. Between July 2011 and April 2013, 30 symptomatic MM patients were enrolled in this trial. They received bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11) by subcutaneous injection, oral dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12), and intravenous doxorubicin (20 mg/m2 on days 1 and 4), every 21 days as their induction regimen. Subcutaneous injections were administrated with reduced-concentration to 2.0mg/ml (3mg bortezomib reconstituted with 1.5ml normal saline). In addition, we studied a pharmacokinetics of bortezomib. Plasma samples were collected in cycle 1 on day 11. Bortezomib plasma concentrations were measured with a validated liquid chromatography. We compared this sPAD therapy with intravenous injection bortezomib dexamethasone (BD) therapy (N=40), as a historical control. Statistical analyses were done with Stata /MP (version 12.1). Results Patient's characteristics at inclusion did not differ between two groups. Overall response rate (VGPR or CR) of sPAD therapy was superior to BD therapy (77% vs. 30%; p<0.001). The CR rate was 2.5% in patients who were treated with BD and 30% in patients who were treated with sPAD (p=0.001). The median progression free survival (PFS) was 6 months for the BD therapy and 22 months for the sPAD therapy. Patients who were treated with sPAD had a significantly better PFS (p<0.001). Median overall survival (OS) was not reached at 24 months in sPAD therapy and 23 months for BD therapy. Patients who were treated with sPAD had a significantly better OS (p=0.0251). Grade 3 or worse PN (5% vs. 28%; p=0.040) was significantly less common with sPAD than BD. Subcutaneous administration was locally well tolerated. Eight patients enrolled in the pharmacokinetic study. Table 1 shows bortezomib concentration profile after subcutaneous administration on day 11, cycle 1. Mean maximum plasma concentration of bortezomib (Cmax) was lower than previously reported level (Cmax = 12.27 ng/mL (7.41-19.40)). However, mean bortezomib systemic exposure (AUClast) was similar to previous report (AUClast = 156.8 ngxh/mL (85.0-240.0)). Conclusion sPAD therapy is promising induction therapy for untreated MM patients because of efficacy and safety. Furthermore, reduced bortezomib-concentration subcutaneous administration may help to reduce PN. Further study might be warranted. Disclosures: No relevant conflicts of interest to declare.

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