Pharmacokinetic study of bortezomib administered intravenously in Taiwanese patients with multiple myeloma

This phase 4, single‐arm, non‐randomized, open‐label, post approval commitment study evaluated the pharmacokinetics and safety of bortezomib in Taiwanese patients with multiple myeloma. Patients (≥20 years) with measurable secretory multiple myeloma (serum monoclonal IgG ≥10, IgA/IgE ≥5, IgD ≥0.5 g/L, IgM present [regardless of level], and urine M protein of ≥200 mg/24 h) received intravenous bortezomib 1.3 mg/m², twice weekly for 2 weeks, followed by a 10‐day resting phase (days 12 to 21). Pharmacokinetics and safety were assessed at pre‐specified time points. All enrolled patients (n = 18, men: 11; women: 7) completed the study. Mean (SD) C_max (maximum observed plasma concentration) on day 11 was 266 (77.5) ng/mL, approximately 60% higher compared with non‐Asian patients receiving a similar bortezomib regimen but with overlapping ranges. Because of the protracted terminal phase, half‐life (t_1/2), area under the plasma concentration‐time curve from time 0 to infinity (AUC_∞), volume of distribution (V_z), and systemic clearance were not assessable. All patients experienced treatment‐emergent adverse events (TEAEs); 78% were drug‐related. Most commonly reported TEAEs were thrombocytopenia (n = 11 [61%]), neutropenia (n = 9 [50%]), leukopenia (n = 6 [33%]), and diarrhoea (n = 6 [33%]); the most common serious adverse event was pneumonia (n = 2 [11%]). One patient had a dose reduction due to a TEAE of thrombocytopenia. Overall, bortezomib exposure (AUC) in Taiwanese patients (AUC_last [SD]: 230 [147] ng·h/mL) with twice weekly intravenous administration was comparable with non‐Asian population (AUC_last [SD]: 241 [82] ng·h/mL). Bortezomib treatment was associated with manageable toxicity profile and did not limit the continuity of therapy.     

Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma

The purpose of this phase I and II study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of bortezomib in Japanese patients with relapsed or refractory multiple myeloma. This was a dose-escalation study designed to determine the recommended dose for Japanese patients (phase I) and to investigate the antitumor activity and safety (phase II) of bortezomib administered on days 1, 4, 8, and 11 every 21 days. Thirty-four patients were enrolled. A dose-limiting toxicity was febrile neutropenia, which occurred in one of six patients in the highest-dose cohort in phase I and led to the selection of 1.3 mg/m² as the recommended dose. Adverse events ≥ grade 3 were rare except for hematological toxicities, although there was one fatal case of interstitial lung disease. The overall response rate was 30% (95% confidence interval, 16–49%). Pharmacokinetic evaluation showed a biexponential decline, characterized by a rapid distribution followed by a longer elimination, after dose administration, whereas the area under the concentration–time curve increased proportionately with the dose. Bortezomib was effective in Japanese patients with relapsed or refractory multiple myeloma. A favorable tolerability profile was also seen, although the potential for pulmonary toxicity should be monitored closely. The pharmacokinetic and pharmacodynamic profiles of bortezomib in the present study warrant further investigations, including more relevant administration schedules. ( Cancer Sci 2008; 99: 140–144)     

Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib

This phase 2 trial was designed to evaluate ixazomib, an orally bioavailable proteasome inhibitor, in patients with myeloma who have limited prior exposure to bortezomib. Thirty-three patients with relapsed multiple myeloma were enrolled. Ixazomib was given at 5.5 mg weekly for 3 of 4 weeks. Dexamethasone was added for lack of a minor response (MR) by end of cycle 2 or lack of a partial response (PR) by end of cycle 4 or for disease progression at any time. Median age was 69 years; patients had a median of two prior therapies (range 1–7). A grade 3 or 4 adverse event considered at least possibly related to drug was seen in 19 (59%) and 6 (19%) patients, respectively. The most common adverse events were thrombocytopenia, fatigue, nausea and diarrhea. Dexamethasone was initiated in 22 (67%) patients, 17 for not reaching the desired response and 5 for progression. Response (⩾PR) to single agent was seen in five patients within four cycles of therapy including three patients with PR, one patient with complete response (CR) and one patient with stringent CR. Six additional patients with either an MR (2) or SD (4) achieved a PR after addition of dexamethasone, translating to an overall response rate of 34%.     

Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma

BACKGROUND: Bortezomib, a first-in-class proteasome inhibitor, is active with manageable toxicities in relapsed and/or refractory myeloma. METHODS: Bortezomib 1.0 or 1.3 mg/m2 was administered Days 1, 4, 8, and 11 every 21 days for up to 8 cycles to patients with relapsed and/or refractory myeloma participating in two Phase II trials. Dexamethasone could be added because of progressive disease after 2 cycles or stable disease after 4 cycles. Continuation of or retreatment with bortezomib was offered to patients who, in the investigator's opinion, would benefit from extended treatment. RESULTS: Sixty-three patients with relapsed/refractory myeloma treated in this extension trial received a median of 7 additional cycles of therapy, for a total of 14 cycles (range, 7-32) over a median duration of therapy of 45.1 weeks in the parent and extension studies. Seventy-eight percent of patients completed this study at the same or higher bortezomib dose than they started on during this study, and the treatment schedule of twice-weekly administration remained unchanged in 89%. Overall, 75% of patients received dexamethasone in combination with bortezomib for a median of 5 cycles starting either in the parent or extension study. The safety profile was similar between the extension and parent trials, with no evidence of new cumulative toxicity. The most commonly reported Grade 3/4 toxicities were thrombocytopenia (29%), with a consistent pattern of recovery during the rest period of each cycle, diarrhea (11%), anemia (11%), and neutropenia (10%). Neuropathy was reported less frequently. CONCLUSIONS: Retreatment with or continuation of bortezomib +/- dexamethasone beyond 6 months was safe, and toxicities were manageable, in patients with relapsed and/or refractory myeloma.     

Escalation therapy with bortezomib, dexamethasone and bendamustine for patients with relapsed or refractory multiple myeloma

In order to improve remission rates without causing undue toxicity, we treated 50 patients with relapsed/refractory multiple myeloma according to an institutional sequential treatment algorithm. Bortezomib was given as monotherapy (1.3 mg/m(2) on day 1 + 4 + 8 + 11) followed by the addition of dexamethasone in a first (40 mg on day 1 + 4 + 8 + 11) and bendamustine (50 - 100 mg/m(2) on day 1 + 8) in a second escalation step for patients with less than a minor response. Bortezomib monotherapy was sufficient in 23 (46%) patients, treatment escalation with dexamethasone was necessary in 20 (40%) patients and 7 (14%) patients needed triple combination therapy. Overall response rate was 84% while toxicity was manageable. Median time to progression and overall survival were 8 and 20 months, respectively. In conclusion, this treatment algorithm resulted in responses in the majority of heavily pre-treated patients while at the same time restricting the toxicity of triple combination therapy to only 14% of non-responding patients.     

Complete response obtained by bortezomib plus dexamethasone in a patient with relapsed multiple myeloma with multiple plasmacytomas

BACKGROUND: A case of relapsed multiple myeloma (MM) with multiple plasmacytomas of the parietal bone and the right orbit in which was achieved a complete response with bortezomib plus dexamethasone (BD) therapy is reported. A Japanese woman with Bench-Jones lambda-type MM who achieved a plateau phase with nine courses of melphalan plus prednisolone therapy complained of right exophthalmos and numbness around her mouth. Computed tomographic (CT) scan and T2-weighted magnetic resonance imaging showed tumours at the parietal bone and the right orbit. A tumour biopsy from the parietal bone revealed the histological morphology of a plasmacytoma. She was therefore diagnosed with relapsed MM with multiple plasmacytomas, and received BD therapy. A CT scan after the end of the second course of treatment revealed the disappearance of the plasmacytomas. At the end of the fifth course, no lambda light chain was detected by immunofixation of serum and urine, and the pathological plasma cells in bone marrow were fewer than 5%; therefore, she had achieved a complete response. The time to disease progression from the first course of BD therapy and the treatment-free interval were 400 days and 134 days, respectively. CONCLUSION: This case report indicates that bortezomib may be a promising agent for MM with multiple plasmacytomas.     

Results from AMBER,a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma

BACKGROUND.

Newer systemic therapies have significantly advanced the treatment of multiple myeloma, but additional agents are needed. Bortezomib is a proteasome inhibitor with efficacy in relapsed/refractory multiple myeloma that inhibits tumor angiogenesis, a process that has been implicated in multiple myeloma pathogenesis.

METHODS.

In AMBER(“A Randomized, Blinded, Placebo‐Controlled, Multicenter, Phase II Study of Bevacizumab in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma”), patients with relapsed or refractory multiple myeloma were randomized to receive bortezomib (1.3 mg/m² on days 1, 4, 8, and 11 of each 21‐day cycle) and either placebo or bevacizumab (15 mg/kg on day 1 of each cycle) for up to 8 cycles. At completion, patients in the bortezomib‐plus‐bevacizumab arm could continue bevacizumab until they developed progressive disease or unacceptable toxicity. The primary endpoint was progression‐free survival (PFS).

RESULTS.

The stratified hazard ratio of PFS for the bevacizumab‐containing arm (n = 49) relative to the bortezomib monotherapy arm (n = 53) was 0.743 (95% confidence interval [CI], 0.43‐1.28; P = .2804); the median PFS was 6.2 months (95% CI, 4.4‐8.5 months) and 5.1 months (95% CI, 4.2‐7.2 months), respectively; the overall response rates were 51% and 43.4% (P = .4029), respectively; and the median response duration was 6.9 months (95% CI, 4.73‐11.83 months) and 6.0 months (95% CI, 4.86‐8.31 months), respectively. Frequent adverse events occurred at similar rates across treatment arms, but hypertension, fatigue, and neuralgia occurred more frequently in the bevacizumab‐containing arm.

CONCLUSIONS.

The addition of bevacizumab to bortezomib in unselected patients with pretreated multiple myeloma did not result in significant improvements in efficacy outcomes. The combination was well tolerated, and no new safety concerns for either agent were identified. Cancer 2013. © 2012 American Cancer Society.     

Intravenous injection of bortezomib,melphalan and dexamethasone in refractory and relapsed multiple myeloma

BackgroundA combination of bortezomib (1.3 mg/m²), melphalan (5 mg/m²), and dexamethasone (40 mg) (BMD), with all three drugs given as a contemporary intravenous administration, was retrospectively evaluated.Patients and methodsFifty previously treated (median 2 previous lines) patients with myeloma (33 relapsed and 17 refractory) were assessed. The first 19 patients were treated with a twice-a-week (days 1, 4, 8, 11, ‘base’ schedule) administration while, in the remaining 31 patients, the three drugs were administered once a week (days 1, 8, 15, 22, ‘weekly’ schedule).ResultsSide-effects were predictable and manageable, with prominent haematological toxicity, and a better toxic profile in ‘weekly’ schedule (36% versus 66% in ‘base’ schedule). The overall response rate was 62%. After median follow-up of 24.5 months (range 2.7–50 months), the median progression-free survival (PFS) was 21.6 with no difference between the two schedules and the median overall survival (OS) was 33.8 months. Independently from the adopted schedule, we found that also in a cohort of relapsed/refractory patients achieving at least partial remission improved PFS (35.2 versus 9 months) and OS (unreached median versus 18 months).ConclusionTaken together, our observations suggest that BMD is an effective regimen in advanced myeloma patients with acceptable toxicity.     

Effect of different doses of dexamethasone combined with bortezomib and thalidomide in treatment of elderly patients with multiple myeloma

Objective: To observe the efficacy and safety of different doses of dexamethasone combined with bortezomib and thalidomide in the treatment of elderly patients with multiple myeloma (MM). Methods: A total of 33 elderly MM patients treated in Shanghai Fifth People's Hospital between August 2014 and August 2019 were enrolled in the study. According to the dosage of dexamethasone, the patients were divided into the observation group (low dose dexamethasone, 20 mg/d on day 1-4, and 11-14) and the control group (high dose dexamethasone, 40 mg/d on day 1-4, 9-12, and 17-20). Twenty-eight days was a course of treatment. The clinical efficacy and safety of patients was assessed after 4 courses of treatment. The patients were followed up till June 30th, 2021. Kaplan-Meier and log-rank were used to analyze the survival. Results: The overall response rate (ORR) and median overall survival (OS) were not significantly different between the observation and control groups (82.4% vs 87.5%, P=0.973; 58 months vs 61 months, P=0.859). The incidence rates of lung infection and hyperglycemia in the observation group were both significantly lower than those in the control group (both P< 0.05). Conclusions: Different doses of dexamethasone combined with bortezomib and thalidomide have definite curative effects in the treatment of elderly MM patients. But low dose dexamethasone has fewer adverse reactions and better safety. © 2022, The Second Affiliated Hospital, College of Medicine, Zhejiang University.. All right reserved.     

硼替佐米治疗多发性骨髓瘤的临床观察

目的:观察硼替佐米治疗多发性骨髓瘤(MM)的疗效及不良反应.方法:5例初治的MM患者接受硼替佐米联合地塞米松治疗,6例复发难治骨髓瘤患者接受VDT方案(硼替佐米+地塞米松+反应停)化疗,每例患者至少接受中位3个周期(1～6个周期)的化疗.评价疗效及不良反应.结果:中位随访9个月,5例初治患者中2例完全缓解(CR),2例部分缓解(PR),1例轻微缓解(MR);6例复发难治患者中,3例PR,1例MR,2例无改变(NC).总反应率(ORR=CR+PR+MR)为81.8%(9/11).主要不良反应:10例(90.9%)胃肠道症状,8例(72.7%)血小板减少,7例(63.6%)白细胞减少,4例(36.3%)周围神经病变等,经对症治疗及调整用药剂量后均能改善.结论:硼替佐米用于治疗初发及复发难治MM是一种有效的新的治疗选择,不良反应较少且易于处理.     

硼替佐米联合地塞米松治疗24例多发性骨髓瘤的疗效分析

背景及目的:硼替佐米(bortezomib)是一种有效、可逆性的蛋白酶体抑制剂,通过诱导骨髓瘤细胞的凋亡,在骨髓瘤患者的治疗中发挥持久的疗效。本研究旨在观察硼替佐米联合地塞米松治疗初治、难治/复发多发性骨髓瘤(multiple myeloma,MM)患者的疗效和毒副作用,及该方案在肾功能不全患者中应用的安全性。方法:24例MM患者接受硼替佐米联合地塞米松方案治疗,每3周为一个疗程。所有患者共接受中位3个疗程(1～8个疗程)的化疗。采用EBMT疗效评价标准评价疗效,按国立癌症研究所的常规毒性判定标准评价不良反应。结果:全组中位随访4个月,总有效率79.2%(19/24)。轻链型患者CR率57.1%(4/7),明显高于非轻链型患者5.9%(1/17),差异有统计学意义(P=0.014)。7例合并肾功能不全的患者与肾功能正常患者的疗效相近,差异无统计学意义(P=0.272)。Ⅲ～Ⅳ级不良反应包括白细胞减少(2/24,8.3%)、血小板减少(8/24,33.3%)、腹泻(2/24,8.3%)和乏力(1/24,4.2%),经对症治疗或推迟化疗后均可恢复。结论:硼替佐米联合地塞米松方案治疗MM患者有明显疗效,在轻链型患者疗效更加显著。副作用可以耐受,在合并肾功能不全的患者可安全应用。