Regina A. Swift

Pharmacokinetics and Pharmacodynamics of Zoledronic Acid in Cancer Patients with Bone Metastases

The pharmacokinetics, pharmacodynamics, and safety of zoledronic acid (Zometa®), a new‐generation bisphosphonate, were evaluated in 36 patients with cancer and bone metastases. Zoledronic acid (by specific radioimmunoassay) and markers of bone turnover were determined in plasma and urine after three consecutive infusions (qx28 days) of 4 mg/5 min (n = 5), 4 mg/15 min (n = 7), 8 mg/15 min (n = 12), or 16 mg/15 min (n = 12). Zoledronic plasma disposition was multiphasic, with half‐lives of 0.2 and 1.4 hours representing an early, rapid decline of concentrations from the end‐of‐infusion Cmax to < 1% of Cmax at 24 hours postdose and half‐lives of 39 and 4526 hours describing subsequent phases of very low concentrations between days 2 and 28 postdose. AUC0‐24h and Cmax were dose proportional and showed little accumulation (AUC0_24h ratio between the third and first dose was 1.28). Prolonging the infusion from 5 to 15 minutes lowered Cmax by 34%, with no effect on AUC0‐24h. Urinary excretion of zoledronic acid was independent of infusion duration, dose, or number of doses, showing average Ae0‐24h of 38% ± 13%, 41% ± 14%, and 37% ± 17%, respectively, after 4, 8, and 16 mg. Only trace amounts of drug were detectable in post 24‐hour urines. Renal clearance (Ae0‐24h)/(AUC0‐24h) was on average 69 ± 28, 81 ± 40, and 54 ± 34 ml/min after 4, 8, and 16 mg, respectively, and showed a moderate correlation (r = 0.5; p < 0.001) with creatinine clearance, which was 84 ± 23, 82 ± 25, and 80 ± 40 ml/min for the dose groups at baseline. Adverse events and changes from baseline in vital signs and clinical laboratory variables showed no relationship in terms of type, frequency, or severity with zoledronic acid dose or pharmacokinetic parameters. Zoledronic acid produced significant declines from baseline in serum and/or creatinine‐corrected urine C‐telopeptide (by 74%), N‐telopeptide (69%), pyridinium cross‐links (19–33%), and calcium (62%), with an increasing trend (by 12%) in bone alkaline phosphatase. There was no relationship of the magnitude and duration of these changes with zoledronic acid dose, Ae0‐24j, AUC0‐24h, or Cmax. The antiresorptive effects were evident within 1 day postdose and were maintained over 28 days across all dose levels, supporting monthly dosing with 4 mg zoledronic acid.

Phase I/II Trial Assessing Bortezomib and Melphalan Combination Therapy for the Treatment of Patients With Relapsed or Refractory Multiple Myeloma

PURPOSE Bortezomib has shown synergy with melphalan in preclinical models. We assessed the safety, tolerability, and response rate in a dose-escalation study of this combination for relapsed or refractory multiple myeloma patients. METHODS Bortezomib was administered from 0.7 to 1.0 mg/m(2) on days 1, 4, 8, and 11 of a 28-day cycle for up to eight cycles. Oral melphalan was administered in escalating doses from 0.025 to 0.25 mg/kg on days 1 to 4. RESULTS Thirty-five patients with relapsed or refractory myeloma were enrolled, 34 of whom were assessable for response. Dose-limiting toxicity of grade 4 neutropenia in two of six patients in the highest dose cohort led to the assignment of bortezomib 1.0 mg/m2 and melphalan 0.10 mg/kg as the maximum-tolerated dose (MTD). Responses (minimal [MR], partial [PR], or complete [CR]) occurred in 23 of 34 patients (68%), including two CRs (6%), three immunofixation-positive CRs (9%), 11 PRs (32%), and seven MRs (21%). Responses were observed in five of six assessable patients (83%) at the MTD. Median progression-free survival for all patients was 8 months (range, 2 to 18 months). Grade > or = 3 toxicities were related mostly to myelosuppression. Among the 15 patients with grade 1/2 neuropathy at baseline, it resolved during treatment in one, worsened in four, and remained stable in 10 patients. Eight other patients developed grade 1/2 neuropathy during the study. CONCLUSION Bortezomib plus melphalan given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for myeloma patients.

A Phase I/II Study of Arsenic Trioxide/Bortezomib/Ascorbic Acid Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma

Purpose: This multicenter, open-label, phase I/II dose escalation study assessed the safety/tolerability and initial efficacy of arsenic trioxide/bortezomib/ascorbic acid (ABC) combination therapy in patients with relapsed/refractory multiple myeloma. Experimental Design: Enrolled in six cohorts, patients were given arsenic trioxide (0.125 or 0.250 mg/kg), bortezomib (0.7, 1.0, or 1.3 mg/m2), and a fixed dose of ascorbic acid (1 g) i.v. on days 1, 4, 8, and 11 of a 21-day cycle for a maximum of eight cycles. The primary end point was safety/tolerability of the ABC regimen. Results: Twenty-two patients (median age, 63 years) were enrolled, having failed a median of 4 (range, 3-9) prior therapies. One occurrence of grade 4 thrombocytopenia was observed. One patient had asymptomatic arrhythmia and withdrew from the study. Objective responses were observed in 6 (27%) patients, including two partial responses and four minor responses. Median progression-free survival was 5 months (95% confidence interval, 2-9 months), and median overall survival had not been reached. The 12-month progression-free survival and overall survival rates were 34% and 74%, respectively. One (minor response) of six patients receiving the lowest dose of bortezomib (0.7 mg/m2) and 5 (2 partial responses and 3 minor responses) of 16 patients receiving the higher doses (1.0 or 1.3 mg/m2) responded. Conclusions: The ABC regimen was well tolerated by most patients, and it produced preliminary signs of efficacy with an objective response rate of 27% in this heavily pretreated study population. These findings warrant further clinical evaluation of the ABC combination for treatment of relapsed/refractory multiple myeloma.

Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single‐arm study

We assessed the safety and efficacy of melphalan, arsenic trioxide (ATO) and ascorbic acid (AA) (MAC) combination therapy for patients with multiple myeloma (MM) who failed more than two different prior regimens. Patients received melphalan (0·1 mg/kg p.o.), ATO (0·25 mg/kg i.v.) and AA (1 g i.v) on days 1–4 of week 1, ATO and AA twice weekly during weeks 2–5 and no treatment during week 6 of cycle 1; during cycles 2–6, the schedule remained the same except ATO and AA were given twice weekly in week 1. Objective responses occurred in 31 of 65 (48%) patients, including two complete, 15 partial and 14 minor responses. Median progression‐free survival and overall survival were 7 and 19 months respectively. Twenty‐two patients had elevated serum creatinine levels (SCr) at baseline, and 18 of 22 (82%) showed decreased SCr levels during treatment. Specific grade 3/4 haematological (3%) or cardiac adverse events occurred infrequently. Frequent grade 3/4 non‐haematological adverse events included fever/chills (15%), pain (8%) and fatigue (6%). This steroid‐free regimen was effective and well tolerated in this heavily pretreated group. These results indicate that the MAC regimen is a new therapeutic option for patients with relapsed or refractory MM.

Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival

Although TNFRSF17 (also designated as B‐cell maturation antigen (BCMA)) is expressed on tumour cells in B‐cell malignancies, it has not been found in serum. The present study found that BCMA concentrations were higher in the supernatants of cultured bone marrow mononuclear cells from multiple myeloma (MM) patients than in healthy subjects. Serum BCMA levels were measured in samples from MM patients (n = 209), monoclonal gammopathy of undetermined significance (MGUS) individuals (n = 23) and age‐matched controls (n = 40). BCMA was detected in the serum of untreated MM patients (n = 50) and levels were higher than in MGUS patients (P = 0·0157) and healthy subjects (P < 0·0001). Serum BCMA levels were higher among patients with progressive disease (n = 80) compared to those with responsive disease (n = 79; P = 0·0038). Among all MM patients, overall survival was shorter among patients whose serum BCMA levels were above the median (P = 0·001). We also demonstrated that sera from mice with human MM xenografts contained human BCMA, and levels correlated with the change in tumour volume in response to melphalan or cyclophosphamide with bortezomib. These results suggest that serum BCMA levels may be a new biomarker for monitoring disease status and overall survival of MM patients.

Phase I/II trial assessing bendamustine plus bortezomib combination therapy for the treatment of patients with relapsed or refractory multiple myeloma

Bendamustine, active in multiple myeloma (MM), is a bifunctional mechlorethamine derivative with alkylating properties. Bortezomib, approved to treat MM, is effective in combination with alkylators. The tolerability and efficacy of bendamustine plus bortezomib in relapsed/refractory MM was assessed in an open‐label, dose‐escalating, phase I/II study. Patients aged ≥18 years received intravenous bendamustine 50, 70, or 90 mg/m2 (days 1 and 4) plus bortezomib 1·0 mg/m2 (days 1, 4, 8, and 11) for up to eight 28‐day cycles. No dose‐limiting toxicity was observed after cycle 1; bendamustine 90 mg/m2 plus bortezomib 1·0 mg/m2 was designated the maximum tolerated dose (MTD). The most common grade 3/4 adverse events were leucopenia (58%), neutropenia (50%), lymphopenia (45%), and thrombocytopenia (30%). Primary efficacy measure was overall response rate (ORR), which was the combined complete response (CR), very good partial response (VGPR), partial response (PR), and minimal response (MR). ORR was 48% (one CR, two VGPR, nine PR, and seven MR) for all 40 enrolled patients, 52% (16/31) at the MTD (90 mg/m2), and 42% and 46% for prior use of bortezomib (n = 31) or alkylators (n = 28) respectively. Bendamustine plus bortezomib was well tolerated with promising efficacy in this heavily pretreated population.

Zoledronic Acid Markedly Improves Bone Mineral Density for Patients with Monoclonal Gammopathy of Undetermined Significance and Bone Loss

Purpose: Patients with monoclonal gammopathy of undetermined significance (MGUS) have increased rates of bone resorption, osteopenia, osteoporosis, and risk of fractures. This study was undertaken to determine the efficacy and safety of zoledronic acid for patients with MGUS and enhanced bone loss. Experimental Design: In this phase II open-label study, 54 patients with MGUS and osteopenia or osteoporosis were administered zoledronic acid 4 mg i.v. at 0, 6, and 12 months. The primary efficacy end point was bone mineral density, assessed using a dual-energy X-ray absorptiometry scan in the lumbar (L)-spine done at screening and at 13 months (1 month after the final zoledronic acid infusion). Results: At study end for all patients (N = 54), L-spine T-scores improved by a median of +0.27 (range, −0.38 to +3.91), corresponding to a median increase in bone mineral density of +15.0% (range, −18.0% to +1,140.0%; P < 0.0001). Hip T-scores improved by a median of +0.10 (range, −2.40 to +2.03), corresponding to a median increase of +6.0% (range, −350.0% to +165.0%). During the study, no new fractures, osteonecrosis of the jaw, or significant renal adverse events were reported. Conclusions: Zoledronic acid administered i.v. at a dosage of 4 mg every 6 months for three doses total was well-tolerated and substantially improved bone mineral density for patients with MGUS and bone loss. Zoledronic acid may be effective for the prevention of new fractures in this high-risk population.

A phase I study of samarium lexidronam/bortezomib combination therapy for the treatment of relapsed or refractory multiple myeloma.

Purpose: This open-label, phase I dose-escalation study assessed the safety, tolerability, and initial efficacy of Samariam 153 (153Sm)-lexidronam/bortezomib combination therapy for patients with relapsed/refractory multiple myeloma. Experimental Design: Patients were enrolled in six cohorts and given bortezomib (1.0 or 1.3 mg/m2) on days 1, 4, 8, and 11 and 153Sm-lexidronam (0.25, 0.5, or 1.0 mCi/kg) on day 3 of a 56-day cycle (maximum of four cycles). The primary endpoints were safety and tolerability of the 153Sm-lexidronam/bortezomib regimen. Results: Twenty-four patients were enrolled. Median values for age, time since diagnosis, and number of prior treatments were 63 years, 29 months, and three regimens, respectively. The most common toxicities were hematologic; during the first cycle, median neutrophil and platelet nadirs were 1,000/mm3 and 98,500/mm3, respectively, and observed generally 3 to 4 weeks post-treatment. The incidences of grade 4 neutropenia and thrombocytopenia were 12.5% and 8.3%, respectively, during treatment cycle 1. Dose-limiting toxicity, reached in cohort 6 as a result of hematologic toxicity, defined the maximum tolerated dose as 0.5 mCi/kg 153Sm-lexidronam in combination with 1.3 mg/m2 bortezomib. The maximum tolerated dose for 153Sm-lexidronam in combination with the 1.0 mg/m2 bortezomib was not reached. No nonhematologic dose-limiting toxicities were observed; both the incidence and the severity of peripheral neuropathy were low. Responses occurred in 5 (21%) patients, including 3 (12.5%) complete and 2 (8.3%) minimal responses. Conclusions: Bortezomib combined with 153Sm-lexidronam appears to be a well-tolerated regimen, which showed clinical activity in this phase I trial for patients with relapsed or refractory multiple myeloma.

A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients

The combination of pegylated liposomal doxorubicin (PLD), bortezomib and dexamethasone has shown efficacy in the treatment of multiple myeloma (MM) patients. Our earlier retrospective study suggested that modification of the doses, schedules and route of administration of these drugs appears to reduce toxicity without compromising anti‐MM activity. As a result, we evaluated this modified drug combination in the frontline setting in a prospective multicentre phase II trial. Thirty‐five previously untreated MM patients were enrolled. Dexamethasone IV 40 mg, bortezomib 1 mg/m2 and PLD 5 mg/m2 were administered on days 1, 4, 8 and 11 of a 4‐week cycle. Patients were treated to their maximum response plus two additional cycles. The treatment regimen was discontinued after a maximum of eight cycles. Our modified schedule and dosing regimen achieved a high overall response rate of 86%, while showing a marked decrease in the incidence and severity of peripheral neuropathy, palmar‐plantar erythrodysesthesia and myelosuppression compared to the standard dosing on a 3‐week cycle using these drugs. This modified regimen of dexamethasone, bortezomib and PLD shows improved tolerability and safety while maintaining a high response rate when compared to standard treatment with these agents in the frontline setting.

Bortezomib, ascorbic acid and melphalan (BAM) therapy for patients with newly diagnosed multiple myeloma: an effective and well-tolerated frontline regimen

Background:  We conducted a single‐arm, multicentre phase 2 study to evaluate bortezomib, ascorbic acid and melphalan (BAM) for patients with newly diagnosed multiple myeloma (MM).