James R. Berenson

Efficacy of Pamidronate in Reducing Skeletal Events in Patients with Advanced Multiple Myeloma

BACKGROUND Skeletal complications are a major clinical manifestation of multiple myeloma. These complications are caused by soluble factors that stimulate osteoclasts to resorb bone. Bisphosphonates such as pamidronate inhibit osteoclastic activity and reduce bone resorption. METHODS Patients with stage III multiple myeloma and at least one lytic lesion received either placebo or pamidronate (90 mg) as a four-hour intravenous infusion given every four weeks for nine cycles in addition to antimyeloma therapy. The patients were stratified according to whether they were receiving first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy at entry into the study. Skeletal events (pathologic fracture, irradiation of or surgery on bone, and spinal cord compression), hypercalcemia (symptoms or a serum calcium concentration > or = 12 mg per deciliter [3.0 mmol per liter]), bone pain, analgesic-drug use, performance status, and quality of life were assessed monthly. RESULTS Among 392 treated patients, the efficacy of treatment could be evaluated in 196 who received pamidronate and 181 who received placebo. The proportion of patients who had any skeletal events was significantly lower in the pamidronate group (24 percent) than in the placebo group (41 percent, P < 0.001), and the reduction was evident in both stratum 1 (P = 0.04) and stratum 2 (P = 0.004). The patients who received pamidronate had significant decreases in bone pain and no deterioration in performance status and quality of life. Pamidronate was tolerated well. CONCLUSIONS Monthly infusions of pamidronate provide significant protection against skeletal complications and improve the quality of life of patients with stage III multiple myeloma.

A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma

In a phase 2 open‐label study of the novel proteasome inhibitor bortezomib, 54 patients with multiple myeloma who had relapsed after or were refractory to frontline therapy were randomized to receive intravenous 1·0 or 1·3 mg/m2 bortezomib twice weekly for 2 weeks, every 3 weeks for a maximum of eight cycles. Dexamethasone was permitted in patients with progressive or stable disease after two or four cycles respectively. Responses were determined using modified European Group for Blood and Marrow Transplantation criteria. The complete response (CR) + partial response (PR) rate for bortezomib alone was 30% [90% confidence interval (CI), 15·7–47·1] and 38% (90% CI, 22·6–56·4) in the 1·0 mg/m2 (8 of 27 patients) and 1·3 mg/m2 (10 of 26 patients) groups respectively. The CR + PR rate for patients who received bortezomib alone or in combination with dexamethasone was 37% and 50% for the 1·0 and 1·3 mg/m2 cohorts respectively. The most common grade 3 adverse events were thrombocytopenia (24%), neutropenia (17%), lymphopenia (11%) and peripheral neuropathy (9%). Grade 4 events were observed in 9% (five of 54 patients). Bortezomib alone or in combination with dexamethasone demonstrated therapeutic activity in patients with multiple myeloma who relapsed after frontline therapy.

Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group.

PURPOSE To determine the efficacy and safety of 21 monthly cycles of pamidronate therapy in patients with advanced multiple myeloma. PATIENTS AND METHODS Patients with stage III myeloma and at least one lytic lesion received either placebo or pamidronate 90 mg intravenously administered as a 4-hour infusion monthly for 21 cycles. At study entry, the patients were stratified according to whether they were to receive first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy. Skeletal events (pathologic fracture, radiation or surgery to bone, and spinal cord compression) and hypercalcemia were assessed monthly. RESULTS The results of the first nine previously reported cycles are extended to 21 cycles. Of the 392 randomized patients, efficacy could be evaluated in 198 who received pamidronate and 179 who received placebo. After 21 cycles, the proportion of patients who developed any skeletal event was lower in the pamidronate-group (P = .015). The mean number of skeletal events per year was less in the pamidronate-group (1.3) than in placebo-treated patients (2.2; P = .008). Although survival was not different between the pamidronate-treated group and placebo patients overall, stratum 2 patients who received pamidronate lived longer than those who received placebo (14 v 21 months, P = .041). Pamidronate was safe and well tolerated during the 21 cycles of therapy. CONCLUSION Long-term monthly infusions of pamidronate as an adjunct to chemotherapy are superior to chemotherapy alone in reducing skeletal events in stage III multiple myeloma patients, and may improve the survival of patients on salvage therapy.

Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution.

BACKGROUND The potential benefits of haematopoietic stem-cell transplantation are tempered by the depletion of T-cells accompanying this procedure. We used a new technique which quantifies the excisional DNA products of T-cell-receptor (TCR) gene rearrangement to measure thymic output directly in patients with multiple myeloma, and thus assessed the contribution of the thymus to immune recovery after transplantation. METHODS We studied 40 patients, 34-66 years of age, who had been randomly assigned myeloablative chemotherapy and autologous peripheral-blood haematopoietic stem-cell transplantation with unmanipulated grafts or grafts enriched for CD34 stem cells. CD4 and CD8 T-cell counts were measured, thymic output was estimated serially until 2 years after transplantation, and percentages of naive T-cells were measured. FINDINGS The production of substantial numbers of new naive T cells by the thymus could be detected by 100 days post-transplant; there was a significant inverse relation between age and recovery of new T cells. In the CD34-unselected group, numbers of TCR-rearrangement excision circles returned to baseline after 2 years, whereas in the CD34-selected group, numbers at 2 years were significantly higher than both baseline numbers (p=0.004), and 2-year numbers in the unselected group (p=0.046). Increased thymic output correlated with, and was predictive of, increased naive T-cell numbers and broader T-cell-receptor repertoires. INTERPRETATION Our results provide evidence that the adult thymus contributes more substantially to immune reconstitution after haematopoietic stem-cell transplantation than was previously thought, and therefore could be a target for therapeutic intervention.

American Society of Clinical Oncology Clinical Practice Guidelines: The Role of Bisphosphonates in Multiple Myeloma

PURPOSE To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of lytic bone disease in multiple myeloma and to determine their respective role relative to other conventional therapies for this condition. METHODS An expert multidisciplinary Panel reviewed pertinent information from the published literature through January 2002. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the Panel. Expert consensus was used if there were insufficient published data. The Panel addressed which patients to treat and when to treat them in the course of their disease. Additionally, specific drug delivery issues, duration of therapy, initiation of treatment and management of treatment of lytic bone disease was reviewed and compared with other forms of therapy for lytic bone lesions. Finally, the Panel discussed patient and physician expectations associated with this therapy for bony metastases, as well as public policy implications related to the use of bisphosphonates. The guidelines underwent external review by selected physicians, by the Health Services Research Committee members, and by the ASCO Board of Directors. RESULTS The available evidence involving randomized controlled trials is modest but supports that oral clodronate, intravenous pamidronate, and intravenous zoledronic acid are superior to placebo in reducing skeletal complications. A reduction in vertebral fractures has consistently been seen across all studies. No agent has shown a definitive survival benefit. Intravenous zoledronic acid has recently been shown to be as effective as intravenous pamidronate. Because there are no direct comparisons between clodronate and pamidronate or zoledronic acid, the superiority of one agent cannot be definitively established. However, the panel recommends only intravenous pamidronate or zoledronic acid in light of the use of the time to first skeletal event as the primary end point and more complete assessment of bony complications in studies evaluating it. Additionally, clodronate is not available in the United States. The choice between pamidronate and zoledronic acid will depend on choosing between the higher drug cost of zoledronic acid, with its shorter, more convenient infusion time (15 minutes), versus the less expensive drug, pamidronate, with its longer infusion time (2 hours). CONCLUSION Bisphosphonates provide a meaningful supportive benefit to multiple myeloma patients with lytic bone disease. However, further research on bisphosphonates is warranted, including the following: (1) when to start and stop therapy, (2) how to integrate their use with other treatments for lytic bone disease, (3) how to evaluate their role in myeloma patients without lytic bone involvement, (4) how to distinguish between symptomatic and asymptomatic bony events, and (5) how to better determine their cost-benefit consequence.

Frequency, Characteristics, and Reversibility of Peripheral Neuropathy During Treatment of Advanced Multiple Myeloma With Bortezomib

PURPOSE To determine the frequency, characteristics, and reversibility of peripheral neuropathy from bortezomib treatment of advanced multiple myeloma. PATIENTS AND METHODS Peripheral neuropathy was assessed in two phase II studies in 256 patients with relapsed and/or refractory myeloma treated with bortezomib 1.0 or 1.3 mg/m2 intravenous bolus on days 1, 4, 8, and 11, every 21 days, for up to eight cycles. Peripheral neuropathy was evaluated at baseline, during the study, and after the study by patient-reported symptoms using the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire and neurologic examination. During the study, peripheral neuropathy was also evaluated by investigator assessment. A subset of patients underwent nerve conduction studies (n = 13). RESULTS Before treatment, 194 (81%) of 239 patients had peripheral neuropathy by FACT/GOG-Ntx questionnaire, and 203 (83%) of 244 patients had peripheral neuropathy by neurologic examination. Treatment-emergent neuropathy was reported in 35% of patients, including 37% (84 of 228 patients) receiving bortezomib 1.3 mg/m2 and 21% (six of 28 patients) receiving bortezomib 1.0 mg/m2. Grade 1 or 2, 3, and 4 neuropathy occurred in 22%, 13%, and 0.4% of patients, respectively. The incidence of grade > or = 3 neuropathy was higher among patients with baseline neuropathy by FACT/GOG-Ntx questionnaire compared with patients without baseline neuropathy (14% v 4%, respectively). In all 256 patients, neuropathy led to dose reduction in 12% and discontinuation in 5%. Of 35 patients with neuropathy > or = grade 3 and/or requiring discontinuation, resolution to baseline or improvement occurred in 71%. CONCLUSION Bortezomib-associated peripheral neuropathy seemed reversible in the majority of patients after dose reduction or discontinuation. Although severe neuropathy was more frequent in the presence of baseline neuropathy, the overall occurrence was independent of baseline neuropathy or type of prior therapy.

Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases: A double-blind, randomized dose-response study

This study evaluated the dose–response relation for zoledronic acid, a new generation high potency bisphosphonate, given as a 5‐minute infusion in patients with malignant osteolytic disease.

Detection and localization of tumor necrosis factor in human atheroma

Tumor necrosis factor (TNF) is a secretory product of normal macrophages that can cause cell necrosis, new blood vessel formation and thrombosis. These are also 3 characteristic features of the progression of stable atheroma to endothelial disruption. Accordingly, an immunohistochemical method was developed to detect TNF in human tissue. Using this method TNF positivity was demonstrated in 57 of 65 (88%) of tissue sections classified as atherosclerotic and in 5 of 11 (45%) sections classified as minimally atherosclerotic. TNF was absent in 6 sections classified as normal. TNF positivity was found not only in the cytoplasm of macrophages, but also in the cytoplasm and attached to the cell membrane of smooth muscle cells and endothelial cells of the human atheroma. Because TNF is known to cause new vessel formation, hemorrhagic necrosis and increased thrombogenicity, it may play a role in the evolution of uncomplicated to complex atheroma.

American Society of Clinical Oncology Guideline on the Role of Bisphosphonates in Breast Cancer

PURPOSE: To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone metastases in breast cancer and their role relative to other therapies for this condition. METHODS: An expert multidisciplinary panel reviewed pertinent information from the published literature and meeting abstracts through May 1999. Additional data collected as part of randomized trials and submitted to the United States Food and Drug Administration were also reviewed, and investigators were contacted for more recent information. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the panel. Expert consensus was used if there were insufficient published data. The panel addressed which patients to treat and when in their course of disease, specific drug delivery issues, duration of therapy, management of bony metastases with other therapies, and the public policy implications. The guideline underwent external review by selected p...

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.