Purpose: Osteonecrosis of the jaw (ONJ) has been reported in patients with a history of aminobisphosphonate use. This study was conducted in order to define ONJ clinically and radiographically and gain insights into its pathophysiology. Experimental Design: Eleven multiple myeloma (MM) patients with ONJ were included in the study. Patients underwent clinical, biochemical, radiographic, and molecular profiling. Ten MM patients on aminobisphosphonates without ONJ and five healthy volunteers were used as controls for biochemical and molecular studies. Results: MM patients with ONJ were treated with either pamidronate (n = 3), zoledronate (n = 4), or both agents sequentially (n = 4) for a mean of 38.7 months. Radiographic studies showed bone sclerosis and fragmentation on plain films and computerized tomography. Quantitative regional analysis of NaF-PET and FDG-PET scans confirmed an increased standardized uptake value (SUVmax) in areas of ONJ. The target to background ratio of SUVmax was significantly greater for NaF-PET compared with FDG-PET scan. Biochemical bone marker data and transcriptional profiling studies showed that genes and proteins involved in osteoblast and osteoclast signaling cascades were significantly down-regulated in patients with ONJ. Conclusions: ONJ was associated with a mean duration of 38.7 months of aminobisphosphonate exposure. Radiographic and functional imaging confirmed sites of clinically established ONJ. Gene and protein studies are consistent with altered bone remodeling, evidenced by suppression of both bone resorption and formation.
Osteonecrosis of the Jaw and Bisphosphonatesto the editor: Cases of osteonecrosis of the jaw in connection with the use of bisphosphonates were reported in 2003. 1,2 In 2004, the International Myeloma Foundation conducted a Web-based survey to assess the risk factors for osteonecrosis of the jaw. Of 1203 respondents, 904 had myeloma and 299 breast cancer. Both osteonecrosis and suspicious findings, including bone erosions and spurs plus exposed bone, were assessed. Sixtytwo patients with myeloma had osteonecrosis of the jaw and 54 had suspicious findings; 13 patients with breast cancer had osteonecrosis and 23 had suspicious findings -a total of 152 patients with either osteonecrosis or suspicious findings. Of the patients with myeloma, 71 percent had received zoledronic acid and 29 percent had received only pamidronate.Figure 1 displays the cumulative incidence of osteonecrosis of the jaw among patients receiving either zoledronic acid alone or pamidronate alone who responded to the survey. With censoring at 36 months, osteonecrosis of the jaw developed in 10 percent of 211 patients receiving zoledronic acid, as compared with 4 percent of 413 patients receiving pamidronate (P=0.002 by the log-rank test). The earlier onset of osteonecrosis of the jaw among patients receiving zoledronic acid during the first 36 months reflects remarkably well the reported increase in the occurrence of osteonecrosis in the first 36 months after the Food and Drug Administration approved the drug in 2001.The censored 36-month estimates of osteonecrosis, suspicious findings, or both did not differ between patients with myeloma and those with breast cancer (P>0.50). No other therapies, including corticosteroids and thalidomide, conferred an added risk over time (P>0.50). However, a history of underlying dental problems, such as infection or dental extraction, was present in 81 percent of patients with myeloma and in 69 percent of patients with breast cancer who had osteonecrosis of the jaw, as compared with 33 percent of those without osteonecrosis (P<0.001 and P=0.01, respectively, in a two-sided test). Maxillofacial surgery was a particular problem for patients with osteonecrosis of the jaw, since the surgery resulted in areas of nonhealing bone and soft tissue that were larger than those in patients who did not undergo surgery.In September 2004, Novartis, the manufacturer of pamidronate (Aredia) and zoledronic acid (Zometa), issued post-marketing guidelines 3 for both drugs in relation to osteonecrosis of the jaw that emphasized a particular risk with surgical intervention. The International Myeloma Foundation is working collaboratively with Novartis to raise awareness and develop enhanced guidelines. The full results of the study were presented to the Food and Drug Administration at an Oncology Drug Advisory Committee meeting held on March 4, 2005. 4
VP-16-213, a congener of epipodophyllotoxin, is a useful chemotherapeutic agent especially against small-cell carcinoma of the lung, germ cell carcinoma, and lymphoma. The standard dose of this drug is limited by myelosuppression. Autologous transplantation of cryopreserved bone marrow assures the restoration of hematopoiesis after marrow ablative cytotoxic therapy. By using this technique, VP-16-213 was dose-escalated using a Fibonacci scheme from the previous highest dose administered to humans (1,500 mg/m2) to 2,700 mg/m2 (900 mg/m2 per day for three consecutive days). At 2,700 mg/m2, severe extramedullary toxicity of the mucous membranes was observed in three of three courses. At the next highest dose (2,400 mg/m2), two of 18 courses (11%, p less than 0.01) resulted in severe mucositis, thus defining this dose as the maximally tolerated dose based on extramedullary toxicities. As anticipated, myelotoxicity was severe but based on the kinetics of marrow recovery, VP-16-213 in these doses appeared not to be marrow ablative. Based on responses observed in this study, high-dose VP-16-213 should be explored in phase II studies or used in combination chemotherapy.
Introduction: Bortezomib and lenalidomide are active agents in multiple myeloma (MM), and preclinical data showing additive activity in MM in vitro suggest that enhanced clinical benefit may be derived from combining the two drugs. Bortezomib is approved in MM patients (pts) who have received at least one prior therapy in both the US and EU. Lenalidomide has produced durable responses in the relapsed and refractory MM setting, including in those who received prior bortezomib. Toxicities of bortezomib and lenalidomide do not overlap unfavorably. These observations suggest that this regimen, compared with either agent alone, may provide better clinical anti-MM activity. In phase 1 trials, the maximum tolerated doses (MTD) of single-agent bortezomib and lenalidomide were 1.3 mg/m2 (IV bolus twice weekly) and 25 mg/d (PO days 1–21 of a 28–day cycle), respectively. The objective of this phase 1 dose-escalation trial was to determine the MTD and activity of this combination in pts with relapsed and/or refractory MM. Methods: Eight 3-pt cohorts were planned with bortezomib 1.0 or 1.3 mg/m2 and lenalidomide 5, 10, 15, or 20 mg/day. Pts received bortezomib on days 1, 4, 8, and 11 and lenalidomide on days 1–14 of a 21-day cycle. Dexamethasone 20 mg orally could be added on days 1, 2, 4, 5, 8, 9 and 11, 12 in the event of PD. Toxicity was assessed using NCI-CTC, version 3.0. Dose-limiting toxicity (DLT) was defined as grade ≥ 3 nonhematologic toxicity, grade 4 neutropenia lasting ≥ 5 days and/or neutropenic fever, or a platelet count ≤ 10,000 on > 1 occasion despite transfusion. Modified EBMT criteria were used to assess response. Results: Nineteen pts with MM have been enrolled to date to cohorts 1–5, including 8 with relapsed and 11 with relapsed and refractory disease. Median number of prior therapies was 4 (range, 1–9). Twelve pts had prior SCT; 17 had received thalidomide, 9 bortezomib, 2 lenalidomide. With a median of 7 cycles completed (range, 2–16), pts have received bortezomib 1.0–1.3 mg/m2 and lenalidomide 5–15 mg/d. Two pts with rapid disease progression were not evaluable and were removed from study within the first cycle. One DLT was observed (cohort 4, grade 3 hyponatremia). To date, doses of study drugs were reduced in 6 pts beyond cycle 3. Bortezomib was reduced for thrombocytopenia [n = 3] and hypotension [n = 1] and lenalidomide was reduced for neutropenia [n = 1] and fatigue [n = 1]. No significant treatment-emergent PN has been seen. Responses by cohort are shown in the table, and of 17 evaluable pts, 10 (59%) achieved CR + PR. Conclusions: In heavily treated pts with relapsed and/or refractory MM, the combination of bortezomib and lenalidomide has been well tolerated and has demonstrated very promising activity, even in pts who had previously received either agent alone. Dose escalation is continuing until MTD is reached. Phase II evaluation of this regimen is planned both in relapsed and/or refractory and in newly diagnosed MM. Cohort Bortezomib, mg/m2 Lenalidomide, mg Best Response NE = not evaluable. 1 1.0 5 2 PR, 1 MR 2 1.3 5 1 CR, 2 PR 3 1.0 10 1 nCR, 2 PR, 1 NE 4 1.3 10 2 PR, 2 MR, 1 SD, 1 PD 5 1.0 15 2 SD, 1 NE
Introduction: Bortezomib, a first in class proteasome inhibitor, has become a standard of care in the treatment of relapsed and refractory MM. A recent randomized Phase 3 trial showed an improvement in time to progression (TTP) and overall survival relative to dexamethasone (dex) in patients with relapsed MM and 1–3 prior lines of therapy. In relapsed MM, the rate of treatment -emergent significant peripheral neuropathy (PN) with bortezomib was higher in patients with baseline neuropathy. The incidence and severity of PN in front-line treatment will be important to define. This multi-center, Phase 2 study was planned to evaluate the activity and toxicity (in particular PN) of single agent bortezomib in previously untreated pts. Methods: Response rate, TTP, tolerability, incidence and severity of PN, and the effect of dose modification, symptomatic treatment and nutritional supplements on PN were evaluated in previously untreated, symptomatic MM pts. Pts received bortezomib 1.3 mg/m2 on D 1, 4, 8, and 11 of a 21-d cycle and response to treatment was assessed every 2 cycles. Dex was not permitted. Neurologic evaluation was required before and after treatment, and if significant PN developed during therapy. Results: 28 pts with symptomatic MM have been treated with a median age of 60 yrs, IgG isotype in 68% and Stage III disease in 52%. Analysis of best paraprotein response after ≥ 2 cycles revealed CR in 1 (5%) pt and PR in 8 (36%), for an ORR of 41% in 22 evaluable pts. An additional 5 pts (23%) achieved MR, with stable disease in 6 pts (27%); 2 pts progressed (9%). The most commonly reported adverse events included PN, fatigue, GI symptoms and rash. Neurological evaluation has been performed in all pts, including nerve conduction studies (NCS), assessment of autonomic function and skin biopsy for EM imaging of small fibers in a subset (n=19). Six of 28 pts (21%) so far have developed PN with most being G2: 1 pt experienced G3 PN and drug was discontinued. Dose modification was required in 4 pts and supplements have been used in all pts with PN. Preliminary results of neurological testing and NCS have indicated subclinical PN at baseline prior to therapy in 6/19 (30%) of pts evaluated by NCS, with small fiber, axonal PN documented in 1 pt with treatment-emergent PN. Bortezomib-related toxicity has otherwise been manageable. Conclusion: Single agent bortezomib is a promising approach for newly diagnosed pts and is without the complications of high-dose dex. The incidence of subclinical PN by NCS at baseline prior to therapy is currently 30%; G2 or greater treatment-emergent PN has occurred in 21% of pts and was G3 in only 1 pt (4%) to date. Further assessment of PN including analysis of skin biopsies is ongoing.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.