A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma

Musto, Pellegrino; Petrucci, Maria Teresa; Bringhen, Sara; Guglielmelli, Tommasina; Caravita, Tommaso; Bongarzoni, Velia; Andriani, Alessandro; D’Arena, Giovanni; Balleari, Enrico; Pietrantuono, Giuseppe; Boccadoro, Mario; Palumbo, Antônio

doi:10.1002/cncr.23783

Cited by 166 publications

(115 citation statements)

References 48 publications

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“…Prognostic models for predicting asymptomatic MM progression, 8,12,15 including the model described in the current study, would allow the identification of low-risk patients who harbor a very indolent disease similar to MGUS and high-risk patients who might benefit from close follow-up and who may be optimal candidates for experimental therapies aimed at delaying the progression of MM. [35][36][37][38][39][40][41] …”

Section: Discussionmentioning

confidence: 99%

Beta‐2‐microglobulin is an independent predictor of progression in asymptomatic multiple myeloma

Rossi

Fangazio

Paoli

et al. 2010

Cancer

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BACKGROUND: Although serum beta-2 microglobulin (B2M) represents a key variable for symptomatic multiple myeloma (MM) prognostication, its role in predicting the risk of progression of asymptomatic MM to symptomatic disease has not been explored. METHODS: This study was bases on a consecutive series of 148 patients with asymptomatic MM and explored the cumulative probability of progression to symptomatic MM as the primary endpoint. RESULTS: In univariate analysis, a serum B2M level >2.5 mg/L was associated with an increased probability of disease progression (5-year risk, 64.5%; P < .001) along with serum monoclonal component (sMC) (P < .001), urinary monoclonal component (uMC) (P < .001), and bone marrow plasma cells (BMPCs) (P < .001). In multivariate analysis, serum B2M was selected as an independent predictor of progression (hazard ratio, 3.30; P ¼.002). Serum B2M was combined with sMC, uMC, and BMPC to create a risk-stratification model based on 4 groups with different risk of progression: very low (5-year risk, 0%), low-intermediate (5-year risk, 19.6%), high-intermediate (5-year risk, 60.7%), and high (5-year risk, 80.7%). The model that included serum B2M along with sMC, uMC, and BMPC was able to predict disease progression better than the model that was based on sMC, uMC, and BMPC without serum B2M (C statistics, 0.760 vs 0.726). CONCLUSIONS: The current results indicated that 1) serum B2M is an independent predictor of asymptomatic MM progression, and 2) serum B2M adds prognostic information when combined with the most widely used prognosticators of asymptomatic MM progression.

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Section: Discussionmentioning

confidence: 99%

Beta‐2‐microglobulin is an independent predictor of progression in asymptomatic multiple myeloma

Rossi

Fangazio

Paoli

et al. 2010

Cancer

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“…In addition, ZOL was administered for only 12 months, and it is possible that a longer duration of treatment may have been more effective. 62 Indeed, in a pilot study of patients who were receiving initial chemotherapy for MM (N ¼ 94), ZOL (4 mg per month iv) significantly improved the 5-year OS rate from 46% to 80% compared with chemotherapy alone (P < .01). 63 Similarly, a pilot study in patients with bone metastases from bladder cancer (N ¼ 40) demonstrated that ZOL (4 mg per month iv for 6 months) significantly reduced the risk of SRE by 58% (P ¼ .008), reduced pain scores by 1.42 units versus placebo (P ¼ .015), and improved the 1-year OS rate 6-fold (P ¼ .02) versus placebo.…”

Section: Anticancer Effects In the Advanced Disease Settingmentioning

confidence: 97%

Zoledronic acid use in cancer patients

Coleman

Cook

Hirsh

et al. 2010

Cancer

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Bone is the most common site for metastasis from solid tumors, and the majority of patients will develop bone metastases during the natural course of their disease. Bisphosphonates are an effective treatment for preventing skeletal-related events in patients with bone metastases and may preserve functional independence and quality of life. Although several bisphosphonates have been investigated in patients with solid tumors, only zoledronic acid (ZOL) is approved by the US Food and Drug Administration and the European Medicines Agency for preventing skeletalrelated events in patients across a broad range of solid tumors. In addition, bisphosphonates, notably ZOL, prevent cancer treatment-induced bone loss in breast and prostate cancer patients who are receiving endocrine therapy. It also has been demonstrated that ZOL directly and indirectly inhibits cancer cell growth in vitro and growth and tumorigenesis in animal model systems. These properties may produce clinically meaningful benefits. In recent clinical studies in patients with cancer, ZOL improved overall and prolonged disease-free survival. Ongoing clinical trials in patients with solid tumors will provide further insight into the potential of ZOL to prevent distant metastases and improve survival. Cancer 2011;117:11-23. V C 2010 American Cancer Society.KEYWORDS: adjuvant setting, bisphosphonate, bone metastases, cancer, survival, zoledronic acid.During the progression of cancer, many patients will develop distant metastases, for which a common site is bone. 1For example, an estimated 75% of patients with advanced breast cancer (BC) or prostate cancer (PC), and 40% of patients with advanced lung cancer (LC) develop bone metastases.2,3 Without bone-targeted therapies, most patients with bone metastases will experience potentially debilitating skeletal-related events (SREs), such as pathologic fractures, spinal cord compression, the need for surgery or palliative radiotherapy to bone, or hypercalcemia of malignancy.1 These SREs can have debilitating consequences and reduce quality of life and survival. 4 Moreover, declines in performance status resulting from SREs could preclude the receipt of chemotherapy and radiotherapy by patients with some solid tumors. 5Bisphosphonates, which are inhibitors of osteoclast-mediated bone resorption, currently are the standard of care for preventing SREs in patients with bone metastases.6 Several bisphosphonates currently are approved by the US Food and Drug Administration and the European Medicines Agency for preventing SREs in patients with metastatic BC and multiple myeloma (MM). In addition, the nitrogen-containing bisphosphonate (N-BP) zoledronic acid (ZOL) has received widespread regulatory approval for patients with bone involvement from PC, LC, and the entire range of other solid tumors (OSTs). 6 In randomized phase 3 trials, ZOL (4 mg intravenously [iv] every 3 to 4 weeks [monthly]) demonstrated significant efficacy in delaying the onset and reducing the risk of SREs and in palliating bone pain, reducing analges...

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“…Several studies have also evaluated the antitumor effect of bisphosphonate monotherapy in patients with asymptomatic/smoldering MM. [11][12][13][14][15][16] Although these studies demonstrated some benefit of bisphosphonates on bone resorption, no clear tumor responses or benefits in terms of progression-free or overall survival were observed. Patients with smoldering MM probably do not constitute the ideal target population for such studies because, given their low rate of progression, 24 a large number of patients and long follow up would be needed to demonstrate a survival benefit for a drug that would have only a minor antitumor activity, if any.…”

confidence: 99%

“…Moreover, in patients with smoldering MM, treatment with bisphosphonates did not delay transformation into symptomatic disease although it was associated with a reduction in the onset of skeletal-related events. [11][12][13][14][15][16] Accordingly, the real anti-tumor effect of bisphosphonates remains to be elucidated. Patients at biochemical relapse, in whom the standard of care is to delay treatment until symptoms emerge, represent an ideal group to investigate the anti-myeloma effect of ZA.…”

Section: Introductionmentioning

confidence: 99%

Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial

Oriol¹,

Moreno

Rubia

et al. 2015

Haematologica

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© F e r r a t a S t o r t i F o u n d a t i o n R. García-Sanz et al. 1208haematologica | 2015; 100(9)Myeloma Group (GEM/PETHEMA) in order to evaluate whether treatment with ZA delays the time to next therapy (TNT) in patients with MM in biochemical relapse, compared to the standard management with observation only. Methods Trial designIn 2010, GEM/PETHEMA activated the "Analysis of Zoledronic Acid therapy in MM in BioCHEmical relapses" (AZABACHE) trial. This randomized, prospective, open label, phase IV trial included MM patients in asymptomatic biochemical relapse after a prior response to standard therapy. Patients were randomly distributed into two groups: (i) the experimental group, in which patients received ZA, and (ii) the control group in which patients did not receive any treatment. Patients in the experimental group received zolendronic acid, 4 mg in a 15-minute intravenous infusion every 4 weeks, for a total of 12 doses, plus standard supportive care; the control group received only supportive care. The trial and all procedures were performed in accordance with the Helsinki Declaration and were reviewed and approved by the Spanish National Agency and the Ethics Committees of all the centers involved. Inclusion and exclusion criteriaAll patients had to meet the following inclusion criteria: (i) 18 years of age or older; (ii) confirmed biochemical relapse of MM after an initial response, without symptoms derived from the disease and (iii) signed informed consent to participation in the trial. Relapse was defined according to the IMWG criteria of 2006. 2Patients treated for any symptom of myeloma-related organ or tissue impairment or who had received bisphosphonates in the preceding 3 months were excluded; this meant that most patients had had a prior response longer than 24 months, which is the usual time that bisphosphonates are given in Spanish trials. 17 Variables for evaluationThe main end-point was TNT, which was calculated as the time that elapsed between inclusion in the protocol, and the moment at which new antimyeloma therapy was initiated based on the appearance of a clinical relapse or death from any cause. The appearance of a significant paraprotein relapse was not considered as a clinical relapse but it was qualified as a cause for initiating anti-myeloma when considering the TNT. Other end-points for evaluation were: (i) response rate during the follow-up period (12 months of therapy or follow-up, or until drop-out of the trial) according to the IMWG criteria; 3 (ii) time to clinical symptoms, defined as the time between inclusion in the trial and the development of a clinical (CRAB) relapse; 3 and (iii) time to a skeletal-related event, defined as the time between inclusion in the trial and the occurrence of any the following: bone fracture (vertebral and non-vertebral), requirement for bone radiotherapy, requirement for bone surgery, or hypercalcemia. The presence of osteonecrosis of the jaw and/or renal dysfunction was carefully assessed throughout the treatment and follow-up ...

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A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma

Cited by 166 publications

References 48 publications

Beta‐2‐microglobulin is an independent predictor of progression in asymptomatic multiple myeloma

Beta‐2‐microglobulin is an independent predictor of progression in asymptomatic multiple myeloma

Zoledronic acid use in cancer patients

Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial

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