Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study

D’Arena, Giovanni; Gobbi, Paolo G.; Broglia, Chiara; Sacchi, Stefano; Quarta, Giovanni; Baldini, Luca; Iannitto, Emilio; Falcone, Antonietta; Guariglia, Roberto; Pietrantuono, Giuseppe; Villani, Oreste; Martorelli, Maria Carmen; Mansueto, Giovanna; Sanpaolo, Grazia; Cascavilla, Nicola; Musto, Pellegrino

doi:10.3109/10428194.2011.553000

Cited by 85 publications

(45 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The response rate was 37% in the thalidomide arm (whereas no responses were seen in the zoledronate arm), but there were no significant differences in the TTP to symptomatic MM (4.3 vs. 3.3 years) or in OS (74% vs. 73% at 5 years) [41]. Earlier trials of bisphosphonate treatment demonstrated the absence ofclearantitumoral effects, whereas a strong effect on the bone metabolism was uniformly described with a significant reduction in the incidence of skeletal-related events [42][43][44][45]. Given the anabolic effects on bone metabolism, bisphosphonates are recommended for those SMM patients with osteoporosis identified by dualenergy x-ray absorptiometry scan in doses used for osteoporosis [46].…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

The Changing Landscape of Smoldering Multiple Myeloma: A European Perspective

et al. 2016

View full text Add to dashboard Cite

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and bridges monoclonal gammopathy of undetermined significance to multiple myeloma (MM), based on higher levels of circulating monoclonal immunoglobulin and bone marrow plasmocytosis without end-organ damage. Until a Spanish study reported fewer MM-related events and better overall survival among patients with high-risk SMM treated with lenalidomide and dexamethasone, prior studies had failed to show improved survival with earlier intervention, although a reduction in skeletal-related events (without any impact on disease progression) has been described with bisphosphonate use. Risk factors have now been defined, and a subset of ultra-high-risk patients have been reclassified by the International Myeloma Working Group as MM, and thus will require optimal MM treatment, based on biomarkers that identify patients with a >80% risk of progression. The number of these redefined patients is small (∼10%), but important to unravel, because their risk of progression to overt MM is substantial (≥80% within 2 years). Patients with a high-risk cytogenetic profile are not yet considered for early treatment, because groups are heterogeneous and risk factors other than cytogenetics are deemed to weight higher. Because patients with ultra-high-risk SMM are now considered as MM and may be treated as such, concerns exist that earlier therapy may increase the risk of selecting resistant clones and induce side effects and costs. Therefore, an even more accurate identification of patients who would benefit from interventions needs to be performed, and clinical judgment and careful discussion of pros and cons of treatment initiation need to be undertaken. For the majority of SMM patients, the standard of care remains observation until development of symptomatic MM occurs, encouraging participation in ongoing and upcoming SMM/early MM clinical trials, as well as consideration of bisphosphonate use in patients with early bone loss.

show abstract

Section: Therapeutic Strategiesmentioning

confidence: 99%

The Changing Landscape of Smoldering Multiple Myeloma: A European Perspective

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Early intervention in the high-risk SMM group would avoid development of CRAB criteria and thus improve patients' survival. The current practice guidelines of withholding treatment until end-organ damage develops put patients at risk of renal failure 6 and adverse skeletal events. 7 This strategy of delaying treatment does not only influence patients' morbidity and overall costs, but also mortality, since renal insufficiency at diagnosis of MM has been shown to predict for inferior survival 8 except when bortezomib was included in the upfront management.…”

Section: Introductionmentioning

confidence: 99%

Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120)

et al. 2015

View full text Add to dashboard Cite

© F e r r a t a S t o r t i F o u n d a t i o nGenomics of high-risk SMM haematologica | 2015; 100(9) 1215 Methods Eligibility criteria and study designPatients with SMM seen at the Myeloma Institute for Research and Therapy were included in a prospective, observational clinical trial (SWOG S0120) as part of a national cooperative group trial to identify biological correlates that may relate to progression to symptomatic disease. Other eligibility criteria included no prior therapy for the plasma cell disorder and willingness to submit samples for research. Diagnostic criteria for SMM were based on the International Myeloma Working Group convention.3 All patients signed informed consent, in keeping with the Declaration of Helsinki and federal and institutional guidelines. The protocol was approved by the National Cancer Institute and all participating centers' internal review boards.All patients underwent detailed clinical staging at initial registration, including full blood count, analysis of blood chemistry, and standard MM-related serological and urinary measurements. Nephelometric analysis was performed to determine serum immunoglobulin levels. Immunofixation analyses of serum and urine were performed to define the nature of the monoclonal protein present in serum and/or urine. Bone marrow aspirates and biopsies were obtained for cytological and histopathological evaluation of the degree of plasma cell infiltration, including immunohistochemical clonality assessment. Metaphase karyotyping was performed on at least 20 Giemsa-stained metaphases. 23 In most patients, serum FLC assays were used to quantify k and l light chains. Imaging studies involved standard metastatic bone surveys by X-ray examination, and, when possible, MRI of the entire spine was used to identify focal lesions. The minimum follow-up of patients involved MM-related laboratory studies at 3, 6, and 12 months in the first year, and then every 6 to 12 months. Gene expression profiling and statistical methodsA sample of bone marrow aspirate was collected to isolate CD138 + plasma cells with immunomagnetic bead selection (autoMACS; Miltenyi Biotec) as described elsewhere. 24 The purity of the plasma cells was monitored by flow cytometry and >85% purity was used as a criterion for inclusion of GEP data. Total RNA from these plasma cells was used for the GEP with Affymetrix U133 Plus 2.0 microarrays. We identified patients with SMM and baseline GEP data who were cared for at this institution. We evaluated 54,675 Affymetrix gene probes for their potential to predict time to myeloma therapy (TTT). Probes were ranked by their qvalues; 25 we used 10-fold cross validation to identify the number of genes at the top of this list, which collectively maximized the concordance between risk score and survival. Gene scores were computed by subtracting the sum of the expressions of the up-regulated probes from the sum of the expressions of the down-regulated probes, then dividing by the total number of probes. A running log-rank test was used to iden...

show abstract

“…This supports the findings of several other studies in which the use of bisphosphonates always translated into a reduction of skeletal-related events. 8,9,[11][12][13][14][15][16]22 This reduction in skeletal-related events could also help to explain why the overall survival was marginally favored by the use of ZA, with a more pronounced effect in patients with bone disease or skeletal-related events, as the MRC trial had already demonstrated. 9 However, the number of patients and differences in this study are limited, which should be taken into consideration when interpreting the results.…”

confidence: 99%

“…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%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

© 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 ...

show abstract

Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study

Cited by 85 publications

References 25 publications

The Changing Landscape of Smoldering Multiple Myeloma: A European Perspective

The Changing Landscape of Smoldering Multiple Myeloma: A European Perspective

Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120)

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

Contact Info

Product

Resources

About