A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma

Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine and Mayo Foundation, Rochester, MN, USA.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 08/2012; 27(1). DOI: 10.1038/leu.2012.236
Source: PubMed


Patients with asymptomatic (smoldering) multiple myeloma (AMM) have a high risk of transformation to active multiple myeloma (MM). Bisphosphonates such as zoledronic acid (ZLD) reduce skeletal events in MM and the immunomodulatory agent thalidomide (Thal) has proven effectiveness in active MM. We hypothesized that treatment with Thal and ZLD would prolong the time to progression (TTP) to MM over ZLD alone. Eligible patients had asymptomatic MM and all patients received ZLD 4 mg intravenous monthly; the treatment arm also received Thal 200 mg per day. The TTP was superior for Thal/ZLD (n=35) patients compared with ZLD alone (n=33); median TTP of 2.4 years (95% confidence interval (CI): 1.4-3.6) versus 1.2 years (95% CI: 0.7-2.5) (hazard ratio (HR), 2.05; 95% CI: 1.1-3.8; P-value: 0.02). At 1 year, 86% of Thal/ZLD patients were progression free compared with 55% on ZLD alone (P=0.0048). The overall response rate after year 1 was 37% for Thal/ZLD with a median duration of response of 3.3 years (95% CI: 1.1-NA); there were no confirmed responses to ZLD alone (P=0.0004). The addition of Thal to standard ZLD produces anti-tumor responses whereas ZLD alone does not. Thal/ZLD also prolongs TTP from AMM to MM. This study provides the rationale for further studies in patients with AMM to delay chemotherapy.Leukemia advance online publication, 2 October 2012; doi:10.1038/leu.2012.236.

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Available from: Shaji K Kumar, Jul 07, 2014
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    • "Investigators have since begun to carry out clinical trials to evaluate novel drugs and new combinations of existing treatments in SMM. From the year 2003 onwards, two phase randomized, controlled trials (RCTs) have been completed [19], [20] and one phase III RCT with 370 SMM patients is ongoing. Immuno-modulatory agents (IMiDs) were used in each of these three more recent RCTs. "
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    ABSTRACT: Purpose Whether patients with smoldering multiple myeloma (SMM) needed to receive early interventional treatment remains controversial. Herein, we conducted a meta-analysis comparing the efficacy and safety of early treatment over deferred treatment for patients with SMM. Methods MEDLINE and Cochrane Library were searched to May 2014 for randomized controlled trials (RCTs) that assessed the effect of early treatment over deferred treatment. Primary outcome measure was mortality, and secondary outcome measures were progression, response rate, and adverse events. Results Overall, 5 trials including 449 patients were identified. There was a markedly reduced risk of disease progression with early treatment (Odds Ratio [OR] = 0.13, 95% confidence interval [CI] = 0.07 to 0.24). There were no significant differences in mortality and response rate (OR = 0.85, 95% CI = 0.45 to 1.60, and OR = 0.63, 95% CI = 0.32 to 1.23, respectively). More patients in the early treatment arm experienced gastrointestinal toxicities (OR = 10.02, 95%CI = 4.32 to 23.23), constipation (OR = 8.58, 95%CI = 3.20 to 23.00) and fatigue or asthenia (OR = 2.72, 95%CI = 1.30 to 5.67). No significant differences were seen with the development of acute leukemia (OR = 2.80, 95%CI = 0.42 to 18.81), hematologic cancer (OR = 2.07, 95%CI = 0.43 to 10.01), second primary tumors (OR = 3.45, 95%CI = 0.81 to 14.68), nor vertebral compression (OR = 0.18, 95%CI = 0.02 to 1.59). Conclusions Early treatment delayed disease progression but increased the risk of gastrointestinal toxicities, constipation and fatigue or asthenia. The differences on vertebral compression, acute leukemia, hematological cancer and second primary tumors were not statistically significant. Based on the current evidence, early treatment didn’t significantly affect mortality and response rate. However, further much larger trials were needed to provide more evidence.
    PLoS ONE 10/2014; 9(10):e109758. DOI:10.1371/journal.pone.0109758 · 3.23 Impact Factor
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    • "Nitrogen-containing bisphosphonates, such as zoledronic acid, have a predominant role in the supportive therapy of MM patients [110] with benefit in survival [111–113]. Nitrogen-containing bisphosphonates inhibit bone resorbing osteoclasts, delay tumor growth rate as a consequence of MDSC depletion, and increased recruitment of T cells in murine models of solid tumors [99, 114]. However, no data are currently available about MDSC amount in MM patients treated with bisphosphonates. "
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    ABSTRACT: Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.
    BioMed Research International 06/2014; 2014(7):198539. DOI:10.1155/2014/198539 · 2.71 Impact Factor
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    • "Thalidomide is an anti-angiogenic drug [5] with a broad spectrum of current clinical applications ranging from therapy of multiple myeloma [6] to erythema nodosum leprosum [7]. In addition to these clinical applications, different studies proved the molecular effects of thalidomide to reduce systemic and local tumor necrosis factor alpha (TNF-α) production and VV neovascularisation in early atherosclerotic lesions with a concomitant decrease of lesion growth [8–10]. "
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    ABSTRACT: Plaque progression in atherosclerosis is closely connected to angiogenesis due to vasa vasorum (VV) growth. Objective of this study was to determine the unknown long-term effect of thalidomide on adventitial VV neovascularization and plaque progression using nano-focussed computed tomography (nano-CT). Proliferation and migration assays in human coronary artery endothelial cells (HCAEC) measured number of viable cells after incubation with thalidomide. Male ApoE(-/-)/LDLR(-/-) (AL) mice (n = 5) received a thalidomide containing western diet (WD) over 29 weeks. Another five male AL mice (WD without thalidomide) served as control group. Descending aortas were scanned with nano-CT at (1.5 μm)(3) isotropic voxel size. Number and area of adventitial VV as well as plaque cross sectional area were measured. Results were complemented by histology. Thalidomide inhibited proliferation and migration of HCAEC dose-dependently. VV neovascularization decreased in number per cross section (7.66 ± 0.301 vs. 8.62 ± 0.164, p < 0.001) and in cross sectional area (0.0183 ± 0.0011 vs. 0.0238 ± 0.0008 mm(2), p < 0.001). Cross sectional area of plaque decreased significantly when treated with thalidomide (0.57 ± 0.0187 vs. 0.803 ± 0.0148 mm(2), p < 0.001). Nano-CT imaging revealed a reduced plaque growth and VV neovascularization after long-term application of thalidomide. Therefore, nano-CT can be considered as a new method to detect therapeutic effects in experimental models of atherosclerosis.
    The international journal of cardiovascular imaging 02/2014; 30(4). DOI:10.1007/s10554-014-0380-5 · 1.81 Impact Factor
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