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- Consensus statements
On February 25, 2009, a panel of international experts on plasma cell dyscrasia and skeletal disease met to discuss monoclonal gammopathy of undetermined significance (MGUS). This non-malignant B-cell disorder is the most common plasma cell dyscrasia and is associated with an increased risk of developing serious B-cell disorders. Individuals with MGUS also have an increased risk of osteoporosis and osteopenia associated with an increased likelihood of developing fractures especially in the vertebral column, peripheral neuropathy and thromboembolic events. The goal of the meeting was to develop a consensus statement regarding the appropriate tests to screen, evaluate and follow-up patients with MGUS. The panel also addressed the identification and treatment of MGUS-related skeletal problems, thromboembolic events and neurological complications. The following consensus statement outlines the conclusions and marks the first time that a consensus statement for the screening and treatment of MGUS has been clearly stated.
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- Consensus statements
A. Prevention of serious B-cell disorders
Although patients with MGUS are at increased risk to develop more serious B-cell disorders, no treatment to prevent this outcome has been established as effective. The low rate of development of serious B-cell disorders (1%/year) among patients with MGUS means that any studies to determine the efficacy of interventions to prevent this must involve very large numbers of patients with long follow-up (>10 years). However, recent advances in identification of individuals at higher risk for transformation may allow the design of trials that can be completed in a reasonable time frame with much smaller numbers of MGUS patients.
Because MGUS individuals show a much higher degree of bone loss and fractures than age- and sex-matched controls (Jakob et al, 2002; Melton et al, 2004; Politou et al, 2004; Pepe et al, 2006; Bida et al, 2009), prevention and treatment of bone-related problems is important in these patients. The frequent occurrence of Vitamin D deficiency in the elderly (Omdahl et al, 1982; Gloth et al, 1995) – a population at high risk for MGUS (International Myeloma Working Group, 2003) – makes it important to assess serum levels of this vitamin at baseline. Regardless, MGUS patients with T-scores ≤ −1 should maintain an oral intake of 800–1000 iu/d vitamin D, and be instructed to maintain a calcium intake (dietary, plus supplemental if necessary) of between 1200 and 1500 mg/d. For those patients who are found to be vitamin D-deficient, vitamin D supplementation should be increased accordingly, and periodic testing of 25-hydroxyvitamin D levels should be performed.
b. Anti-bone resorptive therapy
We recommend that MGUS patients who have evidence of VCFs or who are osteoporotic be initiated on anti-bone resorptive therapy, and that MGUS patients with osteopenia be strongly considered for this type of treatment. Recent results showed the ability of bisphosphonates to improve bone density in this clinical setting (Berenson et al, 2008; Pepe et al, 2008). A recent open-label study of 54 patients with MGUS and either osteoporosis or osteopenia demonstrated that zoledronic acid 4 mg significantly improved bone density when administered at 0, 6 and 12 months (Berenson et al, 2008). After 13 months of treatment, BMD of the posteroanterior lumbar spine and nondominant proximal femur increased by 22% and 8%, respectively. A second study that included MGUS patients with evidence of either osteoporosis or VCFs showed that 18 months of treatment with oral alendronate 70 mg/week increased BMD 6·1% in the lumbar spine and 1·5% in the hip (Pepe et al, 2008). Importantly, neither study was powered to assess fracture outcomes as a primary endpoint. No randomized studies comparing these two bisphosphonates to placebo or each other in MGUS patients have been completed to date. However, since the MGUS patients in these trials, unlike cancer patients, were not on other treatments that may have improved their bone density, these two studies suggest the benefits of bisphosphonates for treatment of MGUS-associated osteopenia/osteoporosis. Certainly, other classes of drugs have proven effective in the setting of osteoporosis without cancer including calcitonin, raloxifene, teriparatide, other orally administered bisphosphonates and, most recently, the receptor for activation of nuclear factor-κB ligand inhibitor, denosamab (Overgaard et al, 1992; Lieberman et al, 1995; Ettinger et al, 1999; Harrington et al, 2004; McClung et al, 2006; Saag et al, 2007), but whether these drugs would be effective for patients with MGUS is unknown. Moreover, denosumab has received favorable support from regulatory advisory committees in both Europe and the United States but it has not yet been approved. Although teriparatide, raloxifene and calcitonin are approved for the treatment of osteoporosis in the benign setting and may be considered alternative therapies for MGUS subjects with osteoporosis, the panel favors the use of bisphosphonates for their superior anti-fracture efficacy among patients with osteoporosis and their demonstrated ability to improve bone density in the setting of MGUS with bone loss. At present, the data are insufficient to recommend only zoledronic acid for the management of MGUS patients with osteoporosis or osteopenia at a dosing schedule (every 6 months) as shown to be effective in a single-arm clinical trial (Berenson et al, 2008) but is more frequent than that which is currently Food and Drug Administration (FDA)-approved for the standard therapy of osteoporosis from benign causes (annually). Other bisphosphonates licensed for the treatment of osteoporosis, including alendronate or risedronate administered orally once weekly, may also be administered in the setting of MGUS, as we described from the positive results of the alendronate trial (Pepe et al, 2008). In terms of duration of therapy, data from the Fracture Intervention Trial Long-term Extension study suggests that 10 years of alendronate therapy did not significantly reduce the incidence of all fractures but did reduce clinically recognized VCFs compared to 5 years of treatment in the setting of osteoporosis from benign causes (Black et al, 2006). However, whether these results apply to patients with a higher risk of fractures, especially in the vertebral bodies, in the setting of MGUS is unknown. Thus, we would recommend 5 years of initial therapy and then a discussion between the patient and health care provider regarding whether to continue the treatment based on updated results from clinical trials and the relative perceived benefits compared to risk of continued treatment with bisphosphonates.
While side effects associated with bisphosphonate treatment may occur, zoledronic acid 4 mg every 6 months when administered to MGUS or other cancer patients has not been associated with an increased incidence of the most serious complications including osteonecrosis of the jaw (ONJ) or renal impairment (Brufsky et al, 2007; Berenson et al, 2008). Nonetheless, MGUS patients receiving bisphosphonates should be monitored for these potential harmful side effects. Patients receiving bisphosphonate therapy should visit their dentist before treatment begins and at least once a year during treatment. This will facilitate early detection and treatment of potential dental problems that may increase the risk of ONJ (Bagan et al, 2007).
2. Skeletal evaluation and consideration for surgical management
As mentioned previously, persons with MGUS are at increased risk for fractures, especially involving the vertebral bodies (Melton et al, 2004; Gregersen et al, 2006). Patients in whom fractures are identified should be further evaluated by a bone specialist. Other reasons to visit a bone specialist include prolonged or increased back pain for more than 4–6 weeks, new onset of soft tissue swelling, deep bone pain, or an increase in the requirement for pain medication. Patients who are clinically considered at high risk based upon physical examination for a VCF (e.g. those with significant back pain) should undergo an MRI with sagittal short tau inversion recovery sequences to image osseous oedema. These individuals may also be more likely to have MM, and it is important to rule out this diagnosis in this high-risk group.
For patients with painful VCFs regardless of whether these fractures are from malignant or non-malignant causes, balloon kyphoplasty has proven to be a safe and efficient minimally invasive surgical technique with a quick recovery time that markedly reduces bone pain and improves quality of life (Lieberman et al, 2001; Berenson et al, 2009; Wardlaw et al, 2009); and, thus, this procedure should be considered for MGUS patients with symptomatic VCFs. In a randomized trial of cancer patients (median age of 64 years, range 40–88 years; 37% with MM) with VCFs, kyphoplasty markedly improved Roland-Morris Disability and pain scores compared to patients who received non-surgical interventions (Berenson et al, 2009). The number of adverse events was not different between the two groups. In a recent randomized trial involving 300 patients with VCFs without malignancy except in four cases (median age of 73 years), kyphoplasty significantly improved short-form (SF)-36 physical component summary scores compared to controls (Wardlaw et al, 2009). In addition, kyphoplasty, unlike vertebroplasty (see below), also confers the added benefit of potential height restoration, which can help to correct altered biomechanics (Shen & Kim, 2006). As this procedure has been shown to be effective and without significant morbidity for both cancer and non-cancer patients with VCFs, it is likely to offer similar benefits for MGUS patients with VCFs although no specific studies have been done in this patient population.
Vertebroplasty is another minimally invasive procedure which has been used to reduce pain for patients with VCFs. However, two recent double-blind, randomized studies showed that patients treated with vertebroplasty had no benefits compared to those undergoing a sham procedure as assessed with Roland Morris Disability and pain scores (Buchbinder et al, 2009; Kallmes et al, 2009). Vertebroplasty has also been associated with rare but serious local neurological and cardiopulmonary complications resulting from cement extravasation, leakage and embolization (Orsini et al, 1987; Pinto, 1993; Padovani et al, 1999; Ratliff et al, 2001). The incidence of cement extravasation ranges from 30% to 70% after vertebroplasty compared with less than 10% after kyphoplasty (Chiras et al, 1997; Hulme et al, 2006; Taylor et al, 2006), and more serious complications are observed less frequently with kyphoplasty (Atalay et al, 2005).
Patients with MGUS are more likely to experience PN in some (Kelly et al, 1981) but not all studies (Bida et al, 2009), and effective treatments for this complication have involved corticosteroids (Roglio et al, 2008), plasmapheresis (Cornblath et al, 1987; Dyck et al, 1991) and rituximab (Zaja et al, 2003). The panel suggested that, in the majority of patients, the risks and side effects of these treatments outweigh the potential benefits. In patients with more significant symptoms and morbidity, these treatments may be necessary. Alternative treatments, such as α-lipoic acid (Ziegler et al, 1995, 1999; Reljanovic et al, 1999), acetyl-Lcarnitine (Bianchi et al, 2005; Maestri et al, 2005), benfotiamine (Simeonov et al, 1997; Haupt et al, 2005), methylcobalamin (Ide et al, 1987; Yaqub et al, 1992), and topical capsaicin (Scheffler et al, 1991; Capsaicin Study Group, 1992), have been extensively used and may offer benefit without the adverse event and addiction profiles that may occur with other PN treatments. More recently, gabapentin and pregabalin have been used to palliate these symptoms in some patients (Tsavaris et al, 2008; Vondracek et al, 2009). Importantly, these therapeutic options have been studied most extensively in diabetic neuropathy but these treatments have also been used in the oncological setting.
Although individuals with MGUS have been shown to be at higher risk to develop DVTs in most (Sallah et al, 2004; Srkalovic et al, 2004; Kristinsson et al, 2008) but not all studies (Bida et al, 2009), routine anticoagulation was not recommended by the panel. However, physicians should be aware of this heightened risk in MGUS compared to non-MGUS individuals. This is likely to lead to diagnosis and treatment of DVTs that may have otherwise gone undetected.