Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. A phase 2 trial of combination therapy with thalidomide, arsenic trioxide, dexamethasone, and ascorbic acid (TADA) in patients with overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) or primary myelofibrosis (PMF) Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. Facilitating exercise adherence for patients with multiple myeloma. UK clinical guideline for the prevention and treatment of osteoporosis The Role of High-Dose Chemotherapy and Stem-Cell Transplantation in Patients with Multiple Myeloma: A Practice Guideline of the Cancer Care Ontario Practice Guidelines Initiative Recommendations for the Use of White Blood Cell Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. Multiple myeloma: effect of daily dichloromethylene bisphosphonate on skeletal complications Long-term effects of dichloromethylene diphosphonate (CI2MDP) on skeletal lesions in multiple myeloma. An open‐label, phase 2 trial of denosumab in the treatment of relapsed or plateau‐phase multiple myeloma Implementing an intervention to improve bone mineral density in survivors of childhood acute lymphoblastic leukemia: BONEII, a prospective placebo-controlled double-blind randomized interventional longitudinal study design. A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma A randomized phase 2 trial of a preparative regimen of bortezomib, high‐dose melphalan, arsenic trioxide, and ascorbic acid Effect of daily etidronate on the osteolysis of multiple myeloma. De-escalated administration of bone-targeted agents in patients with breast and prostate cancer—A survey of Canadian oncologists Fewer bone disease events, improvement in bone remodeling, and evidence of bone healing with bortezomib plus melphalan-prednisone vs. melphalan-prednisone in the phase III VISTA trial in multiple myeloma. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group.
Multiple myeloma is a malignant plasma cell neoplasm that affects more than 20,000 people each year and is the second most common hematologic malignancy . It is part of a spectrum of monoclonal plasma cell disorders , many of which do not require active therapy . During the past decade , considerable progress has been made in our underst and ing of the disease process and factors that influence outcome , along with development of new drugs that are highly effective in controlling the disease and prolonging survival without compromising quality of life . Identification of well-defined and reproducible prognostic factors and introduction of new therapies with unique modes of action and impact on disease outcome have for the first time opened up the opportunity to develop risk-adapted strategies for managing this disease . Although these risk-adapted strategies have not been prospect ively vali date d , enough evidence can be gathered from existing r and omized trials , subgroup analyses , and retrospective studies to develop a working framework . This set of recommendations represents such an effort-the development of a set of consensus guidelines by a group of experts to manage patients with newly diagnosed disease based on an interpretation of the best available evidence Primary myelofibrosis ( PMF ) and overlap myelodysplastic/myeloproliferative neoplasms ( MDS/MPN ) are clonal hematopoietic disorders that share similar clinical features and molecular abnormalities , such as the Janus kinase 2 ( JAK2 ) valine to phenylalanine mutation at codon 617 ( V617F ) and the tet methylcytosine dioxygenase 2 ( TET2 ) mutation . There are limited therapeutic options available for these diseases , and single agents have only modest efficacy . In this phase 2 study , the authors combined multiple active agents ( thalidomide , arsenic trioxide , dexamethasone , and ascorbic acid [ TADA ] ) to treat patients with these disorders BACKGROUND Skeletal complications are a major clinical manifestation of multiple myeloma . These complications are caused by soluble factors that stimulate osteoclasts to resorb bone . Bisphosphonates such as pamidronate inhibit osteoclastic activity and reduce bone resorption . METHODS Patients with stage III multiple myeloma and at least one lytic lesion received either placebo or pamidronate ( 90 mg ) as a four-hour intravenous infusion given every four weeks for nine cycles in addition to antimyeloma therapy . The patients were stratified according to whether they were receiving first-line ( stratum 1 ) or second-line ( stratum 2 ) antimyeloma chemotherapy at entry into the study . Skeletal events ( pathologic fracture , irradiation of or surgery on bone , and spinal cord compression ) , hypercalcemia ( symptoms or a serum calcium concentration > or = 12 mg per deciliter [ 3.0 mmol per liter ] ) , bone pain , analgesic-drug use , performance status , and quality of life were assessed monthly . RESULTS Among 392 treated patients , the efficacy of treatment could be evaluated in 196 who received pamidronate and 181 who received placebo .  The proportion of patients who had any skeletal events was significantly lower in the pamidronate group ( 24 percent ) than in the placebo group ( 41 percent , P < 0.001 ) , and the reduction was evident in both stratum 1 ( P = 0.04 ) and stratum 2 ( P = 0.004 ) . The patients who received pamidronate had significant decreases in bone pain and no deterioration in performance status and quality of life .  Pamidronate was tolerated well . CONCLUSIONS Monthly infusions of pamidronate provide significant protection against skeletal complications and improve the quality of life of patients with stage III multiple myeloma Physical exercise is becoming an accepted part of therapy for many patients with cancer .  Exercise may alleviate patients ' fatigue and improve physical performance and psychological outlook . Much of the research is limited to women with breast cancer and excludes patients with bone metastases . This article reports on the authors ' work in facilitating exercise adherence for patients with multiple myeloma ( MM ) and bone lesions while they were enrolled in a feasibility/pilot exercise study as they were receiving treatment for their disease in an outpatient treatment program . The exercise program for these patients receiving high-dose chemotherapy and stem cell transplantation consisted of aerobic and strength-building components . The program was home based , and patients performed exercises without direct supervision . On average , the patients completed the six-month exercise prescription 75 % of the time . Overall trends showed that all 14 patients in the exercise group  improved in several areas of testing , and the test results of all 10 patients in the usual-care group declined . Flexibility and simplicity are essential when design ing exercise programs for patients , and encouragement and support also are needed to help patients adhere to prescribed exercise Introduction In 2008 , the UK National Osteoporosis Guideline Group ( NOGG ) produced a guideline on the prevention and treatment of osteoporosis , with an up date in 2013 . This paper presents a major up date of the guideline , the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women and men age 50 years or over . Methods Where available , systematic review s , meta-analyses and r and omised controlled trials were used to provide the evidence base . Conclusions and recommendations were systematic ally grade d according to the strength of the available evidence . Results Review of the evidence and recommendations are provided for the diagnosis of osteoporosis , fracture-risk assessment , lifestyle measures and pharmacological interventions , duration and monitoring of bisphosphonate therapy , glucocorticoid-induced osteoporosis , osteoporosis in men , postfracture care and intervention thresholds . Conclusion The guideline , which has received accreditation from the National Institute of Health and Care Excellence ( NICE ) , provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals who are involved in its management After more than three decades of clinical trials testing various st and ard-dose chemotherapy regimens , the disease course of patients with multiple myeloma has not changed appreciably . Conventional chemotherapy can provide effective palliation but is not curative ( 1 ) . Case series have described encouraging results in patients with myeloma undergoing allogeneic or autologous bone marrow or peripheral blood stem-cell transplantation ( 2 ) . Other studies of transplantation , including r and omized trials , have been reported in the past 6 years ( 3 , 4 ) . To facilitate decisions about treatment options , practice guidelines have been developed for use by health care providers and consumers . In Ontario , Canada , cancer treatments and policies are led by a state-funded organization , Cancer Care Ontario . To help derive treatment options , Cancer Care Ontario has developed the Program in Evidence -Based Care , which includes the Practice Guidelines Initiative . Disease Site Groups ( DSGs ) , which comprise physicians , epidemiologists , and consumers , develop guidelines through a systematic process that involves assessment of evidence , consensus , and a validation process involving practitioners from across the province . Guideline topics are chosen through a prioritization process that includes the burden of illness , availability of evidence , perceived variation in practice , the potential to affect treatment decisions , and re source utilization . The Hematology DSG noted that the use of transplantation for patients with myeloma varied among practice s across the province . Variability in practice and emerging evidence of higher quality made this a priority topic for guideline development . To approach this topic , the DSG addressed the following questions : What is optimal st and ard-dose chemotherapy for patients with myeloma ? In terms of survival , is  peripheral blood stem-cell  or  marrow transplantation better than conventional chemotherapy ? What is the relative efficacy of autologous versus allogeneic transplantation ? What specifics of the transplantation process can be recommended ? When should transplantation be performed ? Who should ( or should not ) receive a transplant ? Methods Overview of Guideline Development This guideline was developed by the Cancer Care Ontario Practice Guidelines Initiative ( CCOPGI ) using the methods of the Practice Guidelines Development Cycle ( 5 ) . Members of the CCOPGI 's Hematology DSG selected , review ed , and interpreted the evidence . This DSG comprises 25 members , including hematologists , medical and radiation oncologists , an epidemiologist , and 2 lay representatives . Several of the physician members have background training in epidemiology ; 8 hematologists regularly perform stem-cell transplantation in clinical practice . The DSG 's draft recommendations were circulated through a mailed survey to hematologists and medical or radiation oncologists in Ontario for feedback and involvement in a consensus process . Responses were used to guide the reformatting of the draft into the final guideline recommendations . The Practice Guidelines Co-ordinating Committee ( PGCC ) , which ensures consistency of guideline development across the DSGs of various tumor sites , approved the guideline . The CCOPGI has a st and ardized process to up date each guideline report ; the current guideline was up date d and review ed by the PGCC in October 2000 . Literature Search Strategy We search ed the MEDLINE , CANCERLIT , and Cochrane Library data bases for literature published from 1992 to December 1997 and subsequently up date d the search in October 1998 , June 1999 , and April 2000 . For the search es , we combined multiple myeloma ( as a Medical Subject Heading [ MeSH ] and text word ) with bone marrow transplantation ( MeSH and text word ) and drug therapy ( MeSH ) . Then , we combined these terms with the search terms for the following study design s : practice guidelines ; systematic review s or meta-analyses ; review s ; r and omized , controlled trials ; controlled clinical trials ; and comparative studies . In addition , we search ed the PubMed and Physician Data Query ( PDQ ) ( www.cancer.gov/ search / clinical _ trials/ ) data bases and review ed relevant conference proceedings ( American Society of Hematology , 1997 to 1999 , and American Society of Clinical Oncology , 1999 to 2000 ) , article bibliographies , and personal files . To address the issue of optimal chemotherapy , we performed an additional search of the same data bases using the term multiple myeloma ( MeSH ) combined with r and omized , controlled trials ( MeSH ) and the text word r and om in the title . Inclusion Criteria We selected study reports meeting one of the three following criteria : r and omized trial or meta- analysis of therapy for patients with myeloma that reported survival or quality -of-life outcomes ; nonr and omized comparative trial that addressed transplantation strategy , including a contemporaneous control group , and that reported survival or quality -of-life outcomes ; or economic evaluation that addressed transplantation strategy . Because of insufficient data on the specifics of the transplantation process and the patients who would be most likely to benefit from transplantation , we performed a second search , which identified data from noncomparative case-series studies . Data Extraction and Interpretative Summary Three members of the DSG , including an epidemiologist , determined eligibility of the articles and abstract s obtained from the literature search . The lead DSG member for this guideline extracted and summarized relevant data according to the guideline question addressed . The DSG members then review ed the summarized data and key articles . The DSG met formally three to four times annually ; at these meetings , the members method ologically assessed the articles , interpreted the data , and debated specific points in an attempt to reach a consensus . Synthesizing the Evidence Because all of the nine r and omized trials on transplantation addressed different questions , we did not statistically pool the data . DSG Consensus Process Through an iterative process that included debate at formal meetings and circulation of draft recommendations , we considered the implication s of the appraised data for each guideline question . With this process , attempts were made to reach consensus ; when this was impossible , minority opinions were recorded . Approval by each member of the DSG was required before circulation of the draft version for practitioner feedback and su bmi ssion of the final guideline to the PGCC . Practitioner Feedback To obtain practitioner feedback , we mailed a survey to 211 practitioners in Ontario ( 94 hematologists , 93 medical oncologists , and 24 radiation oncologists ) . The survey consisted of st and ardized items asking the practitioner to rate the quality of each draft guideline and to judge whether the draft recommendations should serve as a practice guideline . Written comments were invited . Follow-up reminders were sent at 2 weeks ( by postcard ) and 4 weeks ( entire package ) . After exclusion of 18 retired practitioners , 137 of 193 practitioners ( 71 % ) responded ; 90 of 137 respondents ( 66 % ) indicated that the guideline was relevant to their practice . Approval of the draft guideline was strong among these 90 practitioners : 91 % agreed or strongly agreed that the summary of the evidence was acceptable , 87 % agreed with the draft recommendations , and 81 % approved of the recommendations as a practice guideline . Thirty-nine respondents provided written comments ; these comments were , like the other responses , incorporated in the final guideline . Results Sixty-six reports met the criteria for inclusion and are categorized in Table 1 . In each section below , we describe the studies , summarize results , and describe the guideline development . Table 1 . Evidence Included in This Practice Guideline Report What Is Optimal St and ard-Dose Chemotherapy  for Patients with Multiple Myeloma ? To properly compare transplantation with conventional chemotherapy , we must define optimal conventional chemotherapy . We identified 30 r and omized trials comparing therapies in previously untreated patients . Four meta-analyses ( 6 - 9 ) evaluated these data . The Myeloma Trialists ' Collaborative Group ( 7 ) compared combination chemotherapy with melphalan plus prednisone in a meta- analysis of 27 trials . Twenty of these trials supplied individual-patient data . No difference in survival was detected . The proportional reduction in the annual odds of death was 1.5 % in favor of combination chemotherapy ( 95 % CI , 8 % to 5 % ; P > 0.2 ) , with an odds ratio ( OR ) of 0.99 ( CI , 0.93 to 1.05 ) . An earlier literature -based meta- analysis ( 6 ) of 18 trials also failed to detect a survival difference between groups ( OR , 1.04 [ CI , 0.90 to 1.19 ] ; P > 0.2 ) . Two meta-analyses evaluated interferon for multiple myeloma . An overview of 24 r and omized trials published in abstract form ( 8) demonstrated that interferon improved recurrence-free survival by 6 months and improved 3-year overall survival by 4 % . Another meta- analysis ( 9 ) measured survival by a unique measure called the mean lifetime survival . This meta- analysis found no difference in survival rate between the group receiving interferon and the group not receiving interferon ( 3.9 vs. 3.4 years , respectively ; P = 0.095 ) . Guideline Recommendation Multiagent chemotherapy or melphalan plus prednisone is appropriate therapy for a control group in a comparison of transplantation versus st and ard-dose therapy . The addition of interferon is unlikely to influence outcomes in the control group . In Terms of Survival , Is Autologous Peripheral Blood Stem-Cell or Bone Marrow Transplantation Better than Conventional Chemotherapy ? We review ed two r and omized and three nonr and omized comparisons ( Table 2 ) . Attal and colleagues ( 3 ) r and omly assigned 200 previously untreated patients younger than 65 years of age with stage II or III ( 40 ) myeloma to conventional chemotherapy or to a strategy that included autologous bone marrow transplantation . Patients were r and omly Purpose To up date the 2006 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors ( CSFs ) . Methods The American Society of Clinical Oncology convened an Up date Committee and conducted a systematic review of r and omized clinical trials , meta-analyses , and systematic review s from October 2005 through September 2014 . Guideline recommendations were based on the review of the evidence by the Up date Committee . Results Changes to previous recommendations include the addition of tbo-filgrastim and filgrastim-sndz , moderation of the recommendation regarding routine use of CSFs in older patients with diffuse aggressive lymphoma , and addition of recommendations against routine dose-dense chemotherapy in lymphoma and in favor of high – dose-intensity chemotherapy in urothelial cancer . The Up date Committee did not address recommendations regarding use of CSFs in acute myeloid leukemia or myelodysplastic syndromes in adults . Recommendations Prophylactic use of CSFs to reduce the risk of febrile neutropenia is warranted when the risk of febrile neutropenia is approximately 20 % or higher and no other equally effective and safe regimen that does not require CSFs is available . Primary prophylaxis is recommended for the prevention of febrile neutropenia in patients who are at high risk on the basis of age , medical history , disease characteristics , and myelotoxicity of the chemotherapy regimen . Dose-dense regimens that require CSFs should only be used within an appropriately design ed clinical trial or if supported by convincing efficacy data . Current recommendations for the management of patients exposed to lethal doses of total-body radiotherapy , but not doses high enough to lead to certain death as a result of injury to other organs , include the prompt administration of CSFs . J Clin Oncol 33:3199 - 3212 . © 2015 by American Society of Clinical Summary In 1989 , a prospect i ve r and omized multicenter study was initiated in order to determine the safety and efficacy of oral clodronate in myeloma patients . The primary objective of this long-term trial is to evaluate whether supportive clodronate is able to prevent or retard the progression of bone disease and reduce the occurrence of characteristic complications : pain , pathologic fractures , and hypercalcemia . We now report first results as an interim analysis , including data obtained from 26 patients ( total number of Tübingen patients n=36 ) who entered the study at theMedizinische Universitätsklinik Tübingen . Patients were r and omized to receive either chemotherapy alone ( melphalan 15 mg/m2 i.v .  on day 1 and prednisolone 60 mg/m2 orally on days 1–4  every 4 weeks ( control group ) or in combination with 1600 mg clodronate/day orally as a single dose for a period of at least 1 year . Repeated radiologic examinations in addition to hematologic and biochemical analysis were performed in order to evaluate the skeletal status with respect to lytic bone lesions and osteoporosis and the course of serum M protein and light chain excretion into urine . Clodronate treatment result ed in a significant decrease of serum calcium concentrations and of biochemical indices for bone resorption . No  clodronate-related toxicity or hypocalcemia was oberved . In patients treated with chemotherapy alone , this effect was less marked and discontinuous . Clodronate-treated patients developed fewer progressive bone lesions ( significant for lytic , not for osteoporotic lesions ) . No hypercalcemic episodes occurred in the clodronate-treated patients , but there were six episodes in the control group . Whereas the number of vertebral fractures was evidently less is clodronate-treated patients , three of those patients suffered from multiple fractures of long bones and ribs . All together , 12 pathologic fractures occurred in five clodronate-treated patients , whereas in the control group 23 pathologic fractures occurred in the same number of patients during the whole observation period . The final analysis of all multicenter included patients should clarify these findings . There was a significant finding that clodronate proved to have an analgesic effect We report the long-term effects of dichloromethylene diphosphonate ( CI2MDP ) , an inhibitor of bone resorption , on the skeletal lesions in multiple myeloma . Thirteen patients received either CI2MDP 1600 mg/d ( seven patients ) or a placebo ( six patients ) in addition to other chemotherapy  , and the effects of treatment were followed over a period of up to 18 months in a double-blind study . CI2MDP treatment result ed in a marked reduction in bone pain , with no progression of radiologic skeletal lesions during the first year . This contrasted with a clinical deterioration and the occurrence of new fractures in half of the patients receiving the placebo . Two patients with  hypercalciuria  and increased excretion of hydroxyproline before treatment had normalized values following CI2MDP . Finally , iliac crest bone biopsies showed a reduction in osteoclast number after CI2MDP administration . We conclude from these results that CI2MDP could be of use in preventing the bone loss that occurs in multiple myeloma RANKL is a key mediator of osteoclast differentiation , activation , and survival . Pre clinical data suggest that aberrant production and activation of osteoclasts may influence proliferation of multiple myeloma ( MM ) cells in the bone marrow . Reports have also shown that inhibiting RANKL may have a direct effect on RANK‐expressing myeloma cells and a therapeutic role in treating the disease . In mouse myeloma models , inhibition of RANKL led to reduced serum paraprotein levels and tumor burden . Based on this hypothesis , this proof‐of‐concept , single‐arm study investigated whether RANKL inhibition with denosumab could reduce serum M‐protein levels in relapsed or plateau‐phase myeloma subjects . All subjects received denosumab monthly , with loading doses on days 8 and 15 of month one , until disease progression or subject discontinuation . Results of this ongoing study demonstrated that no subjects in either cohort met the protocol ‐defined objective response criteria of complete response ( CR ) or partial response ( PR ) , but that denosumab effectively inhibited the RANKL pathway regardless of previous exposure to bisphosphonates , as evidence d by suppressed levels of the bone turnover marker , serum C‐terminal telopeptide of type 1 collagen ( sCTx ) . Eleven ( 21 % ) subjects who relapsed within 3 months before study entry maintained stable disease for up to 16.5 months . Nineteen ( 46 % ) subjects with plateau‐phase myeloma maintained stable disease for up to 18.3 months . The adverse event ( AE ) profile for denosumab and its dosing schedule in these population s was consistent with that for advanced cancer patients receiving systemic therapy . Additional controlled clinical studies of denosumab in subjects with both relapsed and plateau‐phase MM are warranted . Am . J. Hematol . 2009 . © 2009 Wiley‐Liss , The BONEII study is a large two-phase study . The baseline study ( Study 1 ) aims to estimate the prevalence of diminished bone mineral density ( BMD ) in patients treated for childhood acute lymphoblastic leukemia ( ALL ) and identify risk factors for BMD deficits . The interventional phase ( Study 2 ) of BONEII has a placebo-controlled double-blind r and omized longitudinal design to evaluate the effects of nutritional counseling and calcium and vitamin D supplementation on changes in BMD and serum and urine markers of bone metabolism . The extensive information being collected through this large study will serve as a repository of relational data about BMD and bone turnover and will support further investigations to assess the association of calcium metabolism , bone turnover , nutritional intake , lifestyle factors ( such as exercise and the use of alcohol and tobacco ) , and the specific agents used in ALL therapy in this rapidly increasing population of childhood cancer survivors Bisphosphonates ( BPs ) are effective in the prevention and treatment of skeletal‐related events ( SREs ) in patients with symptomatic myeloma who are receiving chemotherapy . Recent data also suggest a possible antineoplastic activity of BPs . Few studies published to date have explored the role of BPs in patients with untreated , asymptomatic myeloma ( AM ) . No data are available on the efficacy of zoledronic acid in these patients Bortezomib is active for newly diagnosed and relapsed multiple myeloma , and it has synergistic activity with melphalan . The authors of this report conducted a r and omized trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide ( ATO ) , ascorbic acid ( AA ) , and melphalan Progressive bone disease in multiple myeloma frequently leads to osteolysis , bone resorption , pathologic fractures , vertebral compression , and hypercalcemia . We conducted a double-blind study in 173 newly diagnosed multiple myeloma patients of etidronate disodium ( EHDP ) , a diphosphonate compound that reduces bone resorption by inhibiting osteoclastic activity . The patients were r and omly assigned to receive oral EHDP 5 mg/kg/d or placebo until death or discontinuation due to intolerance or refusal . The extent of vertebral deformity was measured by a vertebral index as well as height . The frequency of pathologic fractures , hypercalcemia , and bone pain was regularly assessed , as well as size and number of osteolytic lesions . All patients received melphalan and prednisone daily for 4 days every 4 weeks as the primary chemotherapy for their disease . Although the repeated measures analysis showed a significant height loss , there was no difference between treatment arms ( P = .98 ) . There was no significant difference in bone pain , episodes of hypercalcemia , or development of pathologic fractures .  Patients on EHDP  showed less deterioration in their vertebral index , but this difference only approached statistical significance ( P = .07 ) . We conclude that EHDP therapy used in this dosage schedule does not have a clinical ly significant impact in multiple myeloma Objective Questions remain regarding the optimal use of bone-targeted agents in patients with metastatic bone disease . The purpose of this study was to assess current clinical practice regarding the use and administration of bone-targeted agents by Canadian oncologists in patients with metastatic breast and prostate cancer . Methods A survey was design ed to explore ; bone-targeted agent use in metastatic bone disease , variability in the choice and the frequency of administration of these agents . Opinions were sought on potential outcomes for future trials . Results A total of 193 clinicians were contacted and 90 completed our survey ( response rate 49 % after adjustment for inactivity ) . Survey respondents were medical oncologists ( 71.1 % ) , radiation oncologists ( 21.1 % ) and urologists ( 7.8 % ) . The findings suggest that once bone-targeted agents are started they are rarely discontinued . More agents are used in breast cancer than in prostate cancer . There was considerable interest in performing studies of de-escalated therapy in both breast and prostate cancer . Physicians requested ( 86 % ) that the primary study endpoint be the occurrence of skeletal related events and not biomarker driven . Conclusions Despite clinical practice guidelines and widespread use , significant areas of clinical equipoise with respect to use of bone-targeted agents exist . Findings from this survey suggest that physicians are interested in de-escalated therapy for both breast and prostate patients . However , the use of multiple agents in breast cancer and the desire for skeletal related events to be the primary endpoint means that very large r and omized studies will be required OBJECTIVES Bone disease is a key presenting feature of myeloma . This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone ( VMP ) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase ( ALP ) , a marker for osteoblast activation , and serum Dickkopf-1 ( DKK-1 ) , an inhibitor of osteoblast differentiation , during treatment . METHODS Patients received nine 6-wk cycles of VMP ( bortezomib 1.3 mg/m(2 ) , days 1 , 4 , 8 , 11 , 22 , 25 , 29 , 32 , cycles 1 - 4 , days 1 , 8 , 22 , 29 , cycles 5 - 9 , plus melphalan 9mg/m(2 ) and prednisone 60mg/m(2 ) , days 1 - 4 , cycles 1 - 9 ; N=344 ) or MP alone ( N=338 ) . RESULTS Rates of bisphosphonates use during treatment ( 73 % vs. 82 % ) , progression because of worsening bone disease ( 3 % vs. 11 % ) , and requirement for subsequent radiotherapy ( 3 % vs. 8 % ) were lower with VMP vs. MP . Median maximum ALP increase was significantly higher with VMP vs. MP overall ( 49.7 % vs. 30.3 % , P=0.029 ) , and higher by response group ( complete response [ CR ] : 68.7 % vs. 43.9 % ; partial response [ PR ] : 41.5 % vs. 31.2 % ) . Greater maximum ALP increase was strongly associated with achievement of CR ( P≤0.0001 ) and CR/PR ( P≤0.01 ) . Median DKK-1 decreased with VMP by 694.4pg/mL and increased with MP by 1273.3pg/mL from baseline to day 4 ( P=0.0069 ) . Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients , who achieved best responses of three CR , one PR , and two stable disease . CONCLUSIONS These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma PURPOSE To determine the efficacy and safety of 21 monthly cycles of pamidronate therapy in patients with advanced multiple myeloma . PATIENTS AND METHODS Patients with stage III myeloma and at least one lytic lesion received either placebo or pamidronate 90 mg intravenously administered as a 4-hour infusion monthly for 21 cycles . At study entry , the patients were stratified according to whether they were to receive first-line ( stratum 1 ) or second-line ( stratum 2 ) antimyeloma chemotherapy .  Skeletal events ( pathologic fracture , radiation or surgery to bone , and spinal cord compression ) and hypercalcemia were assessed monthly . RESULTS The results of the first nine previously reported cycles are extended to 21 cycles . Of the 392 r and omized patients , efficacy could be evaluated in 198 who received pamidronate and 179 who received placebo .  After 21 cycles , the proportion of patients who developed any skeletal event was lower in the pamidronate-group ( P = .015 ) . The mean number of skeletal events per year was less in the pamidronate-group ( 1.3 ) than in placebo-treated patients ( 2.2 ; P = .008 ) . Although survival was not different between the pamidronate-treated group and placebo patients overall , stratum 2 patients who received pamidronate  lived longer than those who received placebo ( 14 v 21 months , P = .041 ) . Pamidronate was safe and well tolerated during the 21 cycles of therapy . CONCLUSION Long-term monthly infusions of pamidronate as an adjunct to chemotherapy are superior to chemotherapy alone in reducing skeletal events in stage III multiple myeloma patients , and may improve the survival of patients on salvage therapy
Denosumab has shown to be noninferior to zoledronic acid for the prevention of skeletal-related events and provides an alternative .
Fewer adverse events related to renal toxicity have been noted with denosumab compared with zoledronic acid and may be preferred in this setting .
Purpose To up date guideline recommendations on the role of bone-modifying agents in multiple myeloma .