Bortezomib in multiple myeloma and lymphoma: a systematic review and clinical practice guideline 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 Comparison of two long-term chemotherapy regimens, with or without agents to modify skeletal repair, in multiple myeloma. Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update 2014. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Ricolinostat, the First Selective Histone Deacetylase 6 Inhibitor, in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma Phase 3 trial of three thalidomide-containing regimens in patients with newly diagnosed multiple myeloma not transplant-eligible Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. Antitumor activity of thalidomide in refractory multiple myeloma. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Role of 18F-FDG PET/CT in the assessment of bone involvement in newly diagnosed multiple myeloma: preliminary results American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma Effect of daily etidronate on the osteolysis of multiple myeloma. An open‐label, phase 2 trial of denosumab in the treatment of relapsed or plateau‐phase multiple myeloma A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Long-term effects of dichloromethylene diphosphonate (CI2MDP) on skeletal lesions in multiple myeloma. Diabetes and the risk of non-Hodgkin’s lymphoma and multiple myeloma in the European Prospective Investigation into Cancer and Nutrition Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. Circulating microRNA 483-5p as a novel biomarker for diagnosis survival prediction in multiple myeloma Arsenic trioxide in patients with refractory multiple myeloma: a prospective, phase II, single-arm study. A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma
Questions In patients with multiple myeloma , Waldenström macroglobulinemia , or lymphoma , what is the efficacy of bortezomib alone or in combination as measured by survival , quality of life , disease control ( for example , time to progression ) , response duration , or response rate ? What is the toxicity associated with the use of bortezomib ? Which patients are more or less likely to benefit from treatment with bortezomib ? Perspectives Evidence was selected and review ed by two members of the Hematology Disease Site Group and by method ologists from the Program in Evidence -based Care ( pebc ) at Cancer Care Ontario . The practice guideline report was review ed and approved by the Hematology Disease Site Group , which comprises hematologists , medical and radiation oncologists , and a patient representative . As part of an external review process , the report was disseminated to practitioners throughout Ontario to obtain their feedback . Outcomes Outcomes of interest were overall survival , quality of life , response rates and duration , and rates of adverse events . Methodology A systematic search was conducted of the medline , embase , HealthStar , cinahl , and Cochrane Library data bases for primary articles and practice guidelines . The result ing evidence informed the development of clinical practice recommendations . Those recommendations were appraised by a sample of practitioners in Ontario and modified in response to the feedback received . The systematic review and modified recommendations were approved by a review body w theithin pebc . Results The literature review found one r and omized controlled trial ( rct ) —the only published rct of bortezomib in relapsed myeloma . A number of phase ii studies were also retrieved , including a r and omized phase ii study . No r and omized trials were retrieved for lymphoma . The rct found bortezomib to be superior to high-dose dexamethasone for median time to progression and 1-year survival in patients with relapsed myeloma , although grade 3 adverse events were more common in the bortezomib arm . Bortezomib is recommended as the preferred treatment option in patients with myeloma relapsing within 1 year of the conclusion of initial treatment ; it may also be a reasonable option in patients relapsing at least 1 year after autologous stem-cell transplantation . Practice Guideline This evidence -based series applies to adult patients with myeloma , Waldenström macroglobulinemia , or lymphoma of any type , stage , histology , or performance status . Recommendations Based on the results of a large well-conducted rct , which represents the only published r and omized study in relapsed myeloma , the Hematology Disease Site Group ( dsg ) offers the following recommendations : For patients with myeloma refractory to or relapsing within 1 year of the conclusion of initial or subsequent treatment or treatments , including autologous stem-cell transplantation , and who are c and i date s for further chemotherapy , bortezomib is recommended as the preferred treatment option . Bortezomib is also a reasonable option for patients relapsing at least 1 year after autologous stem-cell transplantation . The dsg is aware that thalidomide , alkylating agents , or repeat transplantation may also be options for these patients . However , evaluation of these other options is beyond the scope of this practice guideline . For patients with myeloma relapsing at least 1 year after the conclusion of alkylating agent – based chemotherapy who are c and i date s for further chemotherapy , further treatment with alkylating agent – based chemotherapy is recommended . Evidence is insufficient to support the use of bortezomib in patients with non-Hodgkin lymphoma or Waldenström macroglobulinemia outside of clinical trials . Qualifying Statements Limited evidence supports the appropriateness of a specific time-to-relapse period as being indicative of treatment-insensitive disease . The 1-year threshold provided in the foregoing recommendations is based on the opinion of the Hematology dsg . For specific details related to the administration of bortezomib therapy , the dsg suggests that clinicians refer to the protocol s used in major trials . Some of those details are provided here for informational purpose s. Dosage Bortezomib 1.3,g/m2 is given as a rapid intravenous bolus over 3–5 seconds on days 1 , 4 , 8 , and 11 of a 21-day cycle ; a minimum of 72 hours between doses is required to allow for recovery of normal proteasome function . Vital signs should be checked before and after each dose . A complete blood count is recommended before each dose , with blood chemistries ( including electrolyte and creatinine levels ) monitored at a minimum on days 1 and 8 of each cycle . The dose of bortezomib should be reduced or held immediately upon development of painful neuropathy , as described in the product monograph ; dose modification may also be required for peripheral sensory neuropathy without pain or for other toxicities . Most toxicities are reversible if dose modification guidelines are followed . Response to Treatment Responses are usually apparent by 6 weeks ( 2 cycles ) . For patients achieving complete remission ( determined by negative electrophoresis and immunofixation ) , bortezomib should be given for 2 additional cycles beyond the date of confirmed complete remission . In patients with progressive disease after 2 cycles or stable disease after 4 cycles , dexamethasone added to the bortezomib regimen ( 20 mg by mouth the day of and the day after each bortezomib dose ) may produce an objective response .  Bortezomib ( with or without dexamethasone ) should be continued in patients showing benefit from therapy ( excluding those in complete remission ) unless disease progression or significant toxicity is observed . Therapy should be discontinued in patients who do not respond to bortezomib alone if disease progression is seen within 2 cycles of the addition of dexamethasone . The Hematology dsg recognizes that thalidomide is an active agent in multiple myeloma patients who have relapsed after autologous stem-cell transplantation or who are refractory to alkylating agent – based chemotherapy . To date , no reported rcts have evaluated thalidomide in this role , and specifically , no trials have compared thalidomide with bortezomib . Given these limitations , the members of the Hematology dsg regard thalidomide or bortezomib as therapy alternatives to dexamethasone 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 A r and omized controlled trial was initiated in 1972 to compare two chemotherapeutic regimens [ 1 - 3-bis ( 2-chloroethyl ) 1-nitrosourea ( BCNU ) , cyclophosphamide , and prednisone versus melphalan and prednisone ] , to determine whether the two regimens are cross-resistant , and to evaluate the effectiveness of sodium fluoride , vitamin D , calcium gluconate , and fluoxymesterone in the promotion of bone healing . Initial responses ( 50 % ) and survival ( 36 mo median ) for patients treated with the two chemotherapeutic regimens were the same . Patients on either regimen who failed to respond after 6 mo had a very low response rate to the alternative regimen ( approximately 10 % ) . Initially responding patients were r and omly assigned to either an active drug regimen ( sodium fluoride , vitamin D , calcium gluconate , fluoxymesterone ) or placebo tablets . There was no significant difference in the low percentage of patients demonstrating bone improvement . Thus , the BCNU , cyclophosphamide , prednisone regimen is as effective as melphalan and prednisone . Fluoride , calcium , vitamin D , and and rogenic steroids should not be routinely recommended in myeloma , as they seem to add little to effective chemotherapy and may contribute to morbidity PURPOSE To provide current recommendations about the prophylaxis and treatment of venous thromboembolism ( VTE ) in patients with cancer . METHODS PubMed and the Cochrane Library were search ed for r and omized controlled trials , systematic review s , meta-analyses , and clinical practice guidelines from November 2012 through July 2014 . An up date committee review ed the identified abstract s. RESULTS Of the 53 publications identified and review ed , none prompted a change in the 2013 recommendations . RECOMMENDATIONS Most hospitalized patients with active cancer require thromboprophylaxis throughout hospitalization . Routine thromboprophylaxis is not recommended for patients with cancer in the outpatient setting . It may be considered for selected high-risk patients . Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and /or dexamethasone should receive prophylaxis with either low-molecular weight heparin ( LMWH ) or low-dose aspirin .  Patients undergoing major surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days . Extending prophylaxis up to 4 weeks should be considered in those undergoing major abdominal or pelvic surgery with high-risk features . LMWH is recommended for the initial 5 to 10 days of treatment for deep vein thrombosis and pulmonary embolism as well as for long-term secondary prophylaxis ( at least 6 months ) . Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE because of limited data in patients with cancer . Anticoagulation should not be used to extend survival of patients with cancer in the absence of other indications . Patients with cancer should be periodically assessed for VTE risk . Oncology professionals should educate patients about the signs and symptoms of VTE 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 Purpose : Histone deacetylase ( HDAC ) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity . Pre clinical models suggest that the observed synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degradation . Experimental Design : We conducted a phase I/II trial of the HDAC6-selective inhibitor ricolinostat to define the safety , preliminary efficacy , and recommended phase II dose in combination with st and ard proteasome inhibitor therapy .  Patients with relapsed or refractory multiple myeloma received oral ricolinostat on days 1–5 and 8–12 of each 21-day cycle . Results : Single-agent ricolinostat therapy result ed in neither significant toxicity nor clinical responses . Combination therapy with bortezomib and dexamethasone was well-tolerated during dose escalation but led to dose-limiting diarrhea in an expansion cohort at a ricolinostat dose of 160 mg twice daily . Combination therapy at a ricolinostat dose of 160 mg daily in a second expansion cohort was well tolerated , with less severe hematologic , gastrointestinal , and constitutional toxicities compared with published data on nonselective HDAC inhibitors . The overall response rate in combination with daily ricolinostat at ≥160 mg was 37 % . The response rate to combination therapy among bortezomib-refractory patients was 14 % . Sample s taken during therapy showed dose-dependent increases of acetylated tubulin in peripheral blood lymphocytes . Conclusions : At the recommended phase II dose of ricolinostat of 160 mg daily , the combination with bortezomib and dexamethasone is safe , well-tolerated , and active , suggesting that selective inhibition of HDAC6 is a promising approach to multiple myeloma therapy . Clin Cancer Res ; 23(13 ) ; 3307–15 . © 2017 AACR The introduction of agents such as thalidomide , lenalidomide , and bortezomib has changed the management of patients with multiple myeloma who are not eligible for autologous transplantation , many of whom are elderly . We sought to compare three thalidomide-based oral regimens among such patients in Latin America . We r and omized patients with newly diagnosed multiple myeloma with measurable disease to one of the following regimens : melphalan , prednisone , and thalidomide ( MPT ) ; cyclophosphamide , thalidomide , and dexamethasone ( CTD ) ; and thalidomide and dexamethasone ( TD ) . The TD arm was closed prematurely and was analyzed only descriptively . The primary endpoint was the overall response rate ( ORR ) , whereas progression-free survival ( PFS ) and overall survival ( OS ) were secondary endpoints . The accrual rate was slower than expected , and the study was terminated after 82 patients had been r and omized . The ORRs were 67.9 % with MPT , 89.7 % with CTD , and 68.7 % with TD ( p = 0.056 for the comparison between MPT and CTD ) . The median PFS was 24.1 months for MPT , 25.9 months for CTD , and 21.5 months for TD . There were no statistically significant differences in PFS or OS between MPT and CTD . In an unplanned logistic regression analysis , ORR was significantly associated with treatment with CTD ( p = 0.046 ) and with performance status of 0 or 1 ( p = 0.035 ) . Based on the current results , no definitive recommendations can be made regarding the comparative merit of the regimens tested . Nevertheless and until the results of further studies become available , we recommend either CTD or MPT as suitable frontline regimens for patients with multiple myeloma who are not c and i date s to transplantation in setting s where lenalidomide and bortezomib are not available PURPOSE Bisphosphonates have been found to reduce the incidence of skeletal-related events ( SREs ) in patients with multiple myeloma . This is the first double-blind , r and omized , placebo-controlled study to assess the efficacy of ib and ronate , a third-generation amino-bisphosphonate , in preventing SREs in advanced-stage multiple myeloma patients . PATIENTS AND METHODS Patients with multiple myeloma stage II or III were r and omly assigned to receive either ib and ronate 2 mg or placebo as a monthly intravenous ( IV ) bolus injection for 12 to 24 months in addition to conventional chemotherapy .  SREs such as peripheral pathologic or vertebral fractures , hypercalcemia , severe bone pain , and bone radiotherapy or surgery were analyzed . Bone-turnover markers were also studied . Finally , post hoc analyses of bone morbidity and survival were performed . RESULTS Ninety-nine patients per treatment group were assessable for efficacy analysis . The occurrence of SRE per patient year and the time to first SRE were not significantly different between the two treatment groups . In overall evaluation , no differences were found between the treatment groups regarding bone pain , analgesic drug use , quality of life , and median survival ( 33.1 v 28.2 months , respectively ) . Explorative post hoc analyses revealed that ib and ronate patients with strongly suppressed bone-turnover markers ( > or = 30 % and > or = 50 % mean reduction of serum osteocalcin and urinary C-terminal telopeptides ) developed significantly less bone morbidity .  Ib and ronate was tolerated well during as many as 25 therapy cycles . CONCLUSION Monthly injections of ib and ronate 2 mg IV neither reduced bone morbidity nor prolonged survival in the overall population of stage II/III multiple myeloma patients BACKGROUND Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options . Since increased bone marrow vascularity imparts a poor prognosis in myeloma , we evaluated the efficacy of thalidomide , which has antiangiogenic properties , in patients with refractory disease . METHODS Eighty-four previously treated patients with refractory myeloma ( 76 with a relapse after high-dose chemotherapy ) received oral thalidomide as a single agent for a median of 80 days ( range , 2 to 465 ) . The starting dose was 200 mg daily , and the dose was increased by 200 mg every two weeks until it reached 800 mg per day . Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks . RESULTS The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients ( two had a complete remission ) , at least 75 percent in six patients , at least 50 percent in seven patients , and at least 25 percent in six patients , for a total rate of response of 32 percent . Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels . The microvascular density of bone marrow did not change significantly in patients with a response . At least one third of the patients had mild or moderate constipation , weakness or fatigue , or somnolence . More severe adverse effects were infrequent ( occurring in less than 10 percent of patients ) , and hematologic effects were rare . As of the most recent follow-up , 36 patients had died ( 30 with no response and 6 with a response ) . After 12 months of follow-up , Kaplan-Meier estimates of the mean ( + /-SE ) rates of event-free survival and overall survival for all patients were 22+/-5 percent and 58+/-5 percent , respectively . CONCLUSIONS Thalidomide is active against advanced myeloma . It can induce marked and durable responses in some patients with multiple myeloma , including those who relapse after high-dose chemotherapy Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions ( APEX ) trial of relapsed multiple myeloma patients showed significantly longer time to progression , higher response rate , and improved survival with single-agent bortezomib versus high-dose dexamethasone . In this up date d analysis ( median follow-up : 22 months ) , survival was assessed in both arms , and efficacy up date d for the bortezomib arm . Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone , a 6-month benefit , despite substantial crossover from dexamethasone to bortezomib . Overall and complete response rates with bortezomib were 43 % and 9 % , respectively ; among responding patients , 56 % improved response with longer therapy beyond initial response , leading to continued improvement in overall quality of response . Higher response quality ( 100 % M-protein reduction ) was associated with longer response duration ; response duration was not associated with time to response . These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy Purpose Multiple myeloma ( MM ) is a malignant B cell and plasma cell disorder which involves the skeleton in more than 80 % of patients at diagnosis . The aim of this study was to compare whole-body X-ray ( WBXR ) , MRI and 18F-FDG PET/CT in patients with MM . Methods The study population comprised 28 newly diagnosed MM patients . Findings of 18F-FDG PET/CT were compared with those of WBXR and MRI with regard to the number and site of lesions detected . Results Comparing 18F-FDG PET/CT and WBXR , it was found that in 16/28 pts ( 57 % ) 18F-FDG PET/CT detected more lesions , all of which were located in the skeleton . Nine of these 16 patients had a completely negative WBXR survey . In 12/28 pts ( 43 % ) the two methods yielded equivalent findings . Comparing 18F-FDG PET/CT and MRI , it was found that in 7/28 pts ( 25 % ) , 18F-FDG PET/CT detected more lytic bone lesions , all of which were located outside the field of view of MRI ( bone lesions in six cases and a soft tissue lesion in one ) . In 14/28 pts ( 50 % ) , 18F-FDG PET/CT and MRI detected the same number of lesions in the spine and pelvis , while in 7/28 pts ( 25 % ) MRI detected an infiltrative pattern in the spine whereas 18F-FDG PET/CT was negative . Conclusion 18F-FDG PET/CT appears to be more sensitive than WBXR for the detection of small lytic bone lesions , whereas it has the same sensitivity as MRI in detecting bone disease of the spine and pelvis . On the other h and , MRI may be superior to 18F-FDG PET/CT in diagnosing an infiltrative pattern in the spine . Therefore , careful evaluation of MM bone disease at diagnosis should include both MRI of the spine and 18F-FDG PET/CT PURPOSE To up date the 1999 American Society of Clinical Oncology guideline for antiemetics in oncology . UP DATE METHODOLOGY The Up date Committee completed a review and analysis of data published from 1998 thru February 2006 . The literature review focused on published r and omized controlled trials , and systematic review s and meta-analyses of published phase II and phase III r and omized controlled trials . RECOMMENDATIONS The three-drug combination of a 5-hydroxytryptamine-3 ( 5-HT(3 ) ) serotonin receptor antagonist , dexamethasone , and aprepitant is recommended before chemotherapy of high emetic risk . For persons receiving chemotherapy of high emetic risk , there is no group of patients for whom agents of lower therapeutic index are appropriate first-choice antiemetics . These agents should be reserved for patients intolerant of or refractory to 5-HT3 serotonin receptor antagonists , neurokinin-1 receptor antagonists , and dexamethasone . The three-drug combination of a 5-HT3 receptor serotonin antagonist , dexamethasone , and aprepitant is recommended for patients receiving an anthracycline and cyclophosphamide . For patients receiving other chemotherapy of moderate emetic risk , the Up date Committee continues to recommend the two-drug combination of a 5-HT3 receptor serotonin antagonist and dexamethasone . In all patients receiving cisplatin and all other agents of high emetic risk , the two-drug combination of dexamethasone and aprepitant is recommended for the prevention of delayed emesis . The Up date Committee no longer recommends the combination of a 5-HT3 serotonin receptor antagonist and dexamethasone for the prevention of delayed emesis after chemotherapeutic agents of high emetic risk . CONCLUSION The Up date Committee recommends that clinicians administer antiemetics while considering patients ' emetic risk categories and other characteristics F18-fluorodeoxyglucose positron emission tomography ( FDG-PET ) is a powerful tool to investigate the role of tumor metabolic activity and its suppression by therapy for cancer survival . As part of Total Therapy 3 for newly diagnosed multiple myeloma , metastatic bone survey , magnetic resonance imaging , and FDG-PET scanning were evaluated in 239 untreated patients . All 3 imaging techniques showed correlations with prognostically relevant baseline parameters : the number of focal lesions ( FLs ) , especially when FDG-avid by PET-computed tomography , was positively linked to high levels of beta-2-microglobulin , C-reactive protein , and lactate dehydrogenase ; among gene expression profiling parameters , high-risk and proliferation-related parameters were positively and low-bone-disease molecular subtype inversely correlated with FL . The presence of more than 3 FDG-avid FLs , related to fundamental features of myeloma biology and genomics , was the leading independent parameter associated with inferior overall and event-free survival . Complete FDG suppression in FL before first transplantation conferred significantly better outcomes and was only opposed by gene expression profiling-defined high-risk status , which together accounted for approximately 50 % of survival variability ( R(2 ) test ) . Our results provide a rationale for testing the hypothesis that myeloma survival can be improved by altering treatment in patients in whom FDG suppression can not be achieved after induction therapy Newer systemic therapies have significantly advanced the treatment of multiple myeloma , but additional agents are needed . Bortezomib is a proteasome inhibitor with efficacy in relapsed/refractory multiple myeloma that inhibits tumor angiogenesis , a process that has been implicated in multiple myeloma pathogenesis 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 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 , This multicenter , first-in-human study evaluated the safety , tolerability , and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab . A st and ard 3 + 3 design was used to determine maximum tolerated dose ; dose-limiting toxicities were assessed during cycle 1 . Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks . Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments . No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg . The most common adverse events , regardless of attribution , were cough , headache , back pain , fever , and chills . Adverse events were generally mild to moderate in severity , and adverse events attributed to study medication were primarily infusion-related . Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased , suggesting target-mediated clearance . CS1 on bone marrow-derived plasma cells was reliably saturated ( ≥ 95 % ) at the 10-mg/kg and 20-mg/kg dose levels . Using the European Group for Bone and Marrow Transplantation myeloma response criteria , 9 patients ( 26.5 % ) had stable disease . In summary , elotuzumab was generally well tolerated in this population , justifying further exploration of this agent in combination regimens 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 Background Non-Hodgkin ’s lymphomas are a heterogeneous group of neoplasms arising from the lymphopoietic system including a wide range of subtypes of either B-cell or T-cell lymphomas . The few established risk factors for the development of these neoplasms include viral infections and immunological abnormalities , but their etiology remains largely unknown . Evidence suggests that certain medical conditions may be linked , through immunosuppression , to the risk of non-Hodgkin ’s lymphoma . Multiple myeloma is a neoplasm of plasma cells that accounts for approximately 15 % of lymphopoietic cancers . Increases in the incidence of non-Hodgkin ’s lymphoma and multiple myeloma in the past implicate environmental factors as potential causal agents . Design and Methods In the European Prospect i ve Investigation into Cancer and Nutrition ( EPIC ) , 1,213 histologically confirmed incident cases of non-Hodgkin ’s lymphoma and multiple myeloma ( 594 men ; 619 women ) were identified during a follow-up of 8.5 years . Cox proportional hazard models were used to explore the association between  self-reported diabetes , diagnosed after 30 years of age , and the risk of non-Hodgkin ’s lymphoma overall and multiple myeloma and various lymphoma subtypes . Results We found no association between a personal history of diabetes and the risk of non-Hodgkin ’s lymphoma overall in men ( HR : 1.28 , 95 % CI : 0.89–1.84 ) , in women ( HR : 0.71 , 95 % CI : 0.41– 1.24 ) , or in men and women combined ( HR : 1.09 , 95 % CI : 0.80–1.47 ) . Among the B-non-Hodgkin ’s lymphoma subtypes , we observed a statistically significant increased risk of B-cell chronic lymphocytic leukemia ( HR : 2.0 , 95 % CI : 1.04–3.86 ) in men , but not in women ( HR : 1.07 , 95 % CI : 0.33–3.43 ) . Conclusions This prospect i ve study did not provide evidence for a role of self-reported diabetes in the etiology of non-Hodgkin ’s lymphoma overall or multiple myeloma . We found an increased risk of B-cell chronic lymphocytic leukemia among men with diabetes , but not among women . We hypothesize that diabetes may not play a causal role in the etiology of B-cell chronic lymphocytic leukemia , though the underlying pathogenic mechanisms of both disorders may include shared genetic , host and /or environmental susceptibility factors 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 Dysregulation of miRNA expression plays an important role in cancer development , and circulating miRNAs are biomarkers of several cancers . We explored whether the miRNAs in plasma could be useful clinical biomarkers for multiple myeloma .  miRNA microarray was conducted to identify elevation of four miRNAs and reduced levels of eight miRNAs in the plasma of nine multiple myeloma patients and seven healthy controls . Increased miR-483 - 5p levels and decreased miR-20a were further vali date d in the plasma of 40 myeloma patients and 20 healthy controls using TaqMan quantitative real-time PCR . Receiver operating characteristic ( ROC ) analysis revealed that miR-483 - 5p and miR-20a had considerable diagnostic accuracy , yielding the areas under the ROC curve of 0.745 ( sensitivity 58 % , specificity 90 % ) and 0.74 ( sensitivity 63 % , specificity 85 % ) , respectively . Plasma levels of miR-483 - 5p were associated with ISS staging . Within 14 months of diagnosis , the median progression-free survival of patients with high levels of plasma miR-483 - 5p was 15 months , in comparison with 21 months for patients with low levels of plasma miR-483 - 5p ( p = 0.025 ) . However , miR-20a levels were not correlated with progression-free survival ( p > 0.05 ) . miR-483 - 5p has the potential to be a predictor of myeloma survival Multiple myeloma ( MM ) characterized by proliferation of plasma cells in bone marrow and production of monoclonal immunoglobulin 's . Recently , arsenic trioxide ( ATO ) , has been considered for treatment refractory MM . We assessed the safety and efficacy of ATO for patients with refractory MM . A phase 2 , study of arsenic trioxide was conducted in 12 MM patients , whose refractory to two st and ard therapy . Patients received arsenic trioxide , 0.25 mg/kg/d for 5 d/week during the first 2 consecutive weeks of each 4-week cycle with 2 week rest . Patients who completed one 4-week cycle were evaluated for response to treatment . Twelve patients with refractory multiple myeloma received ATO . Disease assessment was based the amount of serum proteins electrophoresis . Of the10 patients ; stable disease was observed in four patients ( 33 % ) , progression disease in five patients ( 41.6 % ) , complete response in one patient ( 3.8 % ) and the remaining two patients could not be assessed for a response ( because of increased liver enzymes after the first week ) . Some adverse events : increase liver enzymes and serum creatinine , neutropenia , pruritus , nausea , vomiting , lower extremities edema , noninfectious diarrhea was observed . These results indicate that ATO is active and well tolerated as a single-agent salvage therapy , even in patients with late-stage , refractory MM In patients with multiple myeloma , despite a major reduction of bone pain achieved with chemotherapy , skeletal disease continues to progress . The effects of clodronate , an inhibitor of osteoclastic bone resorption , are evaluated on the natural history of skeletal disease in patients with newly diagnosed multiple myeloma . Within the framework of the VIth MRC Multiple Myeloma Trial , 536 patients ( 218 women , 318 men ) with recently diagnosed multiple myeloma were r and omized to receive either clodronate 1600 mg daily ( n=264 ) or an outwardly identical placebo ( n=272 ) in addition to chemotherapy . Treatment with clodronate was associated with a 50 % decrease in the proportion of patients with severe hypercalcaemia ( 5.1 % v 10.1 % , P=0.06 ) and a similar reduction in reported non‐vertebral fractures ( 6.8 % v 13.2 % , P=0.04 ) . Fewer patients receiving clodronate  sustained vertebral fractures after entry to the trial ( 38 % v 55 % , P=0.01 ) and patients also lost less height over 3 years compared to those receiving placebo ( 2.0 v 3.4 cm , P=0.01 ) . Biochemical indices of bone turnover were significantly lower in patients receiving concomitant clodronate , both at plateau and at disease relapse . The frequencies of back pain and poor performance status were significantly lower at 24 months in clodronate than in placebo‐treated patients ( 10.9 % v 19.9 % , P=0.05 , and 18.3 % v 30.5 % P=0.03 respectively . ) There was no statistically significant difference in survival between the clodronate and placebo treated patients . The study indicates that long‐term oral clodronate slows the progression of skeletal disease in multiple myeloma and decreases the associated morbidity . Patients without overt skeletal disease at diagnosis were also found to benefit from clodronate , indicating that this treatment should be initiated as early in the course of the disease as possible
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 .