Background Patients with myeloma who relapse after high-dosechemotherapy have few therapeutic options. Since increased bonemarrow vascularity imparts a poor prognosis in myeloma, we evaluatedthe efficacy of thalidomide, which has antiangiogenic properties,in patients with refractory disease.
Methods Eighty-four previously treated patients with refractorymyeloma (76 with a relapse after high-dose chemotherapy) receivedoral thalidomide as a single agent for a median of 80 days (range,2 to 465). The starting dose was 200 mg daily, and the dosewas increased by 200 mg every two weeks until it reached 800mg per day. Response was assessed on the basis of a reductionof the myeloma protein in serum or Bence Jones protein in urinethat lasted for at least six weeks.
Results The serum or urine levels of paraprotein were reducedby at least 90 percent in eight patients (two had a completeremission), at least 75 percent in six patients, at least 50percent in seven patients, and at least 25 percent in six patients,for a total rate of response of 32 percent. Reductions in theparaprotein levels were apparent within two months in 78 percentof the patients with a response and were associated with decreasednumbers of plasma cells in bone marrow and increased hemoglobinlevels. The microvascular density of bone marrow did not changesignificantly in patients with a response. At least one thirdof the patients had mild or moderate constipation, weaknessor fatigue, or somnolence. More severe adverse effects wereinfrequent (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 ofthe mean (±SE) rates of event-free survival and overallsurvival for all patients were 22±5 percent and 58±5percent, respectively.
Conclusions Thalidomide is active against advanced myeloma.It can induce marked and durable responses in some patientswith multiple myeloma, including those who relapse after high-dosechemotherapy.
Multiple myeloma accounts for approximately 1 percent of allcancers and 10 percent of hematologic cancers. It is incurablewith conventional chemotherapy.1 Melphalan-based high-dose chemotherapywith hematopoietic stem-cell support increases the rate of completeremission and extends event-free and overall survival.2,3,4However, many patients still relapse, and options for salvagetherapy are limited.5,6
Angiogenesis is important in embryogenesis, wound healing, diabeticretinopathy, and tumor progression.7,8 The immunomodulatorydrug thalidomide can inhibit angiogenesis and induce apoptosisof established neovasculature in experimental models.9,10 Forthese reasons, angiogenesis-inhibiting drugs such as thalidomidemay be useful for treating cancers that depend on neovascularization.
Prominent bone marrow vascularization occurs in multiple myeloma.It correlates positively with a high plasma-cell–labelingindex (a poor prognostic sign) and disease activity and independentlyconfers a poor prognosis.11,12,13,14,15,16 Plasma levels ofvarious angiogenic cytokines, such as basic fibroblast growthfactor and vascular endothelial growth factor, are elevatedin patients with active myeloma.11,12,13,16 In 1965, Olson etal. reported slowing of disease progression in one patient whowas treated with thalidomide.17 These considerations led usto administer thalidomide to five patients with end-stage myelomathrough a compassionate-use protocol. One patient with a largetumor burden (as indicated by an IgA level of 8.4 g per deciliter,the presence of more than 95 percent plasma cells in bone marrow,and the need for transfusion), who had had no response to twocycles of high-dose chemotherapy followed by multiple salvagetherapies, had a nearly complete remission within three monthsafter the initiation of thalidomide therapy. This observationprompted a phase 2 investigation of thalidomide in patientswith advanced and refractory myeloma.
Methods
Patients and Treatments
Between December 1997 and June 1998, 84 consecutive, eligiblepatients with previously treated and progressive myeloma begantreatment with oral thalidomide as a single agent after providingwritten informed consent. No patients were excluded on the basisof renal or cardiopulmonary function, whereas patients couldbe excluded if the results of liver-function tests were morethan twice the upper limit of normal levels. All patients weretreated at a single center according to a phase 2 protocol approvedby the institutional review board and the Food and Drug Administration(FDA).
Thalidomide was supplied in 50-mg capsules by Celgene (Warren,N.J.) and was administered nightly at a dose of 200 mg. Thedose was increased by 200 mg every two weeks for six weeks,so that the final dose was 800 mg per day. Data were analyzedas of June 17, 1999, when the duration of treatment ranged from2 to 465 days (median, 80) and the median follow-up of survivingpatients was 13 months.
Table 1 summarizes the characteristics of the patients and detailsof prior therapy. Seventy-six patients (90 percent) had receivedat least one cycle of high-dose chemotherapy with autologoushematopoietic stem-cell support, and 58 (69 percent) had receivedtwo or more cycles of intensive chemotherapy. The median timefrom the last course of high-dose chemotherapy to the beginningof treatment with thalidomide was 14 months. A high-risk cytogeneticabnormality (deletion of chromosome 13) was present in 35 patients(42 percent).20 One patient had received an allograft as a secondintervention, with evidence of full donor-type chimerism innormal lymphohematopoietic cells. At the time of enrollment,all patients had progressive disease, with an increase in paraproteinlevels of at least 25 percent or at least 50 percent plasmacells in bone marrow. Approximately half the patients had beenretreated with dexamethasone or other regimens, but the diseasehad progressed before thalidomide treatment was begun.
The pretreatment evaluation included complete blood counts,tests of renal and liver function, serum and urine protein electrophoresis,and measurements of serum levels of immunoglobulins, beta2-microglobulin,and C-reactive protein. Bone marrow aspirates were obtainedand biopsies were performed to determine the percentage of plasmacells in bone marrow, to identify karyotypic abnormalities (Giemsa-bandedcells in metaphase), and to assess the proliferative activityin plasma cells according to the bromodeoxyuridine method toderive the plasma-cell–labeling index.18 Follow-up studiesincluded a weekly estimation of paraprotein levels — themyeloma protein in serum and Bence Jones protein in urine —for the first two months, followed thereafter by monthly measurements.Whenever possible, bone marrow was examined at the time of themaximal response or when patients with no response left thestudy.
The microvascularity of bone marrow was studied in a semiquantitativefashion in biopsy samples that were obtained with a trephineand stained with an anti-CD34 monoclonal antibody (predilutedClone QBEnd/10, Cell Marque, Austin, Tex.). The results wereexpressed as the number of vessels per high-power field (400x).
Assessment of Response
The primary end point of the study was the finding of a declinein the level of paraprotein in serum or urine of at least 25percent, 50 percent, 75 percent, or 90 percent on two occasionsat least six weeks apart. Among patients with detectable levelsof both urine and serum paraprotein, the response was judgedon the basis of the component showing the smaller decline. Patientswith a reduction of less than 25 percent and those who discontinuedtreatment before a response could be assessed were consideredto have had no response to thalidomide. Thus, the results wereevaluated on an intention-to-treat basis. In patients with aresponse, an increase in serum or urine paraprotein levels bymore than 25 percent above the nadir value was considered evidenceof relapse. In patients who had a complete remission, evidenceof reemergence of the monoclonal protein (determined by immunofixation)on at least two occasions was considered to indicate a relapse.In patients who had a complete remission or a nearly completeremission (90 percent reduction in serum or urine paraproteinlevels), a bone marrow response was defined as the finding ofless than 5 percent plasma cells in the biopsy specimen or aspirate.For the remaining patients with a paraprotein response, thepercentage of plasma cells had to decrease by at least 50 percentto qualify as a bone marrow response.
Assessment of Adverse Effects
All patients, irrespective of the duration of therapy, wereincluded in the evaluation of adverse effects. All patientsreceived diaries after providing informed consent, and 83 patients(99 percent) reported having adverse effects. A comprehensivechecklist of the adverse effects associated with thalidomidetherapy was provided by Celgene; it was based on previous experiencein treating patients with leprosy and had been reviewed by theFDA. The data were verified by the patients by direct or telephoneinterviews. Hematologic values and other laboratory-based measuresof adverse effects were assessed at least monthly by the data-managementoffice.
Statistical Analysis
The primary end point for this phase 2 study was a diminutionin the plasma level of the myeloma protein or the urine levelof Bence Jones protein. Other end points included the time toa response, the time to disease progression, event-free survival,overall survival, the microvascularity of bone marrow, and improvementsin other laboratory values. Response was treated as a categoricalvariable. Comparisons of the response according to other categoricalvariables were assessed with use of the chi-square test or Fisher'sexact test, as appropriate. The times to response and diseaseprogression were calculated with the use of the competing-riskmethods.21 The time to response was defined as the intervalbetween the start of therapy and a given response (i.e., a declinein the serum or urine level of paraprotein of at least 25 percent,50 percent, 75 percent, or 90 percent or a complete remission).Competing risks with respect to the time to response includeddiscontinuation of treatment because of progression or a lackof response, an inability to tolerate thalidomide, or deathor personal reasons. The time to progression was calculatedonly for patients with a paraprotein response and was definedas the time from the start of therapy to disease progression.Competing risks with respect to the time to progression includeddiscontinuation of treatment because of adverse effects or deathor for personal reasons. Event-free survival and overall survivalwere estimated according to the method of Kaplan and Meier.22Event-free survival was calculated from the start of therapyto disease progression, removal from the study for any reason,death from any cause, or the last follow-up visit, whicheveroccurred first. Overall survival was calculated from the startof therapy to death from any cause or the last follow-up visit.Data on patients who had not had an event by the time of thelast follow-up were censored at that time with respect to timesto response and progression, event-free survival, and overallsurvival. Survival was compared with use of the log-rank test.23Univariate and multivariate (stepwise) logistic-regression methodswere used to evaluate the prognostic importance of various characteristicswith respect to the likelihood of achieving at least a 25 percentor 50 percent reduction in serum or urine paraprotein levels.Univariate and multivariate (stepwise) proportional-hazardsregression analyses were used to evaluate the prognostic importanceof various characteristics with respect to event-free survivaland overall survival.
Since the microvascular density of bone marrow was used as ameasure of the antiangiogenic action of thalidomide, this variablewas extensively modeled. To account for the need for multiplemeasurements of each patient over time and missing data, weused mixed-models repeated-measures analysis of variance toevaluate the microvascular density of bone marrow.24 The useof compound symmetry and first-order autoregressive covariancestructures was compared, and the results were found to be similaraccording to Akaike's criterion. Therefore, the values obtainedwith the compound-symmetry models are reported. Measurementsof the microvascular density of bone marrow were grouped accordingto the length of treatment, and values were measured every 50days for a total of seven times, including the pretreatmentvalue. The natural logarithm of the values for the microvasculardensity of bone marrow was used in the analysis. Estimates forpatients with no response and patients with a complete or nearlycomplete response (90 percent reduction in serum or urine paraproteinlevels) were used to predict the response in terms of the microvasculardensity of bone marrow over time.
Improvements in important clinical measures were evaluated onthe basis of the percent change from base line to the time ofthe maximal response or, for those without a response, the timeat which treatment was discontinued. Spearman correlations wereused to assess whether the changes within response groups weresignificant. For variables with no significant correlations,the signed-rank test was used to test the hypothesis withinresponse groups that the change was significantly differentfrom zero. All statistical tests were two-sided.
Results
Decline in Paraprotein Levels
Timely escalations in the daily dose of thalidomide to 400 mg,600 mg, and 800 mg were possible in 83 percent, 62 percent,and 47 percent of the patients, respectively; the proportionsof patients who eventually reached these levels were 86 percent,68 percent, and 55 percent, respectively (Table 1). In 27 patients(32 percent), the serum or urine paraprotein level declinedby at least 25 percent, including 7 (8 percent) with a declineof at least 50 percent, 6 (7 percent) with a decline of at least75 percent, and 6 (7 percent) with a decline of at least 90percent; 2 patients had a complete remission (Table 2). Themedian interval between the start of treatment and a decreasein the paraprotein level of at least 25 percent was 29 days(range, 4 days to 6 months) (Figure 1). Seventy-eight percentof the responses of this magnitude were apparent within twomonths; they were observed within four months in all but twopatients with a response. More marked reductions in paraprotein,by at least 50 percent and 75 percent, occurred after a medianof two and three months of therapy, respectively.
Among patients with a response, the median times to a reduction in the serum or urine paraprotein level of at least 25 percent, 50 percent, 75 percent, and 90 percent were one, two, four, and four months, respectively. Seventy-eight percent of the responses at the lowest level (25 percent reduction) were apparent within two months after the initiation of treatment.
A low plasma-cell–labeling index (assessed as a continuousvariable) was the only statistically significant variable associatedwith a response among both the group with at least a 25 percentdecrease in paraprotein levels (P=0.01) and the group with atleast a 50 percent decrease (P=0.01). Using the median plasma-cell–labelingindex of 0.2 percent as a cutoff value, we found that 46 percentof patients with values below the median had a reduction inparaprotein levels of at least 25 percent, as compared with9 percent of patients with higher values (P<0.05). On univariateanalysis, deletion of chromosome 13 was predictive of an unfavorableresponse, but not on multivariate analysis.
Bone Marrow Response
Bone marrow samples were obtained after one to nine months oftherapy (median, three) in 48 patients. A paraprotein responsewas associated with a bone marrow response in 81 percent ofthe patients who could be evaluated (Table 2). In seven of theeight patients with at least a 90 percent reduction in paraproteinlevels, the concurrently examined bone marrow specimens containedless than 5 percent plasma cells. A decline in the percentageof plasma cells in bone marrow by at least 50 percent occurredin only 4 of 27 patients with no paraprotein response (15 percent)who had follow-up bone marrow examinations.
Microvascular Density of Bone Marrow
The microvascular density of bone marrow was scheduled to beassessed every 50 days for a total of seven measurements, includingthe pretreatment value. At least one measurement of the microvasculardensity of bone marrow was made in 74 patients (88 percent);two or more measurements were made in 37 patients (44 percent).In all, measurements were made in 69 patients before treatmentand (in 50-day increments) in 17 at time 2, in 22 at time 3,in 11 at time 4, in 12 at time 5, in 4 at time 6, and in 3 attime 7. The microvascular density of bone marrow and the percentageof plasma cells in bone marrow correlated significantly at alltimes except the last (r>0.5, P0.01). Although the microvasculardensity of bone marrow decreased markedly in some patients witha complete or nearly complete remission, estimates of the slopewere not significantly different from zero among those witha response (P=0.39) and those without a response (P=0.22).
Other Changes
The percent changes from base line to the time of the maximalresponse among patients with a response and the time of thelast follow-up visit among those without a response were assessedfor beta2-microglobulin, C-reactive protein, lactic dehydrogenase,creatinine, albumin, and hemoglobin levels and the plateletcount. Hemoglobin levels increased only in patients with a response(median increase, 11 percent; P<0.001 for the comparisonwith base-line values). Serum levels of beta2-microglobulinrose (median increase, 43 percent; P<0.001) and serum albuminlevels fell (median decrease, 4 percent; P<0.001) significantlyin patients with no response. Serum creatinine levels did notchange significantly in patients with a response, and they increasedby a median of 13 percent in those without a response (P<0.001).
Adverse Effects
Side effects reported by at least 10 percent of patients atmost dose levels are listed in Table 3. Most adverse effectswere mild or moderate (grade 1 or 2 according to the systemof classification of the World Health Organization). Constipation,weakness or fatigue, and somnolence occurred in one third ormore of the patients. Reports of grade 3 or 4 adverse effectswere infrequent (less than 10 percent in all cases). One quarterof the patients had no appreciable side effects at the 200-mgdose, whereas virtually all patients had adverse effects ofgrade 1 or 2 at higher doses. Fewer than 5 percent of patientshad grade 1 or 2 leukopenia at any dose, and grade 3 or 4 thrombocytopeniaor anemia occurred in only three patients. In most of the patientswho had no response, pretreatment anemia or thrombocytopeniadid not worsen, whereas significant increases in the hemoglobinlevels occurred in patients with a response. Nine patients couldnot tolerate thalidomide (four with a response and five withno response) and discontinued treatment after a median of 36days (range, 10 to 241). In eight patients, an increase in serumcreatinine levels of more than 50 percent was related to progressivedisease, with increasing Bence Jones proteinuria. One of thepatients with a response died suddenly on day 37 of treatment.The death was thought to be related to sepsis, although a possiblecontribution of thalidomide could not be ruled out.
Table 3. Incidence of Grade 1 or 2 Adverse Effects.
Time to Progression, Event-Free Survival, and Overall Survival
Of the 27 patients with a decrease in paraprotein levels ofat least 25 percent, 12 had a recurrence of the disease. Aftera median follow-up of 14.5 months (range, 12 to 16), the mediantime to progression had not been reached. The disease in a mean(±SE) of 44±10 percent of patients was judgedto have progressed at 12 months. The median event-free survivalfor all 84 patients was three months (Figure 2). After 12 monthsof follow-up, 22±5 percent of the 84 patients remainedevent-free and 58±5 percent were alive. Nineteen patientswere still receiving thalidomide 4 to 15 months after startingthe treatment (median, 13), including 15 patients with a responseand 4 with no response who had had some improvement in variousdisease indicators but who had not had a decrease in paraproteinlevels of at least 25 percent. Multivariate analysis indicatedthat increases in lactic dehydrogenase levels (P=0.001), theplasma-cell–labeling index (P=0.006), and C-reactive proteinlevels (P=0.007) were all predictive of a brief period of event-freesurvival, whereas low albumin levels (P<0.001), the deletionof chromosome 13 (P=0.004), and high numbers of plasma cellsin bone marrow (P=0.05) were associated with a relatively shortoverall survival.
Figure 2. Kaplan–Meier Estimates of Overall Survival and Event-free Survival.
Event-free survival was calculated from the start of thalidomide therapy to progression, removal from the study for any reason, death from any cause, or the last follow-up visit, whichever occurred first. I bars indicate standard errors at 12 months.
Thalidomide was discontinued after a median of 52 days (range,2 to 286) because of a lack of response in 53 patients (4 patientscontinued to receive the drug without a response) and becauseof relapse in 12 patients who had had a response. One patientwho had a decrease in the paraprotein level of at least 25 percentand who had not previously received high-dose therapy subsequentlyunderwent autologous stem-cell transplantation at his own request.As of June 17, 1999, 36 patients had died, including 30 patientswithout a response who died of progressive disease or complicationsof subsequent salvage therapy, as well as 6 patients with aresponse who subsequently relapsed and died of progressive disease(3) or toxicity from salvage therapy (3).
Discussion
We found that thalidomide had substantial antitumor activityin patients with advanced myeloma. Ten percent of patients hadcomplete or nearly complete remission, and 32 percent had areduction in serum or urine paraprotein levels of at least 25percent. In most patients, the decline in paraprotein levelswas accompanied by a reduction in the percentage of plasma cellsin bone marrow and an increase in hemoglobin levels, both ofwhich are consistent with the presence of a true antitumor effect.Although not examined quantitatively, bone pain decreased markedlyin patients with a response. We did not evaluate lytic bonelesions, which seldom heal, even in patients with a sustainedcomplete remission.
Thalidomide has a number of properties that could explain itsactivity in myeloma; it can alter the expression of adhesionmolecules,25 suppress the production of tumor necrosis factor,26 increase the production of interleukin-10,27 and enhancecell-mediated immunity by directly stimulating cytotoxic T cells.28Its interactions with type 1 and type 2 helper T cells producecomplex effects on the levels of cytokines such as interleukin-4,interleukin-5, and interferon-.29 Thalidomide also increasesthe total number of lymphocytes as well as CD8+ and CD4+ T-cellcounts, along with substantially increasing mean plasma levelsof soluble interleukin-2 receptor.29
Thalidomide has been shown to inhibit angiogenesis induced byfibroblast growth factor and vascular endothelial growth factorin a rabbit-cornea micropocket assay9 and a murine model ofcorneal vascularization.10 It has also been shown to cause apoptosisof established tumor-associated angiogenesis in experimentalmodels.10 The bone marrow of patients with hematologic cancersshows extensive vascularity,12,13 which has prognostic implicationsin myeloma.14 The apparent lack of a consistent decrease inthe microvascular density of bone marrow in patients in whomthalidomide had a marked antitumor effect requires further study.The persistence of extensive vascularization in some patientswith a response is consistent with the finding of persistentneovascularity in patients with multiple myeloma who had a responseto high-dose chemotherapy.15 The production of angiogenic cytokinessuch as fibroblast growth factor and vascular endothelial growthfactor by undetectable residual myeloma cells may sustain theincreased microvascular density of bone marrow in patients consideredto be in remission on the basis of bone marrow findings. Thepersistence of extensive vascularization in patients with aresponse makes it seem likely that the antimyeloma action ofthalidomide depends on more than one of the actions of the drugoutlined above. The mouse model of severe combined immunodeficiency,which can be used for the in vivo growth of primary human myelomacells, is ideally suited to study the mechanisms by which thalidomideinduces responses in myeloma.30
The antitumor properties of thalidomide are being evaluatedin various malignant diseases,31,32,33,34,35 although only limitedefficacy data are available so far. Prolonged responses to thalidomidein some patients with advanced refractory disease suggest thatthe mechanism of action of thalidomide is distinctly differentfrom that of the other agents active against myeloma. The absenceof myelosuppressive and other important adverse effects suggeststhat thalidomide could be an ideal agent for use in combinationwith chemotherapy. Indeed, a complete remission has been achievedwith such an approach in several patients with myeloma who hadno response to treatment with either regimen alone.36 This approachhas also been shown to have greater antitumor activity thanchemotherapy alone in a murine model of breast cancer.37
In our study, most patients had adverse effects, but the majorityof these reactions were mild or moderate. Reducing the doseof thalidomide alleviated the effects in most cases, and onlynine patients discontinued therapy altogether. The gradual reductionin drowsiness and fatigue in some patients with continued treatmentat the same dose (data not shown) suggests the occurrence oftachyphylaxis.
We conclude that thalidomide is active against multiple myeloma,even in patients who relapsed after repeated cycles of high-dosechemotherapy. Larger studies of thalidomide, its analogues,and other inhibitors of angiogenesis are therefore warrantedin patients with myeloma and other cancers. We are currentlyevaluating thalidomide in combination with chemotherapy forpatients with newly diagnosed multiple myeloma.
Supported in part by a grant from the National Cancer Institute(CA55819). Celgene Corporation contributed to the data collectionand analysis and provided the study drug free of cost.
Dr. Zeldis is an employee of Celgene Corporation, and Drs. Mehtaand Singhal own stock in Celgene, which manufactures thalidomide.
We are indebted to Beth Wolmer for her persistence in recommendingthe clinical evaluation of thalidomide in the treatment of multiplemyeloma; to the members of the myeloma data-management teamfor their dedication; and to Caran Swanson for her excellentsecretarial assistance. This article is dedicated to the memoryof Ira Wolmer, M.D.
Source Information
From the Myeloma and Lymphoma Program, South Carolina Cancer Center, University of South Carolina, Columbia (S.S., J.M.); the Myeloma and Transplantation Research Center, University of Arkansas for Medical Sciences, Little Rock (R.D., D.A., P.R., P.E., N.M., E.A., C.W., J.Z., B.B.); and the Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York (M.D.). Other authors were David Siegel, M.D., Ph.D., University of Arkansas for Medical Sciences, Little Rock, and John Crowley, Ph.D., Fred Hutchinson Cancer Research Center, Seattle.
Address reprint requests to Dr. Barlogie at the Myeloma and Transplantation Research Center, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 623, Little Rock, AR 72205.
References
Alexanian R, Dimopoulos M. The treatment of multiple myeloma. N Engl J Med 1994;330:484-489. [Free Full Text]
Barlogie B. Advances in therapy of multiple myeloma: lessons from acute leukemia. Clin Cancer Res 1997;3:2605-2613. [Free Full Text]
Attal M, Harousseau J-L, Stoppa A-M, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996;335:91-97. [Free Full Text]
Barlogie B, Jagannath S, Vesole DH, et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 1997;89:789-793. [Free Full Text]
Tricot G, Jagannath S, Vesole DH, Crowley J, Barlogie B. Relapse of multiple myeloma after autologous transplantation: survival after salvage therapy. Bone Marrow Transplant 1995;16:7-11. [Medline]
Singhal S, Tricot G, Jagannath S, et al. Outcome of relapse after transplantation in myeloma. Blood 1996;88:Suppl 1:611a-611a.abstract
Battegay EJ. Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med 1995;73:333-346. [Medline]
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27-31. [CrossRef][Medline]
D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994;91:4082-4085. [Free Full Text]
Kenyon BM, Browne F, D'Amato RJ. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res 1997;64:971-978. [CrossRef][Medline]
Vacca A, Ribatti D, Roncali L, et al. Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol 1994;87:503-508. [Medline]
Vacca A, Di Loreto M, Ribatti D, et al. Bone marrow of patients with active multiple myeloma: angiogenesis and plasma cell adhesion molecules: LFA-1, VLA-4, LAM-1, and CD44. Am J Hematol 1995;50:9-14. [Medline]
Vacca A, Ribatti D, Roncali L, Dammacco F. Angiogenesis in B cell lymphoproliferative diseases: biological and clinical studies. Leuk Lymphoma 1995;20:27-38. [Medline]
Munshi N, Wilson CS, Penn J, et al. Angiogenesis in newly diagnosed multiple myeloma: poor prognosis with increased microvessel density (MVD) in bone marrow biopsies. Blood 1998;92:Suppl 1:98a-98a.abstract
Rajkumar SV, Fonseca R, Witzig TE, Gertz MA, Greipp PR. Bone marrow angiogenesis in patients achieving complete response after stem cell transplantation for multiple myeloma. Leukemia 1999;13:469-472. [CrossRef][Medline]
Vacca A, Ribatti D, Presta M, et al. Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 1999;93:3064-3073. [Free Full Text]
Olson KB, Hall TC, Horton J, Khung CL, Hosley HF. Thalidomide (N-phthaloylglutamimide) in the treatment of advanced cancer. Clin Pharmacol Ther 1965;6:292-297.
Greipp PR, Witzig TE, Gonchoroff NJ, et al. Immunofluorescence labeling indices in myeloma and related monoclonal gammopathies. Mayo Clin Proc 1987;62:969-977. [Medline]
Bartl R, Frisch B, Fateh-Moghadam A, Kettner G, Jaeger K, Sommerfeld W. Histologic classification and staging of multiple myeloma: a retrospective and prospective study of 674 cases. Am J Clin Pathol 1987;87:342-355. [Medline]
Tricot G, Barlogie B, Jagannath S, et al. Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. Blood 1995;86:4250-4256. [Free Full Text]
Gaynor JJ, Feuer EJ, Tan CC, et al. On the use of cause-specific failure and conditional failure probabilities: examples from clinical oncology data. J Am Stat Assoc 1993;88:400-9.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81.
Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163-170. [Medline]
Geitz H, Handt S, Zwingenberger K. Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade. Immunopharmacology 1996;31:213-221. [CrossRef][Medline]
Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991;173:699-703. [Free Full Text]
Corral LG, Muller GW, Moreira AL, et al. Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity. Mol Med 1996;2:506-515. [Medline]
Haslett PAJ, Corral LG, Albert M, Kaplan G. Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. J Exp Med 1998;187:1885-1892. [Free Full Text]
McHugh SM, Rifkin IR, Deighton J, et al. The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen- and antigen-stimulated human peripheral blood mononuclear cell cultures. Clin Exp Immunol 1995;99:160-167. [Medline]
Yaccoby S, Barlogie B, Epstein J. Primary myeloma cells growing in SCID-hu mice: a model for studying the biology and treatment of myeloma and its manifestations. Blood 1998;92:2908-2913. [Free Full Text]
Minchinton AI, Fryer KH, Wendt KR, Clow KA, Hayes MM. The effect of thalidomide on experimental tumors and metastases. Anticancer Drugs 1996;7:339-343. [Medline]
Figg WD, Bergan R, Brawley O, et al. Randomized phase II study of thalidomide in androgen-independent prostate cancer (AIPC). Proc Am Soc Clin Oncol 1997;16:333a. abstract.
Fine HA, Loeffler JS, Kyritsis A, et al. A phase II trial of the anti-angiogenic agent, thalidomide, in patients with recurrent high-grade gliomas. Proc Am Soc Clin Oncol 1997;16:385a. abstract.
Long G, Vredenburgh J, Rizzeri DA, et al. Pilot trial of thalidomide post-autologous peripheral blood progenitor cell transplantation (PBPC) in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 1998;17:181a. abstract.
Eisen T, Boshoff C, Vaughan MM, et al. Anti-angiogenic treatment of metastatic melanoma, renal cell, ovarian and breast cancers with thalidomide: a phase II study. Proc Am Soc Clin Oncol 1998;17:441a. abstract.
Barlogie B, Desikan R, Munshi N, et al. Single course D.T. PACE anti-angiochemotherapy effects CR in plasma cell leukemia and fulminant multiple myeloma (MM). Blood 1998;92:Suppl 1:273b-273b.abstract
Nguyen M, Tran C, Barsky JR, et al. Thalidomide and chemotherapy combination: preliminary results of preclinical and clinical studies. Int J Oncol 1997;10:965-969.
Cavo, M., Di Raimondo, F., Zamagni, E., Patriarca, F., Tacchetti, P., Casulli, A. F., Volpe, S., Perrone, G., Ledda, A., Ceccolini, M., Califano, C., Bigazzi, C., Offidani, M., Stefani, P., Ballerini, F., Fiacchini, M., de Vivo, A., Brioli, A., Tosi, P., Baccarani, M.
(2009). Short-Term Thalidomide Incorporated Into Double Autologous Stem-Cell Transplantation Improves Outcomes in Comparison With Double Autotransplantation for Multiple Myeloma. JCO
27: 5001-5007
[Abstract][Full Text]
Lacy, M. Q., Hayman, S. R., Gertz, M. A., Dispenzieri, A., Buadi, F., Kumar, S., Greipp, P. R., Lust, J. A., Russell, S. J., Dingli, D., Kyle, R. A., Fonseca, R., Bergsagel, P. L., Roy, V., Mikhael, J. R., Stewart, A. K., Laumann, K., Allred, J. B., Mandrekar, S. J., Rajkumar, S. V.
(2009). Pomalidomide (CC4047) Plus Low-Dose Dexamethasone As Therapy for Relapsed Multiple Myeloma. JCO
27: 5008-5014
[Abstract][Full Text]
Falanga, A., Marchetti, M.
(2009). Venous Thromboembolism in the Hematologic Malignancies. JCO
27: 4848-4857
[Abstract][Full Text]
Lee, S. M., Woll, P. J., Rudd, R., Ferry, D., O'Brien, M., Middleton, G., Spiro, S., James, L., Ali, K., Jitlal, M., Hackshaw, A.
(2009). Anti-angiogenic Therapy Using Thalidomide Combined With Chemotherapy in Small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial. JNCI J Natl Cancer Inst
101: 1049-1057
[Abstract][Full Text]
Hulin, C., Facon, T., Rodon, P., Pegourie, B., Benboubker, L., Doyen, C., Dib, M., Guillerm, G., Salles, B., Eschard, J.-P., Lenain, P., Casassus, P., Azais, I., Decaux, O., Garderet, L., Mathiot, C., Fontan, J., Lafon, I., Virion, J. M., Moreau, P.
(2009). Efficacy of Melphalan and Prednisone Plus Thalidomide in Patients Older Than 75 Years With Newly Diagnosed Multiple Myeloma: IFM 01/01 Trial. JCO
27: 3664-3670
[Abstract][Full Text]
Varettoni, M., Corso, A., Pica, G., Mangiacavalli, S., Pascutto, C., Lazzarino, M.
(2009). Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients. Ann Oncol
0: mdp329v1-mdp329
[Abstract][Full Text]
Dahut, W. L., Aragon-Ching, J. B., Woo, S., Tohnya, T. M., Gulley, J. L., Arlen, P. M., Wright, J. J., Ventiz, J., Figg, W. D.
(2009). Phase I Study of Oral Lenalidomide in Patients With Refractory Metastatic Cancer. J Clin Pharmacol
49: 650-660
[Abstract][Full Text]
Harousseau, J.-L., Dreyling, M., On behalf of the ESMO Guidelines Working Group,
(2009). Multiple myeloma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol
20: iv97-iv99
[Full Text]
Knop, S., Gerecke, C., Liebisch, P., Topp, M. S., Platzbecker, U., Sezer, O., Vollmuth, C., Falk, K., Glasmacher, A., Maeder, U., Einsele, H., Bargou, R. C.
(2009). Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom). Blood
113: 4137-4143
[Abstract][Full Text]
Ocio, E. M., Maiso, P., Chen, X., Garayoa, M., Alvarez-Fernandez, S., San-Segundo, L., Vilanova, D., Lopez-Corral, L., Montero, J. C., Hernandez-Iglesias, T., de Alava, E., Galmarini, C., Aviles, P., Cuevas, C., San-Miguel, J. F., Pandiella, A.
(2009). Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks. Blood
113: 3781-3791
[Abstract][Full Text]
Ludwig, H., Hajek, R., Tothova, E., Drach, J., Adam, Z., Labar, B., Egyed, M., Spicka, I., Gisslinger, H., Greil, R., Kuhn, I., Zojer, N., Hinke, A.
(2009). Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood
113: 3435-3442
[Abstract][Full Text]
Brenner, H., Gondos, A., Pulte, D.
(2009). Expected long-term survival of patients diagnosed with multiple myeloma in 2006-2010. haematol
94: 270-275
[Abstract][Full Text]
Baumann, P., Mandl-Weber, S., Volkl, A., Adam, C., Bumeder, I., Oduncu, F., Schmidmaier, R.
(2009). Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells. Molecular Cancer Therapeutics
8: 366-375
[Abstract][Full Text]
Saad, A. A, Sharma, M., Higa, G. M
(2009). Treatment of Multiple Myeloma in the Targeted Therapy Era. The Annals of Pharmacotherapy
43: 329-338
[Abstract][Full Text]
Palumbo, A., Bringhen, S., Liberati, A. M., Caravita, T., Falcone, A., Callea, V., Montanaro, M., Ria, R., Capaldi, A., Zambello, R., Benevolo, G., Derudas, D., Dore, F., Cavallo, F., Gay, F., Falco, P., Ciccone, G., Musto, P., Cavo, M., Boccadoro, M.
(2008). Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood
112: 3107-3114
[Abstract][Full Text]
Barlogie, B., van Rhee, F., Shaughnessy, J. D. Jr, Epstein, J., Yaccoby, S., Pineda-Roman, M., Hollmig, K., Alsayed, Y., Hoering, A., Szymonifka, J., Anaissie, E., Petty, N., Kumar, N. S., Srivastava, G., Jenkins, B., Crowley, J., Zeldis, J. B.
(2008). Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood
112: 3122-3125
[Abstract][Full Text]
Reece, D. E., Rodriguez, G. P., Chen, C., Trudel, S., Kukreti, V., Mikhael, J., Pantoja, M., Xu, W., Stewart, A. K.
(2008). Phase I-II Trial of Bortezomib Plus Oral Cyclophosphamide and Prednisone in Relapsed and Refractory Multiple Myeloma. JCO
26: 4777-4783
[Abstract][Full Text]
Durie, B. G.M.
(2008). Myeloma Therapy: 25 Years Forward--Immune Modulation Then and Now. JCO
26: 4698-4700
[Full Text]
Lafaras, C., Mandala, E., Verrou, E., Platogiannis, D., Barbetakis, N., Bischiniotis, T., Zervas, K.
(2008). Non-thromboembolic pulmonary hypertension in multiple myeloma, after thalidomide treatment: A pilot study. Ann Oncol
19: 1765-1769
[Abstract][Full Text]
Rajkumar, S. V.
(2008). Treatment of Myeloma: Cure vs Control. Mayo Clin Proc.
83: 1142-1145
[Full Text]
van Rhee, F., Dhodapkar, M., Shaughnessy, J. D. Jr, Anaissie, E., Siegel, D., Hoering, A., Zeldis, J., Jenkins, B., Singhal, S., Mehta, J., Crowley, J., Jagannath, S., Barlogie, B.
(2008). First thalidomide clinical trial in multiple myeloma: a decade. Blood
112: 1035-1038
[Abstract][Full Text]
Mei, S.-C., Wu, R.-T.
(2008). The G-rich promoter and G-rich coding sequence of basic fibroblast growth factor are the targets of thalidomide in glioma. Molecular Cancer Therapeutics
7: 2405-2414
[Abstract][Full Text]
Palumbo, A., Gay, F., Bringhen, S., Falcone, A., Pescosta, N., Callea, V., Caravita, T., Morabito, F., Magarotto, V., Ruggeri, M., Avonto, I., Musto, P., Cascavilla, N., Bruno, B., Boccadoro, M.
(2008). Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma. Ann Oncol
19: 1160-1165
[Abstract][Full Text]
Khong, T., Sharkey, J., Spencer, A.
(2008). The effect of azacitidine on interleukin-6 signaling and nuclear factor-{kappa}B activation and its in vitro and in vivo activity against multiple myeloma. haematol
93: 860-869
[Abstract][Full Text]
Rajkumar, S. V., Rosinol, L., Hussein, M., Catalano, J., Jedrzejczak, W., Lucy, L., Olesnyckyj, M., Yu, Z., Knight, R., Zeldis, J. B., Blade, J.
(2008). Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Thalidomide Plus Dexamethasone Compared With Dexamethasone As Initial Therapy for Newly Diagnosed Multiple Myeloma. JCO
26: 2171-2177
[Abstract][Full Text]
Palumbo, A., Facon, T., Sonneveld, P., Blade, J., Offidani, M., Gay, F., Moreau, P., Waage, A., Spencer, A., Ludwig, H., Boccadoro, M., Harousseau, J.-L.
(2008). Thalidomide for treatment of multiple myeloma: 10 years later. Blood
111: 3968-3977
[Abstract][Full Text]
Chanan-Khan, A. A., Cheson, B. D.
(2008). Lenalidomide for the Treatment of B-Cell Malignancies. JCO
26: 1544-1552
[Abstract][Full Text]
Kyle, R. A., Rajkumar, S. V.
(2008). Multiple myeloma. Blood
111: 2962-2972
[Abstract][Full Text]
Hwang, S. H., Rait, A., Pirollo, K. F., Zhou, Q., Yenugonda, V. M., Chinigo, G. M., Brown, M. L., Chang, E. H.
(2008). Tumor-targeting nanodelivery enhances the anticancer activity of a novel quinazolinone analogue. Molecular Cancer Therapeutics
7: 559-568
[Abstract][Full Text]
Brenner, H., Gondos, A., Pulte, D.
(2008). Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood
111: 2521-2526
[Abstract][Full Text]
Kumar, S. K., Rajkumar, S. V., Dispenzieri, A., Lacy, M. Q., Hayman, S. R., Buadi, F. K., Zeldenrust, S. R., Dingli, D., Russell, S. J., Lust, J. A., Greipp, P. R., Kyle, R. A., Gertz, M. A.
(2008). Improved survival in multiple myeloma and the impact of novel therapies. Blood
111: 2516-2520
[Abstract][Full Text]
Abdelkefi, A., Ladeb, S., Torjman, L., Othman, T. B., Lakhal, A., Romdhane, N. B., Omri, H. E., Elloumi, M., Belaaj, H., Jeddi, R., Aissaoui, L., Ksouri, H., Hassen, A. B., Msadek, F., Saad, A., Hsairi, M., Boukef, K., Amouri, A., Louzir, H., Dellagi, K., Abdeladhim, A. B., on behalf of the Tunisian Multiple Myeloma Study G,
(2008). Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood
111: 1805-1810
[Abstract][Full Text]
Bensinger, W.
(2008). Stem-Cell Transplantation for Multiple Myeloma in the Era of Novel Drugs. JCO
26: 480-492
[Abstract][Full Text]
Matsui, W., Wang, Q., Barber, J. P., Brennan, S., Smith, B. D., Borrello, I., McNiece, I., Lin, L., Ambinder, R. F., Peacock, C., Watkins, D. N., Huff, C. A., Jones, R. J.
(2008). Clonogenic Multiple Myeloma Progenitors, Stem Cell Properties, and Drug Resistance. Cancer Res.
68: 190-197
[Abstract][Full Text]
Johnson, B. E., Rudin, C. M., Salgia, R.
(2008). Novel and Targeted Agents for Small Cell Lung Cancer. Am Soc Clin Oncol Ed Book
2008: 363-367
[Abstract][Full Text]
Dimopoulos, M., Spencer, A., Attal, M., Prince, H. M., Harousseau, J.-L., Dmoszynska, A., Miguel, J. S., Hellmann, A., Facon, T., Foa, R., Corso, A., Masliak, Z., Olesnyckyj, M., Yu, Z., Patin, J., Zeldis, J. B., Knight, R. D., the Multiple Myeloma (010) Study Investigators,
(2007). Lenalidomide plus Dexamethasone for Relapsed or Refractory Multiple Myeloma. NEJM
357: 2123-2132
[Abstract][Full Text]
Weber, D. M., Chen, C., Niesvizky, R., Wang, M., Belch, A., Stadtmauer, E. A., Siegel, D., Borrello, I., Rajkumar, S. V., Chanan-Khan, A. A., Lonial, S., Yu, Z., Patin, J., Olesnyckyj, M., Zeldis, J. B., Knight, R. D., the Multiple Myeloma (009) Study Investigators,
(2007). Lenalidomide plus Dexamethasone for Relapsed Multiple Myeloma in North America. NEJM
357: 2133-2142
[Abstract][Full Text]
Dimopoulos, M. A., Souliotis, V. L., Anagnostopoulos, A., Bamia, C., Pouli, A., Baltadakis, I., Terpos, E., Kyrtopoulos, S. A., Sfikakis, P. P.
(2007). Melphalan-induced DNA damage in vitro as a predictor for clinical outcome in multiple myeloma. haematol
92: 1505-1512
[Abstract][Full Text]
Rajkumar, S. V., Richardson, P. G., Lacy, M. Q., Dispenzieri, A., Greipp, P. R., Witzig, T. E., Schlossman, R., Sidor, C. F., Anderson, K. C., Gertz, M. A.
(2007). Novel Therapy with 2-Methoxyestradiol for the Treatment of Relapsed and Plateau Phase Multiple Myeloma. Clin. Cancer Res.
13: 6162-6167
[Abstract][Full Text]
Aerbajinai, W., Zhu, J., Gao, Z., Chin, K., Rodgers, G. P.
(2007). Thalidomide induces {gamma}-globin gene expression through increased reactive oxygen species mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis. Blood
110: 2864-2871
[Abstract][Full Text]
Palumbo, A., Falco, P., Corradini, P., Falcone, A., Di Raimondo, F., Giuliani, N., Crippa, C., Ciccone, G., Omede, P., Ambrosini, M. T., Gay, F., Bringhen, S., Musto, P., Foa, R., Knight, R., Zeldis, J. B., Boccadoro, M., Petrucci, M. T.
(2007). Melphalan, Prednisone, and Lenalidomide Treatment for Newly Diagnosed Myeloma: A Report From the GIMEMA Italian Multiple Myeloma Network. JCO
25: 4459-4465
[Abstract][Full Text]
Pujol, J. L., Breton, J. L., Gervais, R., Tanguy, M.-L., Quoix, E., David, P., Janicot, H., Westeel, V., Gameroff, S., Geneve, J., Maraninchi, D.
(2007). Phase III Double-Blind, Placebo-Controlled Study of Thalidomide in Extensive-Disease Small-Cell Lung Cancer After Response to Chemotherapy: An Intergroup Study FNCLCC cleo04 IFCT 00-01. JCO
25: 3945-3951
[Abstract][Full Text]
Rao, K. V.
(2007). Lenalidomide in the treatment of multiple myeloma. Am J Health Syst Pharm
64: 1799-1807
[Abstract][Full Text]
Yildirim, N. D., Ayer, M., Kucukkaya, R. D., Alpay, N., Mete, O., Yenerel, M. N., Yavuz, A. S., Nalcaci, M.
(2007). Leukocytoclastic Vasculitis due to Thalidomide in Multiple Myeloma. Jpn J Clin Oncol
37: 704-707
[Abstract][Full Text]
Katzel, J. A., Hari, P., Vesole, D. H.
(2007). Multiple Myeloma: Charging Toward a Bright Future. CA Cancer J Clin
57: 301-318
[Abstract][Full Text]
Li, Y., Hou, J., Jiang, H., Wang, D., Fu, W., Yuan, Z., Chen, Y., Zhou, L.
(2007). Polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide-based regimens in multiple myeloma. haematol
92: 1246-1249
[Abstract][Full Text]
Plasmati, R., Pastorelli, F., Cavo, M., Petracci, E., Zamagni, E., Tosi, P., Cangini, D., Tacchetti, P., Salvi, F., Bartolomei, I., Michelucci, R., Tassinari, C. A.
(2007). Neuropathy in multiple myeloma treated with thalidomide: A prospective study. Neurology
69: 573-581
[Abstract][Full Text]
Zervas, K, Mihou, D, Katodritou, E, Pouli, A, Mitsouli, C., Anagnostopoulos, A, Delibasi, S, Kyrtsonis, M., Anagnostopoulos, N, Terpos, E, Zikos, P, Maniatis, A, Dimopoulos, M., On behalf of the Greek Myeloma Study Group,
(2007). VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek myeloma study group. Ann Oncol
18: 1369-1375
[Abstract][Full Text]
Sirohi, B, Powles, R, Lawrence, D, Treleaven, J, Kulkarni, S, Leary, A, Rudin, C, Horton, C, Morgan, G
(2007). An open, randomized, controlled, phase II, single centre, two-period cross-over study to compare the quality of life and toxicity experienced on PEG interferon with interferon-{alpha}2b in patients with multiple myeloma maintained on a steady dose of interferon-{alpha}2b. Ann Oncol
18: 1388-1394
[Abstract][Full Text]
Mileshkin, L., Honemann, D., Gambell, P., Trivett, M., Hayakawa, Y., Smyth, M., Beshay, V., Ritchie, D., Simmons, P., Milner, A. D., Zeldis, J. B., Prince, H. M.
(2007). Patients with multiple myeloma treated with thalidomide: evaluation of clinical parameters, cytokines, angiogenic markers, mast cells and marrow CD57+ cytotoxic T cells as predictors of outcome. haematol
92: 1075-1082
[Abstract][Full Text]
Sonneveld, P., van der Holt, B., Segeren, C. M., Vellenga, E., Croockewit, A. J., Verhoef, G. E.G., Cornelissen, J. J., Schaafsma, M. R., van Oers, M. H.J., Wijermans, P. W., Westveer, P. H.M., Lokhorst, H. M.
(2007). Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: long-term follow-up of the Dutch Cooperative Group HOVON 24 trial. haematol
92: 928-935
[Abstract][Full Text]
Tabata, C., Tabata, R., Kadokawa, Y., Hisamori, S., Takahashi, M., Mishima, M., Nakano, T., Kubo, H.
(2007). Thalidomide Prevents Bleomycin-Induced Pulmonary Fibrosis in Mice. J. Immunol.
179: 708-714
[Abstract][Full Text]
Cavo, M., Tosi, P., Zamagni, E., Cellini, C., Tacchetti, P., Patriarca, F., Di Raimondo, F., Volpe, E., Ronconi, S., Cangini, D., Narni, F., Carubelli, A., Masini, L., Catalano, L., Fiacchini, M., de Vivo, A., Gozzetti, A., Lazzaro, A., Tura, S., Baccarani, M.
(2007). Prospective, Randomized Study of Single Compared With Double Autologous Stem-Cell Transplantation for Multiple Myeloma: Bologna 96 Clinical Study. JCO
25: 2434-2441
[Abstract][Full Text]
Richardson, P. G., Mitsiades, C., Schlossman, R., Munshi, N., Anderson, K.
(2007). New Drugs for Myeloma. The Oncologist
12: 664-689
[Abstract][Full Text]
Kristinsson, S. Y., Landgren, O., Dickman, P. W., Derolf, A. R., Bjorkholm, M.
(2007). Patterns of Survival in Multiple Myeloma: A Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2003. JCO
25: 1993-1999
[Abstract][Full Text]
Carlo-Stella, C., Guidetti, A., Di Nicola, M., Lavazza, C., Cleris, L., Sia, D., Longoni, P., Milanesi, M., Magni, M., Nagy, Z., Corradini, P., Carbone, A., Formelli, F., Gianni, A. M.
(2007). IFN-{gamma} Enhances the Antimyeloma Activity of the Fully Human Anti-Human Leukocyte Antigen-DR Monoclonal Antibody 1D09C3. Cancer Res.
67: 3269-3275
[Abstract][Full Text]
Richardson, P.
(2007). Toward a new therapeutic backbone in myeloma. Blood
109: 2672-2673
[Full Text]
Palumbo, A., Ambrosini, M. T., Benevolo, G., Pregno, P., Pescosta, N., Callea, V., Cangialosi, C., Caravita, T., Morabito, F., Musto, P., Bringhen, S., Falco, P., Avonto, I., Cavallo, F., Boccadoro, M., for the Italian Multiple Myeloma Network, Gruppo I,
(2007). Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood
109: 2767-2772
[Abstract][Full Text]
Fonseca, R., Stewart, A. K.
(2007). Targeted therapeutics for multiple myeloma: The arrival of a risk-stratified approach. Molecular Cancer Therapeutics
6: 802-810
[Abstract][Full Text]
Armand, J.-P., Burnett, A. K., Drach, J., Harousseau, J.-L., Lowenberg, B., San Miguel, J.
(2007). The Emerging Role of Targeted Therapy for Hematologic Malignancies: Update on Bortezomib and Tipifarnib. The Oncologist
12: 281-290
[Abstract][Full Text]
Sekimoto, E., Ozaki, S., Ohshima, T., Shibata, H., Hashimoto, T., Abe, M., Kimura, N., Hattori, K., Kawai, S., Kinoshita, Y., Yamada-Okabe, H., Tsuchiya, M., Matsumoto, T.
(2007). A Single-Chain Fv Diabody against Human Leukocyte Antigen-A Molecules Specifically Induces Myeloma Cell Death in the Bone Marrow Environment. Cancer Res.
67: 1184-1192
[Abstract][Full Text]
Sanchorawala, V., Wright, D. G., Rosenzweig, M., Finn, K. T., Fennessey, S., Zeldis, J. B., Skinner, M., Seldin, D. C.
(2007). Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood
109: 492-496
[Abstract][Full Text]
Richardson, P. G., Hideshima, T., Anderson, K. C.
(2007). Plasma cell dyscrasias. ASH-SAP
2007: 298-327
[Full Text]
Baz, R, Walker, E, Karam, M., Choueiri, T., Jawde, R., Bruening, K, Reed, J, Faiman, B, Ellis, Y, Brand, C, Srkalovic, G, Andresen, S, Knight, R, Zeldis, J, Hussein, M.
(2006). Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol
17: 1766-1771
[Abstract][Full Text]
Lin, Y.-C., Shun, C.-T., Wu, M.-S., Chen, C.-C.
(2006). A Novel Anticancer Effect of Thalidomide: Inhibition of Intercellular Adhesion Molecule-1-Mediated Cell Invasion and Metastasis through Suppression of Nuclear Factor-{kappa}B. Clin. Cancer Res.
12: 7165-7173
[Abstract][Full Text]
Lonial, S.
(2006). When "the same" is really "different". Blood
108: 3233-3234
[Full Text]
Richardson, P. G., Blood, E., Mitsiades, C. S., Jagannath, S., Zeldenrust, S. R., Alsina, M., Schlossman, R. L., Rajkumar, S. V., Desikan, K. R., Hideshima, T., Munshi, N. C., Kelly-Colson, K., Doss, D., McKenney, M. L., Gorelik, S., Warren, D., Freeman, A., Rich, R., Wu, A., Olesnyckyj, M., Wride, K., Dalton, W. S., Zeldis, J., Knight, R., Weller, E., Anderson, K. C.
(2006). A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood
108: 3458-3464
[Abstract][Full Text]
Attal, M., Harousseau, J.-L., Leyvraz, S., Doyen, C., Hulin, C., Benboubker, L., Agha, I. Y., Bourhis, J.-H., Garderet, L., Pegourie, B., Dumontet, C., Renaud, M., Voillat, L., Berthou, C., Marit, G., Monconduit, M., Caillot, D., Grobois, B., Avet-Loiseau, H., Moreau, P., Facon, T., for the Inter-Groupe Francophone du Myelome (IFM),
(2006). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood
108: 3289-3294
[Abstract][Full Text]
Barlogie, B., Tricot, G.
(2006). Complete response in myeloma: a Trojan horse?. Blood
108: 2134-2134
[Full Text]
Chang, D. H., Liu, N., Klimek, V., Hassoun, H., Mazumder, A., Nimer, S. D., Jagannath, S., Dhodapkar, M. V.
(2006). Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood
108: 618-621
[Abstract][Full Text]
Eom, K.-S., Min, C.-K., Lee, S., Kim, Y.-J., Kim, S.-Y., Kim, H.-J., Lee, J.-W., Min, W.-S., Kim, C.-C.
(2006). Efficacy of Up-Front Treatment with a Double Stem Cell Transplantation in Multiple Myeloma. Jpn J Clin Oncol
36: 432-438
[Abstract][Full Text]
Richardson, P. G., Briemberg, H., Jagannath, S., Wen, P. Y., Barlogie, B., Berenson, J., Singhal, S., Siegel, D. S., Irwin, D., Schuster, M., Srkalovic, G., Alexanian, R., Rajkumar, S. V., Limentani, S., Alsina, M., Orlowski, R. Z., Najarian, K., Esseltine, D., Anderson, K. C., Amato, A. A.
(2006). Frequency, Characteristics, and Reversibility of Peripheral Neuropathy During Treatment of Advanced Multiple Myeloma With Bortezomib. JCO
24: 3113-3120
[Abstract][Full Text]
Lacy, M. Q.
(2006). Multiple Myeloma: New Options, New Challenges. Mayo Clin Proc.
81: 877-879
[Full Text]
Hussein, M. A., Baz, R., Srkalovic, G., Agrawal, N., Suppiah, R., Hsi, E., Andresen, S., Karam, M. A., Reed, J., Faiman, B., Kelly, M., Walker, E.
(2006). Phase 2 Study of Pegylated Liposomal Doxorubicin, Vincristine, Decreased-Frequency Dexamethasone, and Thalidomide in Newly Diagnosed and Relapsed-Refractory Multiple Myeloma. Mayo Clin Proc.
81: 889-895
[Abstract][Full Text]
Anderson, G., Gries, M., Kurihara, N., Honjo, T., Anderson, J., Donnenberg, V., Donnenberg, A., Ghobrial, I., Mapara, M. Y., Stirling, D., Roodman, D., Lentzsch, S.
(2006). Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1. Blood
107: 3098-3105
[Abstract][Full Text]
Barlogie, B., Tricot, G., Rasmussen, E., Anaissie, E., van Rhee, F., Zangari, M., Fassas, A., Hollmig, K., Pineda-Roman, M., Shaughnessy, J., Epstein, J., Crowley, J.
(2006). Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies. Blood
107: 2633-2638
[Abstract][Full Text]
Barlogie, B., Tricot, G., Anaissie, E., Shaughnessy, J., Rasmussen, E., van Rhee, F., Fassas, A., Zangari, M., Hollmig, K., Pineda-Roman, M., Lee, C., Talamo, G., Thertulien, R., Kiwan, E., Krishna, S., Fox, M., Crowley, J.
(2006). Thalidomide and Hematopoietic-Cell Transplantation for Multiple Myeloma. NEJM
354: 1021-1030
[Abstract][Full Text]
Vessella, R. L., Guise, T. A., Susman, E. S., Suva, L. J., Clines, G. A., Kominsky, S. L., Weber, K. L., Chirgwin, J. M., McCauley, L. K., Kozlow, W.
(2006). Meeting Report from Skeletal Complications of Malignancy IV: A symposium jointly sponsored by The Paget Foundation for Paget's Disease of Bone and Related Disorders, the National Cancer Institute, and the University of Virginia School of Medicine * April 28-30, 2005 in Bethesda, Maryland, USA. IBMS BoneKEy
3: 15-42
[Full Text]
Haubitz, M., Peest, D.
(2006). Myeloma - new approaches to combined nephrological-haematological management. Nephrol Dial Transplant
21: 582-590
[Full Text]
Lee, C. P., Patel, P. M., Selby, P. J., Hancock, B. W., Mak, I., Pyle, L., James, M. G., Beirne, D. A., Steeds, S., A'Hern, R., Gore, M. E., Eisen, T.
(2006). Randomized Phase II Study Comparing Thalidomide With Medroxyprogesterone Acetate in Patients With Metastatic Renal Cell Carcinoma. JCO
24: 898-903
[Abstract][Full Text]
Li, P.-K., Pandit, B., Sackett, D. L., Hu, Z., Zink, J., Zhi, J., Freeman, D., Robey, R. W., Werbovetz, K., Lewis, A., Li, C.
(2006). A thalidomide analogue with in vitro antiproliferative, antimitotic, and microtubule-stabilizing activities.. Molecular Cancer Therapeutics
5: 450-456
[Abstract][Full Text]
Colleoni, M., Orlando, L., Sanna, G., Rocca, A., Maisonneuve, P., Peruzzotti, G., Ghisini, R., Sandri, M. T., Zorzino, L., Nole, F., Viale, G., Goldhirsch, A.
(2006). Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol
17: 232-238
[Abstract][Full Text]
Rajkumar, S. V., Blood, E., Vesole, D., Fonseca, R., Greipp, P. R.
(2006). Phase III Clinical Trial of Thalidomide Plus Dexamethasone Compared With Dexamethasone Alone in Newly Diagnosed Multiple Myeloma: A Clinical Trial Coordinated by the Eastern Cooperative Oncology Group. JCO
24: 431-436
[Abstract][Full Text]
Richardson, P., Anderson, K.
(2006). Thalidomide and Dexamethasone: A New Standard of Care for Initial Therapy in Multiple Myeloma. JCO
24: 334-336
[Full Text]
Roccaro, A. M., Hideshima, T., Raje, N., Kumar, S., Ishitsuka, K., Yasui, H., Shiraishi, N., Ribatti, D., Nico, B., Vacca, A., Dammacco, F., Richardson, P. G., Anderson, K. C.
(2006). Bortezomib Mediates Antiangiogenesis in Multiple Myeloma via Direct and Indirect Effects on Endothelial Cells. Cancer Res.
66: 184-191
[Abstract][Full Text]
Orlowski, R. Z.
(2006). Initial Therapy of Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation. ASH Education Book
2006: 338-347
[Abstract][Full Text]
Zonder, J. A.
(2006). Thrombotic Complications of Myeloma Therapy. ASH Education Book
2006: 348-355
[Abstract][Full Text]
Augustson, B. M., Begum, G., Dunn, J. A., Barth, N. J., Davies, F., Morgan, G., Behrens, J., Smith, A., Child, J. A., Drayson, M. T.
(2005). Early Mortality After Diagnosis of Multiple Myeloma: Analysis of Patients Entered Onto the United Kingdom Medical Research Council Trials Between 1980 and 2002--Medical Research Council Adult Leukaemia Working Party. JCO
23: 9219-9226
[Abstract][Full Text]
David, E., Sun, S.-Y., Waller, E. K., Chen, J., Khuri, F. R., Lonial, S.
(2005). The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT. Blood
106: 4322-4329
[Abstract][Full Text]
Rajkumar, S. V.
(2005). Thalidomide Therapy and Deep Venous Thrombosis in Multiple Myeloma. Mayo Clin Proc.
80: 1549-1551
Trieu, Y., Trudel, S., Pond, G. R., Mikhael, J., Jaksic, W., Reece, D. E., Chen, C. I., Stewart, A. K.
(2005). Weekly Cyclophosphamide and Alternate-Day Prednisone: An Effective, Convenient, and Well-Tolerated Oral Treatment for Relapsed Multiple Myeloma After Autologous Stem Cell Transplantation. Mayo Clin Proc.
80: 1578-1582
[Abstract]
Chanan-Khan, A., Miller, K. C., Takeshita, K., Koryzna, A., Donohue, K., Bernstein, Z. P., Mohr, A., Klippenstein, D., Wallace, P., Zeldis, J. B., Berger, C., Czuczman, M. S.
(2005). Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL). Blood
106: 3348-3352
[Abstract][Full Text]
Duyvendak, M., Naunton, M., Kingma, B. J, Brouwers, J. R.
(2005). Thalidomide-Associated Thrombocytopenia. The Annals of Pharmacotherapy
39: 1936-1939
[Abstract][Full Text]
Rajkumar, S. V., Kyle, R. A.
(2005). Multiple Myeloma: Diagnosis and Treatment. Mayo Clin Proc.
80: 1371-1382
[Abstract]
A correction has been published: N Engl J Med 2000;342(5):364.
90 percent reduction in serum or urine paraprotein levels), a bone marrow response was defined as the finding of less than 5 percent plasma cells in the biopsy specimen or aspirate. For the remaining patients with a paraprotein response, the percentage of plasma cells had to decrease by at least 50 percent to qualify as a bone marrow response. 
0.01). Although the microvascular density of bone marrow decreased markedly in some patients with a complete or nearly complete remission, estimates of the slope were not significantly different from zero among those with a response (P=0.39) and those without a response (P=0.22). 
,26 increase the production of interleukin-10,27 and enhance cell-mediated immunity by directly stimulating cytotoxic T cells.28 Its interactions with type 1 and type 2 helper T cells produce complex effects on the levels of cytokines such as interleukin-4, interleukin-5, and interferon-
.29 Thalidomide also increases the total number of lymphocytes as well as CD8+ and CD4+ T-cell counts, along with substantially increasing mean plasma levels of soluble interleukin-2 receptor.29 
Previous
