Originally published as JCO Early Release 10.1200/JCO.2007.14.1853 on March 24 2008

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Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Thalidomide Plus Dexamethasone Compared With Dexamethasone As Initial Therapy for Newly Diagnosed Multiple Myeloma

S. Vincent Rajkumar, Laura Rosiñol, Mohamad Hussein, John Catalano, Wieslaw Jedrzejczak, Lela Lucy, Marta Olesnyckyj, Zhinuan Yu, Robert Knight, Jerome B. Zeldis, Joan Bladé

From the Mayo Clinic, Rochester, MN; Cleveland Clinic, Cleveland, OH; Frankston Hospital, Frankston, Australia; Medical Academy of Warsaw, Warsaw, Poland; Pharmion Corp Boulder, CO; Celgene Corporation, Summit, NJ; and Hospital Clinic, IDIBAPS, Barcelona, Spain

Corresponding author: S. Vincent Rajkumar, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: rajkumar.vincent{at}mayo.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose The long-term impact of thalidomide plus dexamethasone (thal/dex) as primary therapy for newly diagnosed multiple myeloma (MM) is unknown. The goal of this study was to compare thalidomide plus dexamethasone versus placebo plus dexamethasone (placebo/dex)as primary therapy for newly diagnosed MM.

Patients and Methods In this double-blind, placebo-controlled trial, patients with untreated symptomatic MM were randomized to thal/dex (arm A) or to placebo plus dexamethasone (dex) (arm B). Patients in arm A received oral thalidomide 50 mg daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2 (28-day cycles). Oral dex 40 mg was administered on days 1 through 4, 9 through 12, and 17 through 20 during cycles 1 through 4 and on days 1 through 4 only from cycle 5 onwards. Patients in arm B received placebo and dex, administered as in arm A. The primary end point of the study was time to progression. This study is registered at http://ClinicalTrials.gov (NCT00057564).

Results A total of 470 patients were enrolled (235 randomly assigned to thal/dex and 235 to placebo/dex). The overall response rate was significantly higher with thal/dex compared with placebo/dex (63% v 46%), P < .001. Time to progression (TTP) was significantly longer with thal/dex compared with placebo/dex (median, 22.6 v 6.5 months, P < .001). Grade 4 adverse events were more frequent with thal/dex than with placebo/dex (30.3% v 22.8%).

Conclusion Thal/dex results in significantly higher response rates and significantly prolongs TTP compared with dexamethasone alone in patients with newly diagnosed MM.

	INTRODUCTION

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Multiple myeloma (MM) accounts for approximately 10% of hematologic malignancies.¹ Treatment consists of chemotherapy; the most common regimens are melphalan plus prednisone (MP), high-dose dexamethasone, and vincristine, doxorubicin, and dexamethasone (VAD).² In some studies, high-dose therapy with autologous stem-cell transplantation (ASCT) has resulted in significantly prolonged survival compared with conventional-dose chemotherapy.^3,4

Thalidomide plus dexamethasone (thal/dex) has shown encouraging results in newly diagnosed myeloma in small, uncontrolled trials.^5-7 Some studies have reported the superiority of thal/dex compared with intravenous VAD based on short-term response rates.^8-10 In a recent randomized trial, the Eastern Cooperative Oncology Group (ECOG) found significantly higher response rates with thal/dex compared with dexamethasone alone following 4 months of therapy (63% versus 41%).¹¹ However, there was no data on long-term outcome measures, such as time to progression (TTP) and progression-free survival (PFS).

The goal of this clinical trial was to compare the response rate, TTP, and PFS of thal/dex versus dexamethasone alone in a randomized, placebo-controlled trial in patients with newly diagnosed MM.

	PATIENTS AND METHODS

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Eligibility
Patients were eligible if they had previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein of at least 200 mg/24 hours. Patients also needed to have a platelet count of at least 50,000 cells/mm³, absolute neutrophil count more than 1,000 cells/mm³, serum creatinine no higher than3 mg/dL, bilirubin 2 mg/dL or lower, and ALT and AST less than or equal to 3x the upper limit of normal. No prior systemic therapy, with the exception of bisphosphonates, was permitted. Patients were excluded if they had grade 2 or higher peripheral neuropathy, active infection, current or prior deep vein thrombosis, or Eastern Cooperative Oncology Group (ECOG) performance score of 3 or 4. Pregnant or nursing women were not eligible. Women of child-bearing potential who were unwilling to use a dual method of contraception and men who were unwilling to use a condom were not eligible. The study was approved by the institutional review boards in the participating institutions. Patients were enrolled between March 14, 2003, and April 11, 2005, in 77 participating institutions.

Randomization and Treatment Schedule
Patients were randomized in this double-blind placebo controlled trial to thal/dex (arm A) or placebo plus dexamethasone (placebo/dex; arm B). Random assignment was performed by a centralized telephone interactive voice response service with sequence of allocation concealed. Subjects were to be randomly assigned with a 1:1 randomization between the two treatment groups, stratified at random assignment by the following prognostic risk factors: age (< 65 years, 65 years), ECOG performance status score (0 or 1, 2), and beta-2M level (< 2.5 mg/L, 2.5 mg/L). Patients in arm A received thalidomide 50 mg orally daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2; dexamethasone 40 mg was administered orally on days 1 through 4, 9 through 12, and 17 through 20 during cycles 1 through 4 and on day 1 through 4 only beginning with cycle 5. Patients in arm B received placebo (identical to thalidomide administration) and dexamethasone was administered as in arm A. Cycles were 28 days long, and were repeated until progression or undue toxicity; there was no gap between cycles. No specific treatment recommendations were made for treatment after progression. Patients were allowed to interrupt therapy briefly for growth factor–supported stem-cell mobilization; however, patients who received nonprotocol therapy or transplantation had to go off study. Dose adjustments were permitted for toxicity. Patients who developed deep vein thrombosis (DVT) or pulmonary embolism (PE) were required to stop thalidomide therapy temporarily; patients were allowed to resume treatment after therapeutic anticoagulation (warfarin or low molecular weight heparin) was achieved with a 50% dose reduction based on experience in prior studies. Thromboprophylaxis was not mandated during this study; all patients were recommended to receive a bisphosphonate.

Response and Toxicity Criteria
The response criteria used were standard European Group for Blood and Bone Marrow Transplant (ie, EBMT or Bladé) criteria.¹² Partial response (PR) was defined as at least a 50% reduction in the level of the serum monoclonal (M) protein and a reduction in 24-hour urinary M protein of at least 90% or to less than 200 mg, plus no increase in the number or size of lytic bone lesions or any other evidence of progressive disease by other parameters. Complete response (CR) required confirmed disappearance of the monoclonal protein in the serum and urine by immunofixation studies and less than 5% plasma cells on bone marrow examination. All response categories required confirmation by two consecutive measurements at least 6 weeks apart. In addition, patients were classified as having a very good partial response (VGPR) based on the International Myeloma Working Group (IMWG) response criteria.¹³ VGPR required either serum and urine M protein levels detectable only on immunofixation but not on electrophoresis or at least 90% reductions in serum M protein and 24-hour urine M protein to less than 100 mg/24 hours.

Disease progression required any one of the following criteria: (1) increase in serum monoclonal protein more than 25% above the lowest response level and an absolute increase of at least 5 g/L; (2) increase in urine monoclonal protein by 25% above the lowest remission value and an absolute increase in excretion by 200 mg/24 hours or greater; (3) increase in size of soft tissue plasmacytoma or appearance of a new plasmacytoma; (4) definite appearance of bone lesions or increase in the size of existing bone lesions; and (5) unexplained hypercalcemia more than 2.8 mmol/L (>11.5 mg/dL). For patients in CR, relapse included reappearance of monoclonal protein by immunofixation or protein electrophoresis of the serum or urine, or any other sign of progression. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 2, was used to classify and grade adverse events.

Statistical Design and Analysis
All analyses were performed on an intention-to-treat principle. The two principal investigators of the study (S.V.R. and J.B.) had complete access to the data and were responsible for the interpretation of the data and writing of the manuscript. The primary end point was TTP defined using EBMT criteria. TTP was defined as the time from random assignment to disease progression. TTP and all other measures of efficacy were calculated before initiation of any nonprotocol therapy including transplantation; any patient who received such therapy was censored. Thus the reported efficacy measures represent the sole effect of primary therapy with thal/dex or placebo/dex. PFS was defined as time from random assignment to disease progression or death resulting from any cause. Planned sample size was 218 eligible patients in each arm. The study was designed with a one-sided log-rank test ( = 0.025, allowing for one interim analysis) and 80% power to detect a 40% improvement in TTP (16.8 months in arm A v 12 months in arm B) when 282 patients progressed. A preplanned interim analysis of the primary end point and safety was performed by an independent Data Monitoring Committee (DMC). A P value less than .0015 at this interim analysis would indicate that arm A is superior to arm B based on an alpha-spending function of the O'Brien-Fleming type. At this interim analysis, the DMC recommend release of study results and the study was unblinded. The final data set was analyzed for response, progression, and survival by a response review committee blinded to treatment assignment.

Two-sided Fisher's exact tests were used to test for difference in response rate and to assess homogeneity of baseline characteristics for categoric variables between the two arms. Two-sided F-tests from analysis of variance models with treatment as the independent variable were used to assess homogeneity of baseline characteristics between the arms for continuous variables. Survival analysis was done using the method described by Kaplan and Meier.¹⁴ Differences between survival curves were tested for statistical significance using a one-sided log-rank test. The study is registered at http://clinicaltrials.gov (NCT00057564.)

	RESULTS

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Patients were well matched between the two treatment arms; patient characteristics are listed on Table 1. Four hundred seventy patients were registered to the study. Four patients discontinued after random assignment but before receiving study drug (Fig 1). The median follow-up of the whole cohort is 18 months (95% CI, 17 to 19 months), with a median of 17 months for arm A and 18 months for arm B.

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Patient disposition.

The median dose of thalidomide was 200 mg/d through cycle 27. The median dose of thalidomide decreased in subsequent cycles in patients who continued therapy as a result of dose reductions for adverse events; 75 to 100 mg cycle 28 to 31, and 50 mg in patients on therapy beyond cycle 32. Fifty-nine percent of patients in arm A had at least one dose reduction of thalidomide because of adverse effects during the course of the study compared with 40% of patients in arm B who needed at least one dose reduction in the placebo dose because of adverse effects. Primary reasons for dose reductions with thal/dex were infections (17%), muscle weakness (7%), neuropathy and related disorders (8%), and thrombosis (6%). Overall, only seven patients (1.5%) interrupted thalidomide/placebo therapy to pursue stem-cell collection.

Response to Therapy
On the basis of EBMT criteria, overall (CR + PR) response to therapy was significantly higher with thal/dex compared with placebo/dex (63% v 46%, respectively; P < .001; Table 2). A higher proportion of patients also achieved CR with thal/dex than with placebo/dex (7.7% v 2.6%; P = .02). On the basis of the IMWG criteria, the proportion of patients achieving CR or VGPR was 43.8% with thal/dex versus 15.8% with placebo/dex (P < .001).

Progression and Survival
TTP was significantly longer with thal/dex compared with placebo/dex (median, 22.6 v 6.5 months, respectively; P < .001; Fig 2A). PFS was similarly better, with median times of 14.9 versus 6.5 months respectively (P < .001; Fig 2B). Overall survival curves for the two arms are provided in Figure 3; however, survival was not an end point for the study, and the study was not powered to compare differences in survival between arms. Moreover, only 26.6% of patients died on study so far (24.3% in the thal/dex arm and 28.9% in the placebo/dex arm).

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Time to progression of patients receiving thalidomide plus dexamethasone (yellow) versus placebo plus dexamethasone (blue). Time to progression was 22.6 months for thalidomide/dexamethasone median and 6.5 months for placebo/dexamethasone (P < .001; hazard ratio [HR] = 0.43; 95% CI, 0.32 to 0.58). (B) Progression-free survival (PFS) of patients receiving thalidomide/dexamethasone (yellow) versus placebo plus dexamethasone (blue). Median PFS was 14.9 months for thalidomide/dexamethasone and 6.5 months for placebo/dexamethasone (P < .001; HR = 0.50; 95% CI, 0.38 to 0.64).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Overall survival of patients receiving thalidomide and dexamethasone (yellow) versus placebo and dexamethasone (blue).

Toxicity and Deaths
The most common toxicities are listed in Table 3. As expected, constipation, edema, tremor, dizziness were more commonly seen with thal/dex. In addition, grade 1 peripheral neuropathy (assessed as worst grade experienced by each patient) was noted in 32% of patients receiving thal/dex compared with 30% of patients receiving placebo/dex; grade 2 neuropathy in 19% versus 4% of patients, respectively. Table 4 lists the most common grade 3 or higher adverse events seen in the trial. Grade 3 or higher adverse events were more commonly seen with thal/dex than with dex alone (79.5% v 64.2%; P < .001). Grade 4 adverse events were similarly higher with thal/dex (30.3% v 22.8%, respectively).

View this table: [in this window] [in a new window]   Table 3. Most Frequently Observed ( 15%) Adverse Events by Preferred Term (safety population)

DVT was significantly more frequent with thal/dex compared with placebo/dex: 18.8% versus 5.6%, respectively. In the thal/dex arm, most DVTs (98%) occurred within the first 6 months of therapy. Incidence of DVT during the first four treatment cycles was 15.0% and 3.9% in the thal/dex and placebo/dex arms, respectively. The overall response rate to thal/dex was the same regardless of DVT occurrence; 68.2% in patients who had a DVT compared 61.8% in those without DVT. Most patients did not receive DVT prophylaxis; only 34% (thal/dex) and 29% (placebo/dex) of patients had some recorded use of aspirin during the defined time period. Eight of 44 thal/dex patients with a history of DVT had a second event, and two of 13 placebo/dex patients had a second thrombotic event. Forty-one of 234 patients in the thal/dex arm, and 38 of 232 patients in the placebo/dex arm received erythropoietic agents. The DVT rate in the thal/dex arm was significantly higher with use of erythropoietic agents (24.4% v 17.6%; P < .001); no difference was seen in the placebo/dex arm (5.3% v 5.7%, respectively).

	DISCUSSION

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Thalidomide first showed antimyeloma activity in a trial conducted in patients with advanced relapsed refractory myeloma.^15,16 Several trials have since confirmed that thalidomide produces a response rate ranging from 25% to 35% when used as a single-agent in patients with relapsed refractory myeloma.^17,18 Weber et al¹⁹ found that patients who had previously experienced treatment failure with thalidomide and dexamethasone individually respond again when the two drugs are combined. This observation led to several phase II clinical trials with thal/dex in relapsed multiple myeloma,^20,21 as well as newly diagnosed disease.^5-7 A subsequent ECOG randomized trial showed better responses with thal/dex compared with dexamethasone. However, there are no outcome data with long-term thal/dex therapy.

The present trial was designed in parallel with the ECOG trial to answer two separate questions concerning the efficacy of thal/dex: short-term (4 month) response rate in the ECOG trial, and long-term end point of TTP as primary end point in the present study primarily targeting patients unable or unwilling to undergo early ASCT.

Responses were observed in excess of 60% of patients with thal/dex. More importantly, the present study demonstrates that the depth of response is significantly higher with thal/dex; 43.8% of patients achieved CR or VGPR with thal/dex compared with only 15.8% with placebo/dex. Achievement of CR and VGPR are the best predictors of long-term outcome in myeloma.^22,23

This trial provides the first comparative data on TTP and PFS with thal/dex in myeloma. As clearly shown, the significant improvement in response rates achieved with thal/dex does translate into longer TTP and PFS. The TTP seen with thal/dex of 22.6 months in this trial is somewhat lower than what is seen with ASCT (29 months).²² The PFS seen with dexamethasone is short (6.5 months), illustrating the major limitations of high-dose pulse dexamethasone as a single agent; previous studies have estimated a longer PFS of 13 months.²⁴ The study excluded patients with serum creatinine more than 3 mg/dL, and hence the results cannot be extrapolated to such patients.

As expected, there is an increased risk of serious adverse events with thal/dex compared with placebo/dex. Early deaths caused by infections were low in both arms. The trial was initiated at a time when the high thrombosis risk with thal/dex,^5,25 and the efficacy of thromboprophylaxis were not yet well established. Thus, patients in this trial did not receive routine thromboprophylaxis. A recent report by Palumbo et al²⁶ provides strong evidence that routine thromboprophylaxis reduces the risk of DVT/PE when thalidomide is used in combination therapy for newly diagnosed multiple myeloma. This study, and recent reports with the thalidomide analog lenalidomide suggest that avoiding erythropoietic agents may decrease the incidence of DVT.²⁷

The results of this study must be considered in the context of other advances occurring in the treatment of myeloma. The combination of melphalan, prednisone, and thalidomide (MPT) is emerging as the standard of care for patients who are not candidates for ASCT.^26,28 MPT is preferable to thal/dex in patients who are not candidates for ASCT. On the other hand, patients who are candidates for ASCT need to avoid melphalan exposure, and thal/dex is an excellent oral regimen for such patients. Studies show that therapy with thal/dex does not significantly affect stem-cell yield.^5,11 Some of the significant toxicity issues associated with thalidomide are also reduced when the drug is used for shorter periods (ie, for four cycles). As expected, in the absence of routine thromboprophylaxis the incidence of DVT/PE within four cycles was higher with thal/dex than with placebo/dex, and the rate of grade 3 peripheral neuropathy was 5.1%.

Other newly diagnosed regimens being tested need to be compared prospectively with thal/dex.^29-32 In a phase II trial, lenalidomide in combination with dexamethasone has shown higher response rates than reported in the present study.^33,34 However, lenalidomide seems to confer a similar risk for DVT.²⁷ Lenalidomide is also associated with a greater incidence of hematologic adverse events.³⁵ No comparative study has yet been conducted to our knowledge to evaluate the relative efficacy of the two drugs.

One limitation of the present trial was that overall survival comparisons were not possible because the trial was not powered to address the question, mainly because it was believed that a significant number of patients would go on to ASCT in disproportionate levels between the two arms, and at differing time points. Moreover, at the time of the final analysis, fewer than 27% of patients had died, making survival comparisons not possible.

This large phase III study provides precise estimates of the various categories of response, TTP, PFS, and rates of specific adverse events that are seen with thal/dex and dexamethasone in patients with newly diagnosed disease. Thal/dex should be considered a standard front-line regimen for the treatment of patients with myeloma who are candidates for ASCT. Future studies in MM should test new combinations, and explore the role of ASCT in the era of new drugs.³⁶

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Lela Lucy, Pharmion (C); Marta Olesnyckyj, Celgene (C); Zhinuan Yu, Celgene (C); Robert Knight, Celgene (C); Jerome B. Zeldis, Celgene (C) Consultant or Advisory Role: None Stock Ownership: Lela Lucy, Pharmion; Marta Olesnyckyj, Celgene; Zhinuan Yu, Celgene; Robert Knight, Celgene; Jerome B. Zeldis, Celgene Honoraria: Mohamad Hussein, Celgene Research Funding: S. Vincent Rajkumar, Celgene; Laura Rosinol, Celgene; Mohamad Hussein, Celgene; John Catalano, Celgene; Wieslaw Jedrzejczak, Celgene; Joan Bladé, Celgene Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: S. Vincent Rajkumar, Robert Knight, Joan Bladé

Financial support: Marta Olesnyckyj, Robert Knight, Jerome B. Zeldis

Administrative support: Marta Olesnyckyj, Robert Knight, Jerome B. Zeldis

Provision of study materials or patients: S. Vincent Rajkumar, Laura Rosinol, Mohamad Hussein, John Catalano, Wieslaw Jedrzejczak, Joan Bladé

Data analysis and interpretation: S. Vincent Rajkumar, Laura Rosinol, Lela Lucy, Zhinuan Yu, Joan Bladé

Manuscript writing: S. Vincent Rajkumar, Joan Bladé

Final approval of manuscript: S. Vincent Rajkumar, Laura Rosinol, Mohamad Hussein, John Catalano, Wieslaw Jedrzejczak, Lela Lucy, Marta Olesnyckyj, Zhinuan Yu, Robert Knight, Jerome B. Zeldis, Joan Bladé

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The following are MM003 investigators and participating institutions.

North America
Canada. M. Voralia (Saskatoon Cancer Center, Saskatoon Saskatchewan), D. White (Queen Elizabeth II Health Services Centre, Halifax).

United States. J. Berenson (Berenson Oncology, West Hollywood), L. Bertoli (Clinical Research Consultants Inc, Hoover), T. Dobbs (Baptist Regional Cancer Center, Knoxville), H. Fernandez (Miami), M. Goodman (University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami), D. Gravenor (The Family Cancer Center, Collierville), S. Gregory (Rush University Medical Center, Chicago), J. Hays, Centralia, D. Hurd (Wake Forest University School of Medicine, Winston-Salem), M. Hussein (Cleveland), A. Jakubowiak (University of Michigan, Ann Arbor), R. Lambert-Falls (South Carolina Oncology Assoc, Columbia), M. Modiano (Arizona Clinical Research Center, Tucson), S.V. Rajkumar (Mayo Clinic Cancer Center, Rochester), G.D. Roodman (University of Pittsburgh, VA Pittsburgh Health Care System, Pittsburgh), V. Roy (Mayo Clinic, Jacksonville), G. Schiller (University of California, Los Angeles School of Medicine, Los Angeles), R. Sobecks (Cleveland Clinic, Cleveland), D. Vesole, Milwaukee, J. Wade (Medical College of Wisconsin, Milwaukee).

Europe
Belgium. D. Bron (Institut Bordet, Brussel), L. Noens (Gent) A. Janssens (UZ Gent, Gent), H. Schots (VUB, Brussel).

Bulgaria. D. Peytchev (National Center of Hematology and Transfusiology, Sofia).

Hungary. Z. Gasztonyi (Petz Aladar Country Hospital, Gyor).

Italy. M. Baccarani (Policlinico Sant'Orsola-Malpighi, Bologna), F. Dammacco (Universita di Bari Dipartimento di Scienze Biomedichee, Bari); R. Fanin (Policlinico Universitario a Gesttione diretta di Udine, Udine), R. Foa (Univerita La Sapien, Roma), M. Gobbi (Azienda Ospedaliera San Martino, Genova), M. Lazzarino (Policlinico San MatteoViale C. Golgi, Pavia), E. Morra (Ospedale Niguarda Ca Granda, Milano).

Poland. A. Dmoszynska (University School of Medicine, Lublin), A. Hellmann (Institute of Internal Diseases, University of Medicine, Gdansk), W. Jedrzejczak (Akademia Medyczna w Warszawie Samodzielny Publiczny Centralny Szpital Kliniczny, Warsaw), J. Kloczko (Klinika Hematologii Samodzielny Publiczny Szpital Kliniczny Akademii, Bialystok), A. Pluzanska (Uniwersytet Medyczny w Lodzi, Lodz), A. Skotnicki (Oddzial Kliniczny Kliniki Hematologii, Krakow).

Spain. A. Alegre (Hospital Universitario de la Princessa, Madrid), J. Baro (Hospital Universtario Marques de Valdecilla, Santandar), J. Blade (Hospital Clinic, Barcelona), J.-J. Lahuerta (Hospital Doce de Octubre, Madrid), F. Prosper (Clinica Universitaria de Navarra, Pamplona), J. San Miguel (Hospital Universitario de Salamanca, Salamanca).

United Kingdom. M. Drake (Belfast City Hospital Hematology Department, Belfast), Kazmi, London, S. Steve (Kings College Hospital, London).

International
Australia. J. Catalano (Frankston Hospital Oncology Research, Frankston), D. Gill (Princess Alexandra Hospital, Woolloongabba), M. Prince (Peter MacCallum Cancer Centre Divsion of Hematology/Medical Oncology, East Melbourne), A. Spencer (The Alfred Hospital, Melbourne), J. Szer (The Royal Melbourne Hospital, Melbourne), P. Wood (Royal Brisbane Hospital, Herston).

Israel. B. Yehuda (Hadassah University Hospital, Jerusalem), A. Nagler (The Chaim Sheba Medical Center, Tel Hashomer), E. Naparstek (Tel Aviv Sourasky Medical Center Department of Hematology, Tel Aviv), J. M Rowe (Rambam Medical Center, Haifa).

Russia. K. Abdulkadyrov (Institute of Hematology and Blood Transfusion St Petersburg Research, St Petersburg), B. Afanasjev (St Petersburg Pavlov State Medical University Hematology Center, St Petersburg), N. Domnikova, (Novosibirsk State Regional Clinical Hospital, Novosibirsk), T. Konstantinova (Ekaterinburg first Regional Hospital, Ekaterinburg), A. Korobkin (Chelyabinsk Regional Clinical Hospital, Medgarodok Chelyabinski), T. Lysaya (Zhitomir Regional Clinical Hospital, Zhitomir), D. Osmanov (Blokhin Cancer Research Center, Moscow), E. Podoltseva (St Petersburg Hospital #31, St Petersburg), V. Rossiev (Samara Regional Clinical Hospital, Samara), O. Rukavitsin (Burdenko Central Military Clinical Hospital, Moscow), O. Samoilova (Nizhny Novgorod Clinical Hospital, Nizhny Novgorod), V. Savchenko (Russian Academy of Medical Sciences, Moscow), A. Suvorov (Republican Clinical Hospital #1, Izhevsk).

Ukraine. G. Babak (Zaporozhje Regional Clinical Hospital, Zaporozhje), A. Dudnichenko (Kharkov Regional Clinical Oncology Center, Kharkov); N. Glushko (Ivano-Frankovsk Regional Clinical Hospital, Ivano-Frankovsk), P. Kaplan (Dnepropetrovsk City Clinical Hospital #4, Dnepropetrovsk), E. Karamanesht (Kiev Bone Marrow Transplantation Center, Bone Marrow Department, Kiev), V. Kozlov (Odess Regional Clinical Hospital, Odessa), Z. Masliak, (Institute of Blood Pathology and Transfusion Medicine of the UAMS Hematology Department, Lviv), G. Pilipenko (Cherkassy Regional Oncology Center, Cherkassy), S. Sivkovich (Kiev Institute of Oncology of the UAMS Systemic Malignancies Department, Kiev), N. Tretyak (Institute of Hematology and Transfusiology of the UAMS Department of Blood Diseases, Kiev).

	NOTES

 
published online ahead of print at www.jco.org on March 24, 2008.

Supported by Celgene Corporation, Summit, NJ; Pharmion Ltd, Windsor, United Kingdom; Public Health Service Grants No. CA93842, CA 107476, CA 62242, and CA 100080 (S.V.R.) from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services; and Spanish Grant No. RD 06/0020/ (L.R., J.B.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted August 27, 2007; accepted December 20, 2007.

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