Originally published as JCO Early Release 10.1200/JCO.2007.12.3323 on September 4 2007

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Phase II Pethema Trial of Alternating Bortezomib and Dexamethasone As Induction Regimen Before Autologous Stem-Cell Transplantation in Younger Patients With Multiple Myeloma: Efficacy and Clinical Implications of Tumor Response Kinetics

Laura Rosiñol, Albert Oriol, Maria Victoria Mateos, Anna Sureda, Pedro García-Sánchez, Norma Gutiérrez, Adrián Alegre, Juan José Lahuerta, Javier de la Rubia, Carlos Herrero, Xiangyang Liu, Helgi Van de Velde, Jesús San Miguel, Joan Bladé

From the Hospital Clinic Barcelona; Hospital Sant Pau, Barcelona; Hospital Germans Trias i Pujol, Badalona; Hospital Clínico Salamanca, Salamanca; Hospital Clínico Madrid; Hospital La Princesa; Hospital 12 de Octubre; Janssen Cilag Spain, Madrid; Hospital La Fe, Valencia; Johnson & Johnson Pharmaceutical R&D, Beerse, Belgium; and Johnson & Johnson Pharmaceutical R&D, Raritan, NJ

Address reprint requests to Joan Bladé, MD, Department of Hematology, Hospital Clínic, Villarroel, 170, Barcelona 08036 Spain; e-mail: jblade{at}clinic.ub.es

	ABSTRACT

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Purpose This is the first study in which bortezomib and dexamethasone were administered on an alternating basis as up-front therapy in multiple myeloma (MM). We investigated the efficacy and kinetics of response to each drug and safety.

Patients and Methods Patients with newly diagnosed MM who were less than 66 years old were treated with bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11 (cycles 1, 3, and 5) and dexamethasone 40 mg orally on days 1 through 4, 9 to 12, and 17 to 20 (cycles 2, 4, and 6), followed by autologous stem-cell transplantation (ASCT). Responses were evaluated by modified European Bone Marrow Transplantation criteria. Random effects models were used to analyze the tumor response kinetics.

Results Forty patients were enrolled. Partial response (PR) or greater was 65% (12.5% complete response [CR], 10% very good PR [VGPR], and 42.5% PR) plus 17.5% minor response. Time to response was rapid, with 82% serum M-protein reduction achieved within the first two cycles. The M-protein decrease was similar with dexamethasone and with bortezomib (P = .48). Chromosome 13 deletion, t(4;14), and t(14;16) did not have a negative impact on response. Toxicity was low, with no grade 3 to 4 peripheral neuropathy and no grade 2 to 4 thrombocytopenia. The response rate after ASCT was 88%, with 33% CR (negative immunofixation) plus 22% VGPR.

Conclusion Bortezomib alternating with dexamethasone is a highly effective induction regimen with low toxicity. The kinetic study has shown a high degree of heterogeneity in response and rapid effect from both agents, supporting the use of a short induction regimen before ASCT in MM.

	INTRODUCTION

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High-dose therapy followed by autologous stem-cell transplantation (ASCT) is a gold-standard for the treatment of younger patients with multiple myeloma (MM).^1-5 However, patients who appear to benefit from ASCT are those achieving complete response (CR) or very good partial response (VGPR) after transplantation,^6-8 with the tumor reduction attained with the induction pretransplantation chemotherapy being the major determinant of the post-transplantation CR/VGPR.^6,7 Therefore, high-quality responses, as reflected by CR plus VGPR, after transplantation might be further increased by improving the induction treatment. In this regard, the induction pretransplantation treatment with infusional vincristine, doxorubicin, and dexamethasone (VAD) is currently being replaced by new regimens with higher antimyeloma activity, including bortezomib-based regimens and immunomodulatory-containing therapy.

In recent years, novel drugs such as thalidomide and bortezomib were introduced in the treatment of MM. Bortezomib (Velcade; Millennium Pharmaceuticals, Cambridge, MA; formerly PS-341), as a single agent, produces a response rate ranging from 35% to 50%, including up to a 9% CR rate^9-12 in relapsed/refractory patients. Subgroup analysis of the SUMMIT and CREST phase II studies^9,10 showed that the addition of dexamethasone resulted in an improved response in 18% and 33% of patients included in these trials, respectively.¹³

In the up-front setting, bortezomib alone^14,15 produces a response rate of 40%, with a 10% CR rate. Jagannath et al¹⁶ conducted a phase II trial in which dexamethasone was added to bortezomib in case of suboptimal response, and the final overall response rate was 88%, including a 6% CR rate. Clinical¹⁶ and in vitro¹⁷ data suggest that the combination of bortezomib and dexamethasone is at least additive. Therefore, Harousseau et al¹⁸ combined bortezomib and dexamethasone as induction therapy as part of the pretransplantation regimen and achieved a response rate of 66%, with 21% CR. However, with the simultaneous administration of bortezomib and dexamethasone in the up-front setting, the frequency of grade 2 or greater peripheral neuropathy ranges between 14% and 31%.^16,18 The efficacy of bortezomib and dexamethasone administered on an alternating basis has not been investigated. In this phase II trial, bortezomib and dexamethasone were administered in an alternating schedule as induction therapy to decrease toxicity and to assess the efficacy of each agent separately.

	PATIENTS AND METHODS

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Patient Selection
Patients up to the age of 66 years with newly diagnosed MM were eligible for the study. Other inclusion criteria included good performance status (Eastern Cooperative Oncology Group performance status of < 3), platelet count 50 x 10⁹/L, hemoglobin 8 g/dL, absolute neutrophil count 1 x 10⁹/L, serum calcium 14 mg/dL, and creatinine 2 mg/dL. All patients provided written informed consent before entering the study. This clinical trial was approved by the ethics committee at all participating centers. In conformity with the Spanish and European legislation, this study was subjected to an independent external review.

Study Design and End Points
This phase II trial was conducted in nine centers of Spain. Patients up to the age of 66 years with newly diagnosed MM were scheduled to receive three courses each of bortezomib and dexamethasone on an alternating basis as induction therapy before ASCT. The main end points of the study were to assess the overall response rate and the kinetics of response (ie, serum and urine M-protein variations after each cycle of bortezomib and dexamethasone). The secondary objectives were to assess safety, adequacy of stem-cell collection, and response after ASCT.

Treatment and Dose Modifications
Bortezomib 1.3 mg/m² was administered intravenously on days 1, 4, 8, and 11 of a 21-day cycle in cycles 1, 3, and 5. Dexamethasone 40 mg/d was administered orally on days 1 through 4, 9 through 12, and 17 through 20 of a 28-day cycle in cycles 2, 4, and 6. Peripheral-blood stem cell collection was performed after priming with granulocyte colony-stimulating factor (10 µg/kg). The high-dose therapy regimen consisted of melphalan 200 mg/m².

Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (version 3.0). Bortezomib was withheld for up to 2 weeks in case of grade 4 hematologic toxicity or any grade 3 nonhematologic toxicity related to bortezomib until toxicity returned at least to grade 2. If the toxicity resolved, bortezomib was restarted at a dose reduced by 25% (1.3 to 1.0 mg/m² and 1.0 to 0.7 mg/m²). Dose modification in case of peripheral neuropathy related to bortezomib was managed as previously described.^19,20 For any grade 3 to 4 adverse event related to dexamethasone, the drug was withheld for up to 2 weeks until toxicity returned at least to grade 2. Dexamethasone was restarted at a dose reduced by 25%, and if symptoms remained, a second reduction of 25% was allowed. No antiviral or antibacterial prophylaxis was administered. No thromboprophylaxis was administered.

Response Criteria
Blood and urine samples for serum and urine M-protein measurements were collected at baseline, before each cycle during the induction period, and 3 and 6 months after ASCT. M-components were quantitated by standard electrophoresis. Responses were assessed according to the European Bone Marrow Transplantation criteria,²¹ but a VGPR category ( 90% reduction of serum M-protein) also was included according to the Uniform Response Criteria.²²

Fluorescence In Situ Hybridization Analysis
Bone marrow plasma cells were isolated with anti-CD38–coated magnetic beads. Interphase analysis was performed with specific probes for chromosome 13 deletion, immunoglobulin H (IgH) translocations, and 17p deletion. Patients showing IgH translocations were studied by means of specific probes for t(11;14), t(4;14), and t(14;16).

Statistical Analysis
The ² or t test was used for comparison of different patient characteristics and response to therapy. Linear random effects models were used to analyze the tumor response kinetics to bortezomib and dexamethasone with the absolute value of serum and urine M-protein over time as well as the decrease in M-protein by cycle.²³ Because of the nonlinearity in the change of M-protein over time, a piecewise linear model was used to estimate mean changes in M-protein in each of the six cycles. Patients achieving CR were censored for subsequent kinetic analysis.

	RESULTS

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Patient Characteristics
Between August 22, 2005 and March 3, 2006, 40 patients (18 men and 22 women; median age, 54 years; range, 41 to 65 years) with newly diagnosed MM were enrolled onto the study. Patient demographics and disease characteristics at baseline are listed in Table 1. Six patients had extramedullary plasmacytomas as part of their MM.

Fluorescent in situ hybridization analysis was available in 34 patients (Table 1). There were no differences in response rate among patients with or without Rb or 17p deletion. Similarly, the response rate in patients with or without IgH translocation was not significantly different (93% v 75%, respectively; P = not significant). There were no differences in response rate in patients with t(11;14), t(4;14), or t(14;16).

Stem-Cell Harvest and Response After Transplantation
Three patients did not proceed with stem-cell harvest because of removal from the study as a result of grade 3 skin/liver toxicity, disease progression with poor performance status, and allogeneic stem-cell transplantation (one patient each). Stem-cell harvest was performed in 37 patients. The median number of CD34⁺ cells was 5.6 x 10⁶ CD34⁺ cells/kg (range, 1.5 to 17.8 x 10⁶ CD34⁺ cells/kg), with a median of one collection procedure (range, one to three procedures). There were no mobilization failures.

All 37 patients who were mobilized underwent intensification with ASCT. Thirty-one patients were in response after bortezomib/dexamethasone at the time of transplantation. Three patients with progressive disease received rescue therapy before ASCT. Three patients with progressive disease underwent ASCT with no previous rescue therapy.

Considering the 37 patients who underwent ASCT, the partial or higher response rate at 3 months after transplantation was 88% (33% CR, 22% VGPR, and 33% PR) plus 6% MR and 6% progressive disease. One patient is not yet assessable for response.

Safety
Bortezomib-related toxicity was low (Fig 1). No patient developed grade 4 toxicity. Nine patients (22.5%) developed grade 1 peripheral neuropathy, and one patient (2.5%) developed grade 2 peripheral neuropathy. One patient developed grade 3 skin rash and liver toxicity and was removed from the study. Other grade 3 toxicities included bacterial infections in four patients. No cases of herpes zoster or varicella were seen. The most common hematologic toxicity was neutropenia, which was observed in 27 patients (grade 1, n = 7; grade 2, n = 14; grade 3, n = 6). Eleven patients developed grade 1 thrombocytopenia. Dose reductions from 1.3 to 1 mg/m² of bortezomib were required in only one patient as a result of skin maculopapular rash. In four patients, a single dose of bortezomib was not administered because of nonhematologic toxicity. No patient missed more than one dose of bortezomib.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Summary of adverse events.

Kinetics of Response
The results of serum and urine M-protein evolution in all patients over time are listed in Tables 2 and 3. For the planned 280 serum and urine determinations, 96% of serum and 80% of urine values were available for analysis. The overtime trend for tumor kinetics was nonlinear. Statistically significant decreases in serum M-protein compared with the previous cycle were observed in cycles 1 to 4. The largest reductions in M-protein (both serum and urine) occurred in cycle 1 and 2, with 82% of the serum M-protein decrease observed within the first two cycles. The numerical pattern of reductions in urine M-protein from cycle to cycle was similar to that for serum M-protein. However, no statistically significant reduction was observed in any cycle, probably because of a much higher variability in the urine M-protein size. In fact, the coefficient of variation was three times higher in the urine M-protein data than in the serum M-protein. Numerically, the reduction in M-protein was slightly higher in cycle 2 than in cycle 1 and also higher in cycle 4 compared with cycle 3. However, the total reduction (compared with the immediate prior cycle or baseline for cycle 1) in bortezomib-based cycles was not significantly different from that in dexamethasone-based cycles (difference = 3.31 in serum, P = .4891; difference = 0.15 in urine, P = .9349). Twenty patients responded to both bortezomib and dexamethasone (Fig 2A), whereas 10 patients had a decrease in M-protein only after the cycles of dexamethasone, with five of these patients showing an increase in the M-protein after each cycle of bortezomib (Fig 2B). Three patients responded only to bortezomib (Fig 2C).

View larger version (7K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Evolution of serum M-protein level after each cycle of treatment in (A) one representative patient responding to both bortezomib and dexamethasone, (B) in one patient responding only to dexamethasone, and (C) in one patient only sensitive to bortezomib.

	DISCUSSION

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Bortezomib-containing regimens have resulted in a high response rate in patients with previously untreated MM.^14-16 The aim of our trial was to study the efficacy and safety of bortezomib and dexamethasone administered in an alternating schedule as induction therapy before ASCT. This study also planned to decrease toxicity by using two drugs with no shared toxicity and by prolonging the interval between the administration of the same agent, which allowed analysis of each drug separately. The response rate of 65%, including 12% CR, plus 17% MR by the stringent European Bone Marrow Transplantation criteria is comparable to that obtained in two recent phase II trials in which bortezomib and dexamethasone were administered concomitantly as up-front therapy (Table 4). Jagannath et al¹⁶ reported on 32 patients initially treated with bortezomib alone and then dexamethasone in case of suboptimal response; dexamethasone was added in 22 patients, and the overall response rate at the end of the study was 88% with 6% CR. Harousseau et al¹⁸ reported on 48 patients treated with the combination of bortezomib and dexamethasone. In this trial, the response rate was 66% with 21% CR (defined only by negative electrophoresis). Clinical and laboratory data suggested that the combination of bortezomib and dexamethasone was synergistic.^16,17 However, our results showing a similar response rate with the alternating schedule compared with the simultaneous administration of the two drugs in the study by Harousseau et al¹⁸ strongly support that the effect is only additive. Interestingly, the PR rate with bortezomib alone as up-front therapy is approximately 40% with 10% CR, and the PR rate with dexamethasone alone is 40% to 43% including 0% to 3% CR^25,30,31 (Table 4). A PR rate ranging from 65% to 88% with CR/near CR of 12% to 21% achieved with the administration of both agents is also suggestive of an additive rather than a synergistic effect. A randomized trial comparing the simultaneous versus the alternating schedule to assess the tolerance and efficacy would be of interest.

Chromosome 13 deletion or IgH translocations are associated with poor prognosis in patients with MM. The response rate among our patients with Rb deletion or IgH translocations, including t(4;14) and t(14;16), was similar to that observed in patients without these cytogenetic abnormalities. Our findings and those reported in recently published studies^18,33-35 suggest that the approach of alternating bortezomib and dexamethasone can overcome the negative impact of the poor prognosis cytogenetic abnormalities.

This regimen was extremely well tolerated. Discontinuation as a result of toxicity was only necessary in one patient, and dose reduction of bortezomib was necessary also only in one patient. The number of missing doses was minimal. In our study, no grade 4 adverse events were observed, and of great interest, no grade 3 peripheral neuropathy was observed. In fact, only one patient developed grade 2 peripheral neuropathy. The absence of deep vein thrombosis without the administration of thromboprophylaxis is also of note. This toxicity profile was much better than the toxicity reported in the two trials in which bortezomib and dexamethasone were administered simultaneously.^16,18

The results of the present study augment data on the excellent stem-cell harvesting with bortezomib-based regimens.^16,18 The overall response rate after transplantation was 88%, including 33% CR and 22% VGPR. This response rate is similar to that reported by Harousseau et al¹⁸ with the simultaneous administration of bortezomib and dexamethasone. Taking into account their encouraging results, the Intergroup Francophone du Myelome is conducting a large phase III trial of pretransplantation induction comparing bortezomib plus dexamethasone versus VAD.³⁶ Whether more complex and possibly more toxic combinations (bortezomib/thalidomide/dexamethasone, bortezomib/doxorubicin/dexamethasone, reduced bortezomib/doxorubicin/dexamethasone, and bortezomib/lyposomal doxorubicin/dexamethasone)^32,37-39 will result in a better long-term outcome than double regimens such as thalidomide/dexamethasone or bortezomib/dexamethasone has not yet been established.

In conclusion, bortezomib alternating with dexamethasone is an effective regimen with remarkably low toxicity as induction for younger patients with MM. The kinetic studies performed showed heterogeneity in response, but both agents have a similar and rapid antimyeloma effect. The results of this trial support the study of shorter induction programs with decreased-intensity regimens, such as the alternating bortezomib and dexamethasone approach, before ASCT to improve patient outcome.

	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: Carlos Herrero, Janssen Cilag SA (C); Xiangyang Liu, Johnson & Johnson PRD LLC (C); Helgi Van de Velde, Johnson & Johnson (C) Consultant or Advisory Role: Laura Rosiñol, Janssen Cilag Spain (C); Jesús San Miguel, Johnson & Johnson (C), Pharmion (C), Celgene (C); Joan Bladé, Janssen Cilag (C) Stock Ownership: Xiangyang Liu, Johnson & Johnson Honoraria: Laura Rosiñol, Janssen Cilag Spain; Maria Victoria Mateos, Janssen Cilag; Jesús San Miguel, Johnson & Johnson, Celgene, Pharmion; Joan Bladé, Janssen Cilag, Johnson & Johnson Research Funding: Albert Oriol, Johnson & Johnson; Javier de la Rubia, Janssen Cilag; Joan Bladé, Janssen Cilag Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Laura Rosiñol, Helgi Van de Velde, Jesús San Miguel, Joan Bladé

Administrative support: Juan José Lahuerta, Carlos Herrero, Joan Bladé

Provision of study materials or patients: Laura Rosiñol, Albert Oriol, Maria Victoria Mateos, Anna Sureda, Pedro García-Sánchez, Norma Gutiérrez, Adrián Alegre, Juan José Lahuerta, Javier de la Rubia, Carlos Herrero, Helgi Van de Velde, Jesús San Miguel, Joan Bladé

Collection and assembly of data: Laura Rosiñol, Albert Oriol, Maria Victoria Mateos, Anna Sureda, Pedro García-Sánchez, Adrián Alegre, Javier de la Rubia

Data analysis and interpretation: Laura Rosiñol, Xiangyang Liu, Jesús San Miguel, Joan Bladé

Manuscript writing: Laura Rosiñol, Jesús San Miguel, Joan Bladé

Final approval of manuscript: Laura Rosiñol, Albert Oriol, Maria Victoria Mateos, Anna Sureda, Pedro García-Sánchez, Norma Gutiérrez, Adrián Alegre, Juan José Lahuerta, Carlos Herrero, Javier de la Rubia, Helgi Van de Velde, Xiangyang Liu, Jesús San Miguel, Joan Bladé

	NOTES

 
published online ahead of print at www.jco.org on September 4, 2007.

Supported in part by Grants No. V-2005-F55240-0 and RD 06/0020/005 from Fondo de Investigaciones Sanitarias de la Seguridad Social and by a grant from Johnson and Johnson Pharmaceuticals R&D.

Presented as an oral communication at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

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

	REFERENCES

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1. 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 335:91-97, 1996[Abstract/Free Full Text]

2. Barlogie B, Jagannath S, Desikan KR, et al: Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 93:55-56, 1999[Abstract/Free Full Text]

3. Child JA, Morgan GJ, Davies FE, et al: High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348:1875-1883, 2003[Abstract/Free Full Text]

4. Fermand JP, Katsahian S, Divine M, et al: High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: Long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol 23:9227-9233, 2005[Abstract/Free Full Text]

5. Blade J, Rosiñol L, Sureda A, et al: High-dose therapy intensification versus continued standard chemotherapy in multiple myeloma: Long-term results from a prospective randomized trial from the Spanish Group PETHEMA. Blood 106:3755-3759, 2005[Abstract/Free Full Text]

6. Alexanian R, Weber D, Giralt S, et al: Impact of complete remission with intensive therapy in patients with responsive multiple myeloma. Bone Marrow Transplant 27:1037-1043, 2001[CrossRef][Medline]

7. Nadal E, Gine E, Bladé J, et al: High-dose therapy/autologous stem cell transplantation in patients with chemosensitive multiple myeloma: Predictors of complete remission. Bone Marrow Transplant 33:61-64, 2004[CrossRef][Medline]

8. Moreau P, Garban F, Harousseau JL, et al: The prognostic impact of complete remission (CR) plus very good partial remission (VGPR) in a double-transplantation program for newly diagnosed multiple myeloma (MM): Combined results of the IFM 99 trials. Blood 108:877, 2006 (suppl, abstr 3077)

9. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003[Abstract/Free Full Text]

10. Jagannath S, Barlogie B, Berenson J, et al: A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165-172, 2004[CrossRef][Medline]

11. Richardson PG, Sonneveld P, Schuster MW, et al: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487-2498, 2005[Abstract/Free Full Text]

12. Richardson P, Sonneveld P, Schuster M, et al: Bortezomib continues demonstrates superior efficacy compared with high dose dexamethasone in relapsed multiple myeloma: Updated results of the APEX trial. Blood 106:715, 2005 (suppl, abstr 2547)

13. Jagannath S, Richardson PG, Barlogie B, et al: Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica 91:929-934, 2006[Abstract/Free Full Text]

14. Richardson P, Chanan-Khan A, Schlossman R, et al: A multicenter phase II trial of bortezomib in patients with previously untreated multiple myeloma: Efficacy with manageable toxicity in patients with unexpectedly high rates of baseline peripheral neuropathy. Blood 106:716, 2005 (suppl, abstr 2548)

15. Anderson K, Richardson PG, Chanan-Khan A, et al: Single-agent bortezomib in previously untreated multiple myeloma (MM): Results of a phase II multicenter study. J Clin Oncol 24:423s, 2006 (suppl 18S; abstr 7504)

16. Jagannath S, Durie BG, Wolf J, et al: Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 129:776-783, 2005[CrossRef][Medline]

17. Hideshima T, Richardson P, Chauhan D, et al: The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071-3076, 2001[Abstract/Free Full Text]

18. Harousseau JL, Attal M, Leleu X, et al: Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: Results of an IFM phase II study. Haematologica 91:1498-1505, 2006[Abstract/Free Full Text]

19. Richardson PG, Briemberg H, Jagannath S, et al: Frequency, characteristics and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24:3113-3120, 2006[Abstract/Free Full Text]

20. San Miguel J, Bladé J, Boccadoro M, et al: A practical update on the use of bortezomib in the management of multiple myeloma. Oncologist 11:51-61, 2006[Abstract/Free Full Text]

21. Bladé J, Samson D, Reece D, et al: Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high dose therapy and hematopoietic stem cell transplantation. Br J Haematol 102:1115-1123, 1998[CrossRef][Medline]

22. Durie BGM, Harousseau JL, San Miguel J, et al: International uniform response criteria for multiple myeloma. Leukemia 20:1467-1473, 2006[CrossRef][Medline]

23. Goldstein H: Multilevel Statistical Models. London, United Kingdom, Arnold, 1995

24. Cavo M, Zamagni E, Tosi P, et al: Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 106:35-39, 2005[Abstract/Free Full Text]

25. Rajkumar SV, Blood E, Vesole D, et al: 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. J Clin Oncol 24:431-436, 2006[Abstract/Free Full Text]

26. Rajkumar SV, Hussein M, Catalano J, et al: A randomized, double-blind, placebo-controlled trial of thalidomide plus dexamethasone versus dexamethasone alone as primary therapy for newly diagnosed multiple myeloma. Blood 108:238, 2006 (suppl, abstr 795)[Abstract/Free Full Text]

27. Macro M, Divine M, Uzunhan Y, et al: Dexamethasone + thalidomide (Dex/Thal) compared to VAD as a pretransplant treatment in newly diagnosed multiple myeloma (MM): A randomized trial. Blood 108:22, 2006 (abstr 57)

28. Thomas SK, Giralt SA, Wang M, et al: Survival outcomes of patients receiving thalidomide-dexamethasone for previously untreated multiple myeloma. Blood 108:1019, 2006 (suppl, abstr 3569)

29. Rajkumar SV, Hayman SR, Lacy MQ, et al: Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 106:4050-4053, 2005[Abstract/Free Full Text]

30. Alexanian R, Dimopoulos MA, Delasalle K, et al: Primary dexamethasone treatment of multiple myeloma. Blood 80:887-890, 1992[Abstract/Free Full Text]

31. Facon T, Mary JY, Pégourie B, et al: Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood 107:1292-1298, 2006[Abstract/Free Full Text]

32. Wang M, Delasalle K, Giralt S, et al: Rapid control of previously untreated multiple myeloma with bortezomib-thalidomide-dexamethasone followed by early intensive therapy. Blood 106:231, 2005 (suppl, abstr 784)

33. Mateos MV, Hernández JM, Hernández MT, et al: Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: Results of a multicenter phase I/II study. Blood 108:2165-2172, 2006[Abstract/Free Full Text]

34. Jagannath S, Richardson PG, Sonneveld P, et al: Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 21:151-157, 2007[CrossRef][Medline]

35. Sagester V, Ludwig H, Kaufmann H, et al: Bortezomib in relapsed multiple myeloma: Response rates and duration of response are independent of a chromosome 13q-deletion. Leukemia 21:164-168, 2007[CrossRef][Medline]

36. Harousseau JL, Marit G, Caillot D, et al: Velcade/dexamethasone (Vel/Dex) versus VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM): An interim analysis of the IFM 2005-01 randomized multicenter phase III trial. Blood 108:882, 2006 (suppl, abstr 56)

37. Jakubowiak AJ, A-Zoubi A, Kendall T, et al: High rate of complete and near complete responses (CR/nCR) after initial therapy with bortezomib (Velcade), Doxil, and dexamethasone (VDD) is further increased after autologous stem cell transplantation (ASCT). Blood 108:21, 2006 (suppl, abstr 3093)

38. Oakervee HE, Popat R, Curry N, et al: PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol 129:755-762, 2005[CrossRef][Medline]

39. Popat R, Oakervee HE, Curry N, et al: Reduced dose PAD combination therapy (PS 341/bortezomib, Adriamycin and dexamethasone) for previously untreated patients with multiple myeloma. Blood 106:717, 2005 (suppl; abstr 2554)[Abstract/Free Full Text]

Submitted April 25, 2007; accepted July 3, 2007.

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