A Pilot Study of Bortezomib in Korean Patients with Relapsed or Refractory Myeloma

Keun-Wook Lee; Tak Yun; Eun Kee Song; Im il Na; Hyunchoon Shin; Soo-Mee Bang; Jae Hoon Lee; Seung Tae Lee; Jee Hyun Kim; Sung-Soo Yoon; Jong Seok Lee; Seonyang Park; Byoung Kook Kim; Noe Kyeong Kim

doi:10.3346/jkms.2005.20.4.598

Journal List > J Korean Med Sci > v.20(4) > 1020042

Go to TopGo to Top Go to BottomGo to Bottom

TOOLS

Lee, Yun, Song, Na, Shin, Bang, Lee, Lee, Kim, Yoon, Lee, Park, Kim, and Kim: A Pilot Study of Bortezomib in Korean Patients with Relapsed or Refractory Myeloma

Original Article

Journal of Korean Medical Science

Journal of Korean Medical Science 2005; 20(4): 598-602.

Published online: 31 August 2005

DOI: https://doi.org/10.3346/jkms.2005.20.4.598

A Pilot Study of Bortezomib in Korean Patients with Relapsed or Refractory Myeloma

Keun-Wook Lee^*, Tak Yun^*, Eun Kee Song^*, Im il Na^*, Hyunchoon Shin^*, Soo-Mee Bang^†, Jae Hoon Lee^†, Seung Tae Lee^‡, Jee Hyun Kim^*, Sung-Soo Yoon^*,^§,^∥, Jong Seok Lee^*, Seonyang Park^*,^§,^∥, Byoung Kook Kim^*,^§,^∥, Noe Kyeong Kim^*

^*Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

^†Department of Internal Medicine, Gachon Medical School, Incheon, Korea.

^‡Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

^§Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

^∥Clinical Research Institute, Seoul National University Hospital, Seoul, Korea.

Address for correspondence: Sung-Soo Yoon, M.D. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, Seoul 110-744, Korea. Tel: +82.2-760-3079, Fax: +82.2-762-9662, ssysmc@snu.ac.kr

Received 20 December 2004 Accepted 8 April 2005

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Recent clinical trials showed that bortezomib, a novel proteasome inhibitor, had therapeutic activity in multiple myeloma. However, there was no data about the feasibility of bortezomib in Korean patients. We performed a pilot study of bortezomib in patients with relapsed or refractory myeloma (1.3 mg/m² twice weekly for 2 week in a 3-week cycle). Seven patients were enrolled. The median age of patients was 59 yr. All patients previously received VAD (vincristine, doxorubicin and dexamethasone) and thalidomide chemotherapy. Three patients previously received alkylator-containing chemotherapy and 4 patients, autologous stem cell transplantation. Bortezomib monotherapy resulted in 3 partial remissions (43%), 3 no changes (43%) and 1 progressive disease (14%). One patient who had no response to bortezomib monotherapy experienced partial remission after addition of dexamethasone to bortezomib. The most common serious toxicity was thrombocytopenia (grade 3/4, 10 of 20 cycles (50%)) and grade 3 peripheral neuropathy was developed in 2 of 20 cycles (10%). Drug-related adverse event led to discontinuation of bortezomib in 1 patient. There was no treatment related mortality. Overall, bortezomib seems to be effective and feasible. Conduction of larger clinical studies on Korean patients is necessary to characterize clinical efficacy and safety of bortezomib more precisely.

Keywords: Multiple Myeloma, Drug Therapy, bortezomib, Velcade, Proteasome Endopeptidase Complex, Protease Inhibitors

INTRODUCTION

Multiple myeloma (MM) is a malignant plasma cell disorder accounting for ~10% of hematological malignancies that frequently involves old age patients. The incidence of multiple myeloma has been increasing since the 1980s in Korea (1). Treatment options for patients with symptomatic MM range from relatively simple conventional chemotherapy to high-dose chemotherapy followed by peripheral stem cell or bone marrow transplantation (2).

For the last several decades, conventional chemotherapy using melphalan and prednisolone was the mainstay of myeloma treatment that produced response rates of 50-60%. But, complete remission (CR) was less than 5%, and median remission duration and overall survival (OS) were 18 and 30-36 months (3, 4). There is no evidence that additional cytotoxic agents, such as doxorubicin and nitrosourea, offer survival advantages compared with that achieved with melphalan and prednisolone (5). High-dose chemotherapy followed by hematopoietic stem cell transplantation has been shown to increase the percentage of CR to almost 50% in selected patients. Although conventional chemotherapy and high-dose therapy with hematopoietic stem cell rescue can prolong survival, few, if any, patients are cured (6-10). However, salvage therapies for these patients with relapsed or refractory MM are disappointing, and although thalidomide has shown some promise (11-15), more effective treatment strategies are urgently required.

Recent clinical trials showed that bortezomib (Velcade®, formerly PS341), a novel proteasome inhibitor, had therapeutic activity in patients with relapsed or refractory myeloma (16, 17). Richardson et al. reported that the response rate to bortezomib was 35% and a median duration of response was 12 months in relapsed or refractory myeloma (16). However, only 2 phase II clinical trials that showed the efficacy of bortezomib in myeloma patients were published (16, 17) and no data is available upon bortezomib in Korean patients with relapsed or refractory MM. Therefore, a pilot study of bortezomib in these myeloma patients was conducted in 3 institutions. This pilot study aimed to assess the feasibility of bortezomib in Korean patients.

PATIENTS AND METHODS

Patients

The eligibility criteria for patients were as follows; 1) patient age ≥18 yr, 2) multiple myeloma which was relapsed or refractory to previous chemotherapy or autologous stem cell transplantation, 3) patients with measurable disease [M-protein], 4) an ECOG performance status of 0-3, 5) aspartate aminotransferase or alanine aminotransferase ≤3× upper limit of normal, and total bilirubin ≤2× upper limit of normal, 6) creatinine clearance ≥10 mL/min, 7) platelet count ≥30×109/L, hemoglobin ≥8.0 g/dL and absolute neutrophil count ≥0.5×10⁹/L. All patients gave written informed consent before study entry.

Treatment

Patients received bortezomib (Velcade®, 1.3 mg per square meter of body-surface area) as an intravenous bolus (taking 3 to 5 sec to administer) twice weekly for 2 weeks (days 1, 4, 8 and 11) in a 21-day cycle. Treatment was withheld from patients with drug-related grade 3 or worse non-hematologic adverse events or grade 4 hematologic adverse events until the events had diminished to grade 1 or better. Then, treatment was resumed at a dose of 1.0 mg per square meter upon resolution of the adverse events. Further reduction to 0.7 mg per square meter was allowed, but lower doses were not permitted. Patients with no change or progressive disease after 2 cycles were permitted to receive 20 mg of oral or intravenous dexamethasone on the day of and the day following each dose of bortezomib.

Assessment of efficacy and safety

The primary end-point was overall response rate to bortezomib. Response to bortezomib was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT) (18) before initiation of each bortezomib chemotherapy cycle. Complete remission (CR) was defined as the absence of M-protein on immunofixation (or immunoelectrophoresis) for 6 weeks and 5% or fewer plasma cells in the bone marrow, with no increase in size or number of bone lesions and the disappearance of soft tissue plasmacytomas. Partial remission (PR) was defined as ≥50% decrease of serum M-protein and/or ≥90% decrease of urine M-protein for 6 weeks, with no increase in size or number of bone lesions. Minimal response (MR) was defined as 25-49% decrease of serum M-protein and/or 50-89% reduction in urine M-protein, which still exceeded 200 mg/day for 6 weeks. No change (NC) was defined as not meeting the criteria of either minimal response or progressive disease, and progressive disease (PD) was defined as ≥25% increase of serum M-protein, which must have represented an absolute increase of at least 0.5 g/dL, and/or ≥25% increase of urine M-protein, which must have represented an absolute increase of at least 200 mg/day and have been confirmed by at least one repeated test.

Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0, from the first dose until 20 days after the last dose of bortezomib.

Statistical analysis

Time to progression (TTP) was defined as the interval from the initial administration of bortezomib to disease progression. Overall survival (OS) was defined as the time elapsed from the onset of bortezomib to death whatever the cause of death. Distributions over time were estimated by Kaplan-Meier analysis.

RESULTS

Patient characteristics

Seven patients were accrued onto this study between November 2003 and April 2004 from 3 centers. All 7 patients had measurable serum M-protein amount. The median age was 59 yr (range: 57-67 yr). All patients previously received VAD (vincristine, doxorubicin and dexamethasone) and thalidomide (±dexamethasone) chemotherapy. Three patients previously received alkylator-containing chemotherapy and 4 patients received autologous peripheral blood stem cell transplantation. Table 1 shows the summary of base-line characteristics and treatment courses of enrolled patients.

Treatment and efficacy

A total of 20 cycles of bortezomib and/or dexamethasone treatment was performed (Table 1). Among 3 patients who experienced NC after 2 cycles of bortezomib treatment, dexamethasone was added to the bortezomib treatment regimen in 2 patients (case 4 and 6) in cycle 3. Two patients (case 3 and 7) received only one cycle of bortezomib; additional bortezomib chemotherapy was not performed in one patient (case 7) because of disease progression and the other (case 3) received tandem autologous stem cell transplantation after achievement of PR following one cycle of bortezomib. Two patients (case 2 and 5) received 2 cycles of bortezomib; one patient (case 2) dropped out of the study because of the economic problem for the treatment and the other patient (case 5) with the response of NC after 2 cycles of bortezomib received other salvage chemotherapy. As shown in Table 1, 3 patients (43%) achieved PR. Three patients (43%) experienced NC and one patient (14%), PD. Among 2 patients who experienced NC after 2 cycles of bortezomib monotherapy and received additional dexamethasone in cycle 3, 1 patient (case 6) achieved PR after the addition of dexamethasone. So, overall response to bortezomib and/or dexamethasone was 57%.

Adverse events

Commonly reported adverse events in this pilot study are shown in Table 2. Thrombocytopenia, emesis, leucopenia, anemia, peripheral neuropathy and hepatic enzyme elevation were common. Emesis was mild to moderate and easily manageable with routine support. The most commonly reported serious adverse event was thrombocytopenia (grade 3/4, 10 of 20 cycles (50%) and 4 of 7 patients (57%)). Grade 3 peripheral neuropathy developed in 2 of 20 cycles (10%) and 1 of 7 patients (14%). There was no treatment related mortality.

Drug-related adverse event led to discontinuation of bortezomib therapy in 1 patient (case 6). After 2 cycles of bortezomib monotherapy and 4 cycles of bortezomib/dexamethasone combination, this patient suffered from severe pneumonia and needed mechanical ventilation care. After recovery, peripheral neuropathy (grade 3) persisted and further administration of bortezomib was not done.

Time to progression and overall survival

Median follow-up duration was 10.5 months (range 6.4-11.2 months). During follow-up period, four cases (57%) showed increased M-protein amount (disease progression) during or after the completion of bortezomib and/or dexamethasone treatment. Other two patients received another treatment after documentation of PR (case 3) and NC (case 5). These two patients (case 3 and 5) were considered as 'censored' cases in this study. Only one case (case 2) was in the status of continuous PR at the last follow-up. When time to progression (TTP) was defined as the interval from the initial administration of bortezomib to disease progression, median TTP in patients who received bortezomib and/or dexamethasone was 5.1 months (95% confidence interval: 3.3-6.9 months). During the follow-up period, four patients (57%) were still alive and three patients died. Cause of death was disease progression in all three patients (Table 1).

DISCUSSION

The proteasome is a multi-enzyme complex that is present in all cells. It degrades proteins that regulate cell-cycle progression (19, 20) and causes proteolysis of IκB the endogenous inhibitor of nuclear factor-κB (NF-κB). Degradation of IκB by proteasome activates NF-κB, which up-regulates the transcription of proteins that promote cell survival, stimulate growth, and reduce susceptibility to apoptosis. Also, NF-κB activation induces drug resistance in myeloma cells (16). Bortezomib, a boronic acid dipeptide, reversibly inhibits proteasome function by targeting the chymotrypsin-like site of the proteasome (21) and has antitumor activity in a variety of in vitro and in vivo models of tumors. It induces apoptosis in myeloma-cell lines (22, 23). Molecular mechanisms of bortezomib entail more than NF-κB inhibition (24, 25), and in vivo, it enhances the anti-myeloma activity of chemotherapeutic agents (24, 26).

Based on a phase I study of advanced hematologic cancer, in which bortezomib showed activity in 9 patients with MM (27), 2 phase II trials in relapsed or refractory myeloma were reported until now (16, 17, 28). In these 2 studies, overall response rate to bortezomib alone was 33-50% (16, 17). The median duration of response in responders was 12.0 months and median time to progression among all enrolled patients was 7.0 months (16). The overall response rate of bortezomib and/or dexamethasone was 44-62% (17).

In this pilot study, overall response rate to bortezomib alone was 43%, which was similar to previous reports, and 1 additional PR was achieved with the combination of bortezomib and dexamethasone (case 6). Considering that all enrolled patients previously received chemotherapy (±autologous stem cell transplantation) and thalidomide, bortezomib seems to be effective in chemotherapy and thalidomide-failed myeloma patients. As previous reports, serious thrombocytopenia and peripheral neuropathy were developed. The incidence of grade 3 and 4 thrombocytopenia was 50% in this study. This more frequent incidence of serious thrombocytopenia than previous reports (16, 17) might be caused by patient characteristics of this study, in which all of enrolled patients received bortezomib as 3rd to 6th-line treatment and seemed to have poor bone marrow functions. Median TTP in this study, when bortezomib and/or dexamethasone were administered, was 5.1 months. These toxicity profiles and survival data need to be determined in future larger studies on Korean patients.

Overall, bortezomib seems to be effective and feasible in chemotherapy and thalidomide-failed myeloma patients with the dosage of 1.3 mg per square meter twice weekly for 2 week in a 3-week cycle. These observations necessitate the conduction of future larger clinical studies on Korean patients to characterize clinical efficacy and safety of bortezomib more precisely.

Figures and Tables

Table 1

Summary of patient characteristics and treatment outcomes

^*Abbreviations: APBSCT, autologous peripheral blood stem cell transplantation; B, bortezomib; BD, bortezomib/dexamethasone; CD, cyclophosphamide/dexamethasone; DCEP, dexamethasone/cyclophosphamide/etoposide/cisplatin; EDAP, etoposide/dexamethasone/ara-C/cisplatin; IFN, interferon; MP, melphalan/prednisolone; T, thalidomide; TD, thalidomide/dexamethasone; VAD, vincristine/doxorubicin/dexamethasone. ^†Performed cycles of bortezomib chemotherapy ^‡Change of serum M-protein during bortezomib chemotherapy (before bortezomib chemotherapy→maximally decreased amount of serum M-protein during bortezomib chemotherapy). ^§Abbreviations: PR, partial remission; NC, no change; PD, progressive disease. ^∥Abbreviations: TTP, time to progression; (C) and (P) mean 'censored' and 'progressed', respectively. ^¶Abbreviations: OS, overall survival; (A) and (D) mean 'alive' and 'dead' status at last follow-up. ^**Abbreviations: B2, 2 cycles of bortezomib; BD2, 2 cycles of bortezomib/dexamethasone; BD4, 4 cycles of bortezomib/dexamethasone. ^††This patient (case 6) had 3.2 g/dL of serum M-protein before bortezomib treatment. After 2 cycles of bortezomib, M-protein decreased to 2.7 g/dL (NC). When dexamethasone was added, however, M-protein decreased to 0.3 g/dL after additional 4 cycles of bortezomib/dexamethasone (PR).

Table 2

Reported adverse events

AST, aspartate aminotransferase; ALT, alanine aminotransferase.

Notes

Supported by Cancer Research Institute(Cancer Research Center), Seoul National University College of Medicine, CRI-04-5.

References

1. The Korean Society of Hematology. A statistical study of multiple myeloma in Korea. Korean J Hematol. 1995. 30:345–361.

2. Alexanian R, Dimopoulos M. The treatment of multiple myeloma. N Engl J Med. 1994. 330:484–489.

3. Belch A, Shelley W, Bergsagel D, Wilson K, Klimo P, White D, Willan A. A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer. 1988. 57:94–99.

4. Myeloma Trialists' Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol. 1998. 16:3832–3842.

5. Boccadoro M, Marmont F, Tribalto M, Avvisati G, Andriani A, Barbui T, Cantonetti M, Carotenuto M, Comotti B, Dammacco F. Multiple myeloma: VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients. J Clin Oncol. 1991. 9:444–448.

6. Vesole DH, Barlogie B, Jagannath S, Cheson B, Tricot G, Alexanian R, Crowley J. High-dose therapy for refractory multiple myeloma: improved prognosis with better supportive care and double transplants. Blood. 1994. 84:950–956.

7. Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, Monconduit M, Hulin C, Caillot D, Bouabdallah R, Voillat L, Sotto JJ, Grosbois B, Bataille R. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003. 349:2495–2502.

8. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996. 335:91–97.

9. Bang SM, Cho EK, Suh C, Yoon SS, Seong CM, Cho KS, Kang YG, Park S, Ahn MJ, Park YS, Oh D, Kim HC, Jung CW, Kim S, Lee JH. High dose therapy followed by autologous peripheral blood stem cell transplantation as a first line treatment for multiple myeloma: a Korean Multicenter Study. J Korean Med Sci. 2003. 18:673–678.

10. Lee JL, Kim SB, Lee GW, Ryu MH, Kim E, Kim S, Kim WK, Lee JS, Kim SH, Suh C. The efficacy of high-dose melphalan with autologous peripheral blood stem cell transplantation in patients with multiple myeloma. Yonsei Med J. 2003. 44:800–810.

11. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999. 341:1565–1571.

12. Rajkumar SV, Witzig TE. A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma. Cancer Treat Rev. 2000. 26:351–362.

13. Juliusson G, Celsing F, Turesson I, Lenhoff S, Adriansson M, Malm C. Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma. Br J Haematol. 2000. 109:89–96.

14. Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munshi N, Badros A, Zangari M, Anaissie E, Epstein J, Shaughnessy J, Ayers D, Spoon D, Tricot G. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood. 2001. 98:492–494.

15. Kim DY, Im SA, Seong CM, Lee SN, Bang SM, Lee JH, Yoon SS, Kim BK, Park SY, Ahn MJ. Salvage therapy with thalidomide in patients with relapsed or refractory multiple myeloma. Korean J Hematol. 2002. 37:259–264.

16. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003. 348:2609–2617.

17. Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004. 127:165–172.

18. Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, Gertz M, Giralt S, Jagannath S, Vesole D. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998. 102:1115–1123.

19. Kisselev AF, Goldberg AL. Proteasome inhibitors: from research tools to drug candidates. Chem Biol. 2001. 8:739–758.

20. King RW, Deshaies RJ, Peters JM, Kirschner MW. How proteolysis drives the cell cycle. Science. 1996. 274:1652–1659.

21. Adams J, Behnke M, Chen S, Cruickshank AA, Dick LR, Grenier L, Klunder JM, Ma YT, Plamondon L, Stein RL. Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg Med Chem Lett. 1998. 8:333–338.

22. LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, Neuberg D, Goloubeva O, Pien CS, Adams J, Gupta D, Richardson PG, Munshi NC, Anderson KC. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res. 2002. 62:4996–5000.

23. Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Anderson KC. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001. 61:3071–3076.

24. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Treon SP, Munshi NC, Richardson PG, Hideshima T, Anderson KC. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA. 2002. 99:14374–14379.

25. Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D, Richardson P, Schlossman R, Podar K, Munshi NC, Mitsiades N, Anderson KC. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood. 2003. 101:1530–1534.

26. Mitsiades CS, Treon SP, Mitsiades N, Shima Y, Richardson P, Schlossman R, Hideshima T, Anderson KC. TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood. 2001. 98:795–804.

27. Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, Adams J, Esseltine DL, Elliott PJ, Pien CS, Guerciolini R, Anderson JK, Depcik-Smith ND, Bhagat R, Lehman MJ, Novick SC, O'Connor OA, Soignet SL. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002. 20:4420–4427.

28. Bross PF, Kane R, Farrell AT, Abraham S, Benson K, Brower ME, Bradley S, Gobburu JV, Goheer A, Lee SL, Leighton J, Liang CY, Lostritto RT, McGuinn WD, Morse DE, Rahman A, Rosario LA, Verbois SL, Williams G, Wang YC, Pazdur R. Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res. 2004. 10:3954–3964.

TOOLS

Similar articles