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Originally published as JCO Early Release 10.1200/JCO.2005.03.2383 on January 17 2006 © 2006 American Society of Clinical Oncology. Phase I/II Trial Assessing Bortezomib and Melphalan Combination Therapy for the Treatment of Patients With Relapsed or Refractory Multiple MyelomaFrom Oncotherapeutics Inc; Institute for Myeloma & Bone Cancer Research, West Hollywood; Pacific Shores Medical Group, Glendale; Cedars-Sinai Medical Center, Los Angeles, CA, Millennium Pharmaceuticals Inc; and Infinity Pharmaceuticals, Cambridge, MA Address reprint requests to James R. Berenson, MD, Institute for Myeloma & Bone Cancer Research, 9201 West Sunset Blvd, Suite 300, West Hollywood, CA 90069; e-mail: jberenson{at}myelomasource.org
PURPOSE: Bortezomib has shown synergy with melphalan in preclinical models. We assessed the safety, tolerability, and response rate in a dose-escalation study of this combination for relapsed or refractory multiple myeloma patients. METHODS: Bortezomib was administered from 0.7 to 1.0 mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle for up to eight cycles. Oral melphalan was administered in escalating doses from 0.025 to 0.25 mg/kg on days 1 to 4.
RESULTS: Thirty-five patients with relapsed or refractory myeloma were enrolled, 34 of whom were assessable for response. Dose-limiting toxicity of grade 4 neutropenia in two of six patients in the highest dose cohort led to the assignment of bortezomib 1.0 mg/m2 and melphalan 0.10 mg/kg as the maximum-tolerated dose (MTD). Responses (minimal [MR], partial [PR], or complete [CR]) occurred in 23 of 34 patients (68%), including two CRs (6%), three immunofixation-positive CRs (9%), 11 PRs (32%), and seven MRs (21%). Responses were observed in five of six assessable patients (83%) at the MTD. Median progression-free survival for all patients was 8 months (range, 2 to 18 months). Grade CONCLUSION: Bortezomib plus melphalan given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for myeloma patients.
Multiple myeloma (MM) remains an aggressive and incurable malignancy. The combination of melphalan plus prednisone (MP) is used commonly to treat symptomatic myeloma but results in a median survival of only 3 years.1,2 Combination chemotherapy has improved response rates, but an improvement in survival relative to MP has not been demonstrated.3 The addition of thalidomide to MP may improve survival.4 The only therapy that has clearly demonstrated an improvement in survival compared with conventional chemotherapy as first-line treatment is high-dose chemotherapy followed by stem-cell transplantation,5,6 an option unavailable to many elderly patients or those with pre-existing medical conditions. Despite this advance, nearly all patients will experience relapse and require additional treatment, highlighting the need for more effective and tolerable therapies. The proteasome inhibitor bortezomib (Velcade; Millennium Pharmaceuticals Inc, Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development LLC, New Brunswick, NJ) was approved recently in the United States and European Union as a second-line treatment for MM patients.7,8 Bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle for up to eight cycles in patients with relapsed and refractory myeloma in the phase II Study of Uncontrolled Multiple Myeloma Managed with Proteasome Inhibition Therapy (SUMMIT) trial achieved a response rate (complete response [CR] or partial response [PR]) of 27% using the European Group for Blood and Marrow Transplantation criteria,9 a median duration of response of 13 months,10,11 and a median overall survival of 17 months.11 In another phase II trial, the Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma (CREST), patients who experienced relapse after or were refractory to first-line treatment were randomly assigned to bortezomib 1.0 or 1.3 mg/m2 using the same schedule. The lower dose was clinically active (CR + PR = 30%) and well tolerated.12 The most clinically important adverse effect of bortezomib has been peripheral neuropathy (PN), and patients receiving bortezomib 1.0 mg/m2 in CREST had an incidence of PN of 21% compared with 62% in patients receiving bortezomib 1.3 mg/m2.12 Thus, lower doses of bortezomib have the potential to offer activity with less toxicity. A phase III trial (the Assessment of Proteasome Inhibition for Extending Remissions [APEX]) in myeloma patients experiencing relapse after one to three prior therapies demonstrated superiority of bortezomib over dexamethasone in response rate, time to progression, and overall survival.13 In APEX, which recommended specific dose modification guidelines for PN, the incidence of PN was 36% with bortezomib. Lower doses of melphalan may offer clinical utility because myelosuppression is the major dose-limiting toxicity of this alkylating agent. In vitro, exposure of highly melphalan-resistant myeloma cell lines, as well as bone marrow tumor cells from myeloma patients, to noncytotoxic concentrations of bortezomib increased sensitivity to melphalan, but this was not observed in normal bone marrow stem cells or peripheral-blood lymphocytes.14,15 This dose-escalation clinical study evaluated the safety, tolerability, and activity of bortezomib and melphalan among patients with relapsed or refractory MM, starting with lower doses of both agents in an effort to reduce the incidence and severity of toxicities and to develop a potentially synergistic effect of this combination.
Patients Patients with relapsed or refractory MM with active progression after receiving  two prior treatment regimens were eligible for enrollment. Inclusion criteria included age 18 years, measurable disease, Karnofsky performance status 60%, creatinine clearance 30 mL/min, and a life expectancy 3 months.16
Patients were excluded if they had received chemotherapy The Cedars-Sinai and Western institutional review boards approved the treatment protocol, and a written, informed consent was signed by all patients before participation in the study. This study was conducted in accord with the Declaration of Helsinki and the International Conference on Harmonization for Good Clinical Practice.
Study Design and Drug Administration In the first five cohorts, enrolled patients received a fixed dose of intravenous bolus bortezomib 0.7 mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle for a maximum of eight cycles. Oral melphalan was administered in escalating doses from 0.025, 0.05, 0.10, and 0.15 mg/kg, to a maximal dose of 0.25 mg/kg, on days 1 to 4 of the 28-day cycle. Three patients were enrolled onto each cohort. The next three cohorts received a fixed dose of bortezomib 1.0 mg/m2 and escalating doses of melphalan (0.025, 0.10, and 0.25 mg/kg) on the same schedule. After the first patient completed a full cycle without a dose-limiting toxicity (DLT), the remaining two patients were enrolled onto that cohort. Dose escalation continued if no DLT was observed after all three patients completed a 28-day cycle. If a DLT was observed in two or more patients at any dose level, an additional three patients were recruited at the previous dose level.
DLT was defined as any grade 4 neutropenia, thrombocytopenia, or anemia. Grade 3 thrombocytopenia with grade 3 or 4 hemorrhage, grade 3 or 4 nausea and vomiting refractory to antiemetic therapy, and any other nonhematologic toxicity grade
Pretreatment and Safety Assessments
Response Criteria Time to response was defined as the time from first treatment until at least MR was observed. Progression-free survival was defined as the time during and after treatment that a patient maintained a response or stable disease.
Patients and Dose Escalation Thirty-five patients were enrolled between August 1, 2002, and January 3, 2005, and follow-up was until June 15, 2005. Patient and disease characteristics are listed in Table 1.
Fifteen of the 29 patients enrolled onto the first seven cohorts received the maximum eight cycles (32 weeks) of treatment. Eleven patients discontinued prematurely because of PD, including three patients in cohort 6, two patients each in cohorts 1 and 7, and one patient each in cohorts 2, 3, 4, and 5. Treatment of patients in cohorts 7 and 8 is ongoing in five patients, and only two patients (in cohort 8) had to discontinue treatment prematurely because of PD.
Treatment-Emergent Toxicities
Myelosuppression was the most common grade 3 toxicity. Grade 3 neutropenia, thrombocytopenia, and anemia occurred in roughly equal proportions overall but were more frequent in the higher-dose cohorts. Fifty-two percent of the instances of grade 3 cytopenia occurred in patients who had a baseline cytopenia. In 10 patients, doses of one or both agents were withheld or reduced because of transient cytopenias: one because of anemia accompanied by fever (cohort 7); one because of neutropenia accompanied by fever (cohort 1); two because of thrombocytopenia alone (cohorts 4 and 5); three because of neutropenia alone (cohorts 6 and 8 [two patients in cohort 8]); two because of both neutropenia and thrombocytopenia (cohorts 4 and 6); and one because of neutropenia, thrombocytopenia, and anemia (cohort 2). No serious bleeding was observed, and only one patient with grade 4 thrombocytopenia required a platelet transfusion (cohort 8). Sixteen of 35 patients (46%) received erythropoietin, seven of 35 patients (20%) received packed RBCs, and one patient received granulocyte colony-stimulating factor. In addition to neuropathy (see the next paragraph), nonhematologic toxicities primarily were GI (nausea, 63%; vomiting, 34%; diarrhea, 37%; and constipation, 29%) and manageable with routine intervention. Cough (37%), fatigue (71%), pyrexia (26%), and rash (29%) were reported frequently. None of the nonhematologic toxicities showed a clear relationship to the melphalan dose. Four patients required doses to be withheld because of nonhematologic toxicities: one each because of flu-like symptoms accompanied by an erythematous rash (cohort 1), increased serum creatinine and blood urea nitrogen (cohort 1), rash with pruritus (cohort 5), and PN (cohort 6). When PN was observed in cycle 5 in this latter patient, the bortezomib dose was reduced to 0.7 mg/m2. Treatment-emergent PN occurred in 11 patients (31%) but was grade 1 or 2 in all except one patient. In the limited follow-up to date, PN resolved in three of 11 patients and remained stable in the rest. Among the 15 patients who had baseline grade 1 or 2 neuropathy at study entry, the symptoms of neuropathy remained stable in 11 patients, resolved in one patient, and worsened in only three patients (Table 3). In one patient, the dose of bortezomib was reduced to 0.7 mg/m2 because of neuropathic symptoms. Of the patients without baseline neuropathy (n = 20), eight developed grade 1 or 2 neuropathy during the study, including two of nine patients (22%) who received bortezomib 0.7 mg/m2 and six of 11 patients (55%) who received bortezomib 1.0 mg/m2. Of the patients who did not have baseline neuropathy, none required treatment to be reduced, withheld, or discontinued.
Efficacy Overall, responses were achieved in 23 of 34 assessable patients (68%), including two with CR (6%), three with IF-positive CR (9%), 11 with PR (32%), and seven with MR (21%). Eight patients (24%) had stable disease, all of whom had shown PD at the time of study entry. One patient in cohort 7 died before receiving the first treatment cycle and was not assessable. Responses were observed in five of six patients (83%) at the MTD (1.0 mg/m2 bortezomib and 0.1 mg/kg melphalan). In 10 of 23 responding patients (43%), responses were observed during the first two treatment cycles. Median time to response was 3 months (range, 2 to 8 months), and median progression-free survival for all patients was 8 months (range, 2 to 18 months). The pattern of response by cohort and by patient is summarized in Table 4. Responses were observed regardless of type of prior treatment (Table 5).
Responses were observed in all cohorts, although only MRs were observed among patients in cohorts 2 and 4. Among patients achieving PR, one patient was in cohort 3, and two patients each were in cohorts 1, 5, 6, 7, and 8. IF-positive CR was observed in two patients in cohort 7 and in one patient in cohort 8. CR was achieved in one patient each in cohorts 6 and 8. Fifty-eight percent of patients (11 of 19) receiving the higher dose of bortezomib (1.0 mg/m2; cohorts 6 to 8) achieved PR, compared with only 33% of patients (five of 15) receiving the lower dose (0.7 mg/m2; cohorts 1 to 5).
Maintenance Phase
The activity of bortezomib as monotherapy for patients with relapsed and/or refractory MM is well established.10-13 On the basis of preclinical observations,14,16,18,19 treatment of myeloma with bortezomib in combination with other agents has been investigated clinically. Bortezomib in combination with dexamethasone was evaluated in phase II trials.20 Other studies include bortezomib in combination with pegylated liposomal doxorubicin in patients with refractory hematologic malignancies,21 and bortezomib plus thalidomide plus dexamethasone in patients with myeloma relapsing after autologous transplantation.22 In the first-line setting, bortezomib is being evaluated alone, in combination with dexamethasone, and in combination with dexamethasone and thalidomide or doxorubicin or with MP, with and without stem-cell transplantation.23-28 The doses of bortezomib in this study, 0.7 and 1.0 mg/m2 given on days 1, 4, 8, and 11 of a 4-week schedule, represent 40% and 57%, respectively, of the dose-intensity per month administered in the SUMMIT trial,10 in which 1.3 mg/m2 was given four times during a 3-week cycle.29 The starting dose of melphalan at 0.025 mg/kg in cohort 1 is 10% of the amount that is generally used in conventional treatment regimens for myeloma patients. In this study, lower doses of bortezomib (0.7 to 1.0 mg/m2) plus oral melphalan for patients with refractory or relapsed myeloma were active with predictable and manageable toxicities. The observation that seven of 13 patients who previously were treated with melphalan responded to the combination (including two patients who previously were refractory to melphalan) supports clinically the in vitro observation that bortezomib can overcome chemotherapy resistance.14,15 More studies are needed before this conclusion is established firmly. The antimyeloma activity of low-dose melphalan and bortezomib was encouraging, given that all patients had relapsed or were refractory to previous treatments and had progressive disease at enrollment. Previous studies evaluating oral melphalan at higher doses in combination with glucocorticoids in this clinical setting have produced disappointing results, with low response rates.30 In contrast, 23 of 34 assessable patients (68%) responded in this trial (ie, achieved CR, IF-positive CR, PR, or MR). Time to response generally was rapid and responses were observed at all dose levels. However, all CRs or IF-positive CRs were observed among patients who received bortezomib 1.0 mg/m2, and achievement of PR or better also was higher among these patients (55% at bortezomib 1.0 mg/m2, compared with 33% at the 0.7 mg/m2 dose level). This response rate was higher than would be expected with bortezomib alone at 1.0 mg/m2; the CR + PR rate among patients who received bortezomib at this dose was only 30% in the CREST trial.12 Although, the impact of the maintenance phase is not clear, a phase III trial evaluating the importance of bortezomib as maintenance therapy is ongoing.31
Myelosuppression was the DLT of this regimen, but was not associated with major clinical toxicity such as febrile neutropenia or sepsis. In patients treated with bortezomib 1.0 mg/m2 in CREST, thrombocytopenia occurred in 32% of patients (including grade 3 in 29%), whereas neutropenia and anemia occurred in 11% and 21% of patients, respectively.12 In addition, melphalan potentially is more myelotoxic when combined with bortezomib 1.0 mg/m2 than when used alone. Two patients receiving the highest dose of melphalan (0.25 mg/kg) developed grade 4 cytopenias, although this toxicity was not observed at doses
Treatment-emergent PN was observed in 11 of 35 patients (31%), and occurred more frequently among the patients who received the higher dose of bortezomib. However, only one patient developed grade 3 (who had baseline neuropathy) and none developed grade 4 neuropathy. Previous trials have shown a higher incidence of severe neuropathy with bortezomib.10,12 In the SUMMIT trial, 12% of patients developed grade 3 neuropathy but none developed grade 4 neuropathy.10 A similar proportion of patients (15%) receiving the 1.3 mg/m2 dose in the CREST trial developed grade 3 neuropathy but no patient experienced grade 4 neuropathy, whereas patients receiving the 1.0 mg/m2 had a lower incidence of grade 3 or 4 neuropathy (7%). In addition, 10% of the patients discontinued the CREST trial because of neurotoxicity,12 whereas none of the patients discontinued this trial because of treatment-related neuropathy. The rate of grade Melphalan-based regimens continue to be an important foundation of care in newly diagnosed and relapsed/refractory myeloma. The combination of prednisone and a lower dose of melphalan (4 mg/m2), with and without thalidomide 100 mg daily, is under investigation.4 In this ongoing study in an older patient population, thalidomide improved response rate, but the high rate of adverse events, particularly deep venous thrombosis, necessitated discontinuation of thalidomide in more than one third of the patients. Anticoagulation therapy may increase the safety of this combination. Preliminary results of a phase II trial of melphalan (9 mg/m2) and prednisone (60 mg/m2) plus bortezomib (1.3 mg/m2) in elderly, previously untreated patients with myeloma seem promising.28 Thus far, this combination has been well tolerated, and all assessable patients have achieved a response. Therefore, additional dose escalation of bortezomib to 1.3 mg/m2 with melphalan alone may be warranted. An ongoing phase III trial, is comparing MP with and without bortezomib in the first-line treatment of MM in patients who are not transplantation candidates. Although MP is commonly used in patients with newly diagnosed myeloma, the lack of a glucocorticoid is another advantage of the melphalan/bortezomib combination in addition to its high response rate. Many patients with relapsed or refractory disease are resistant to these agents and tolerate them poorly at the time of PD, with significant adverse effects that affect their quality of life.32-34 Bortezomib and melphalan are individually active in myeloma, and when administered together (at lower than generally recommended doses) in this study, were active in relapsed or refractory MM with manageable toxicity. This combination may be suitable for elderly patients with comorbidities. Importantly, responses were observed among patients who experienced treatment failure after a wide variety of prior treatments, including bortezomib, thalidomide, and lenalidomide. Because of the encouraging findings in this trial and the establishment of an MTD, a phase II clinical trial of this combination regimen for patients with newly diagnosed MM has been recently initiated.
We thank Christine Pan James for her assistance in the preparation of this manuscript.
Supported in part by Millennium Pharmaceuticals Inc, and Johnson & Johnson Pharmaceutical Research & Development LLC. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Anderson KC: Multiple myeloma: How far have we come? Mayo Clin Proc 78:15-17, 2003 2. Kyle RA, Gertz MA, Witzig TE, et al: Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 78:21-33, 2003 3. 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—Myeloma Trialists' Collaborative Group. J Clin Oncol 16:3832-3842, 1998 4. Palumbo A, Bertola A, Musto P, et al: A prospective randomized trial of oral melphalan, prednisone, thalidomide (MPT) vs oral melphalan, prednisone (MP): An interim analysis. Blood 104:63a, 2004 (abstr 207) 5. Attal M, Harousseau J-L, Stoppa A-M, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: Intergroupe Francais du Myelome. N Engl J Med 335:91-97, 1996 6. 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 7. VELCADE (bortezomib) for injection. Prescribing information, 2005. http://www.mlnm.com/products/velcade/full_prescrib_velcade.pdf 8. Janssen-Pharmaceutica NV: Summary of VELCADE product characteristics. Prescribing information, 2005. http://www.mlnm.com/clinicians/oncology/velcade/index.asp 9. 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 haemopoietic stem cell transplantation: Myeloma Subcommittee of the EBMT—European Group for Blood and Marrow Transplant. Br J Haematol 102:1115-1123, 1998[CrossRef][Medline] 10. 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 11. Richardson PG, Barlogie B, Berenson J, et al: Factors predictive of clinical outcome with bortezomib (Velcade) in patients with relapsed, refractory multiple myeloma. European Hematology Association 5:365a, 2004 12. 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] 13. 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 14. Ma MH, Yang HH, Parker K, et al: The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9:1136-1144, 2003 15. Mitsiades N, Mitsiades CS, Richardson PG, et al: The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: Therapeutic applications. Blood 101:2377-2380, 2003 16. Yang HH, Vescio R, Schenkein D, et al: A prospective, open-label safety and efficacy study of combination treatment with bortezomib (PS-341, Velcade and melphalan in patients with relapsed or refractory multiple myeloma. Clin Lymphoma 4:119-122, 2003[Medline] 17. National Cancer Institute Common Toxicity Criteria, version 2.0, 2005. http://ctep.cancer.gov/reporting/CTC-3.html 18. 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 19. Hideshima T, Chauhan D, Richardson P, et al: NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277:16639-16647, 2002 20. Jagannath S, Richardson P, Barlogie B, et al: Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma. European Hematology Association 5:369, 2004 (suppl 2) 21. Orlowski RZ, Voorhees PM, Garcia RA, et al: Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 105:3058-3065, 2005 22. Zangari M, Hollmig K, Fassas A, et al: Marked activity of Velcade plus thalidomide (V+T) in advanced and refractory multiple myeloma (MM). Blood 104:413a-414a, 2004 (abstr 1480) 23. Alexanian R, Wang LW, Weber DM, et al: VTD (Velcade, thalidomide, dexamethasone) as primary therapy for newly-diagnosed multiple myeloma. Blood 104:64a, 2004 (abstr 210) 24. 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] 25. Jagannath S, Durie BGM, 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] 26. Richardson PG, Chanan-Khan A, Schlossman RL, et al: Phase II trial of single agent bortezomib (VELCADE) in patients with previously untreated multiple myeloma (MM). Blood 104:100a, 2004 (abstr 336)[CrossRef] 27. Harousseau J, Attal M, Leleu X, et al: Bortezomib (VELCADE) plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: Preliminary results of an IFM phase II study. Blood 104:416a, 2004 (abstr 1490) 28. Mateos MV, Blade J, Mediavilla JD, et al: A phase I/II national, multi-center, open-label study of Velcade plus melphalan and prednisone (V-MP) in elderly untreated multiple myeloma patients. Haematologica 90:149, 2005 (suppl 1; abstr 726) 29. Kane RC, Bross PF, Farrell AT, et al: Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 8:508-513, 2003 30. Palumbo A, Bringhen S, Petrucci MT, et al: Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: Results of a randomized controlled trial. Blood 104:3052-3057, 2004 31. National Institutes of Health: Bortezomib in treating patients with newly diagnosed high-risk stage III multiple myeloma, 2005. http://clinicaltrials.gov/ct/show/NCT00075881?order=3 32. Carlson K, Hjorth M, Knudsen LM: Toxicity in standard melphalan-prednisone therapy among myeloma patients with renal failure: A retrospective analysis and recommendations for dose adjustment. Br J Haematol 128:631-635, 2005[CrossRef][Medline] 33. Genty V, Dine G, Dufer J: Phenotypical alterations induced by glucocorticoids resistance in RPMI 8226 human myeloma cells. Leuk Res 28:307-313, 2004[CrossRef][Medline] 34. Vincent T, Mechti N: Extracellular matrix in bone marrow can mediate drug resistance in myeloma. Leuk Lymphoma 46:803-811, 2005[CrossRef][Medline] Submitted July 1, 2005; accepted November 16, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3 weeks before enrollment, had a baseline platelet count 
