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Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma
A phase 2 trial of the Minnie Pearl Cancer Research Network
Article first published online: 9 JUN 2008
Copyright © 2008 American Cancer Society
Volume 113, Issue 4, pages 765–771, 15 August 2008
How to Cite
Hainsworth, J. D., Spigel, D. R., Barton, J., Farley, C., Schreeder, M., Hon, J. and Greco, F. A. (2008), Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma. Cancer, 113: 765–771. doi: 10.1002/cncr.23606
- Issue published online: 1 AUG 2008
- Article first published online: 9 JUN 2008
- Manuscript Accepted: 27 FEB 2008
- Manuscript Revised: 26 FEB 2008
- Manuscript Received: 14 NOV 2007
- Millennium Pharmaceuticals, Inc.
- Minnie Pearl Foundation
- multiple myeloma;
- proteasome inhibitors;
- response rate
The purpose of the current study was to evaluate the efficacy and toxicity of weekly bortezomib in the treatment of patients with recurrent/refractory multiple myeloma.
A total of 40 patients with multiple myeloma who had received either 1 or 2 previous treatment regimens were treated with bortezomib at a dose of 1.6 mg/m2 intravenously for 4 consecutive weeks, followed by 1 week without treatment. Responses were measured using International Myeloma Working Group criteria.
Twenty-two patients (55%; 95% confidence interval, 40%-70%) achieved objective responses to treatment, with a median response duration of 16 months. The median progression-free survival for all patients was 9.6 months, with a 1-year progression-free survival rate of 39%. The 1-year and 2-year overall survival rates were 75% and 51%, respectively. Weekly bortezomib was generally well tolerated; grade 3/4 (using the National Cancer Institute Common Toxicity Criteria [version 3.0]) neutropenia (13%), thrombocytopenia (20%), fatigue (15%), diarrhea (13%), and neuropathy (10%) were experienced by a minority of patients.
In the current study, a schedule of weekly bortezomib was found to be effective and well tolerated in patients with previously treated multiple myeloma. Although the response rate and duration appear comparable to those achieved with twice-weekly bortezomib, the relative efficacy of these 2 schedules cannot be determined definitively on the basis of this phase 2 study. A weekly schedule of bortezomib is a reasonable option for patients who have logistic difficulties receiving a twice-weekly schedule, and is an attractive schedule for incorporation into combination regimens. Cancer 2008. © 2008 American Cancer Society.
Since its recent introduction, bortezomib has rapidly become an integral part of the treatment of patients with multiple myeloma. In patients who had previously received multiple standard regimens, treatment with bortezomib produced an overall response rate of 43% and resulted in improved survival when compared with treatment with high-dose dexamethasone in a randomized phase 3 trial.1–3 The marked activity in patients with recurrent multiple myeloma has led to the ongoing evaluation of bortezomib as a component of first-line therapy.
Because the activity of bortezomib is based on reversible inhibition of the proteasome, the schedule of administration was investigated in preclinical and phase 1 studies. Preclinical studies demonstrated that continuous inhibition of the proteasome led to intolerable cumulative toxicity.4 After a single bortezomib injection, proteasome inhibition was detectable within 1 hour and was lost within 48 hours. These 2 observations led to the twice-weekly schedule of bortezomib in an attempt to maximize the duration of proteasome inhibition while avoiding the toxicity of continuous inhibition.5–7 After initial phase 1 studies demonstrated activity, the twice-weekly schedule was developed for the treatment of multiple myeloma.
In recent studies, several investigators have evaluated a weekly schedule of bortezomib in malignancies other than multiple myeloma. A phase 1 trial in patients with refractory solid tumors identified a bortezomib dose of 1.6 mg/m2, given weekly for 4 of every 5 weeks, as the maximum tolerated dose.8 This more convenient weekly schedule of bortezomib has shown activity in non-Hodgkin lymphoma as well as a variety of solid tumors. To our knowledge, no randomized comparisons of the efficacy and toxicity of weekly versus twice-weekly bortezomib have been completed. However, a randomized phase 2 trial comparing weekly versus twice-weekly bortezomib (both administered with rituximab) in patients with recurrent/refractory indolent non-Hodgkin lymphoma has been reported.9 In this trial, the response rate and progression-free survival of the 2 regimens were similar, and the weekly bortezomib schedule was associated with less toxicity.9
In this multicenter, community-based phase 2 trial, we evaluated a weekly bortezomib schedule in patients with recurrent or refractory multiple myeloma. Patients with no response to weekly bortezomib were allowed to crossover to the standard twice-weekly schedule. We present the results of this phase 2 study after a median follow-up of 24 months.
MATERIALS AND METHODS
Enrollment to this phase 2 trial was initiated in May 2004. This trial was performed in the Minnie Pearl Cancer Research Network, a collaborative community-based clinical trials group (Table 1).
|Tennessee Oncology, PLLC||Nashville, TN|
|Comprehensive Cancer Institute||Anniston, AL|
|Florida Cancer Specialists||Fort Myers, FL|
|Grand Rapids Clinical Oncology Program||Grand Rapids, MI|
|Louisiana Oncology Associates||Lafayette, LA|
|Miami Mercy Hospital/Oncology Radiation Associates||Miami, FL|
|Phoebe Cancer Center||Albany, GA|
|Spartanburg Regional Medical Center||Spartanburg, SC|
|Watson Clinic Center for Research, Inc.||Lakeland, FL|
|Wellstar Health System Cancer Research||Marietta, GA|
Patients with multiple myeloma who had received either 1 or 2 previous treatment regimens were eligible for this trial. If patients had received previous high-dose therapy, this treatment must have been a part of first-line treatment; these patients may have received only 1 previous regimen. Additional eligibility requirements included an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; measurable or evaluable disease; leukocyte count ≥3000/μL; neutrophil count ≥1000/μL; platelet count ≥75,000/μL; and serum creatinine <2.0 mg/dL (or a calculated or measured creatinine clearance >30 mL/minute). Patients previously treated with bortezomib were ineligible. Additional exclusion criteria included peripheral neuropathy > grade 1, other active malignancies, and other medical conditions that would interfere with trial participation. All patients were required to provide written informed consent before participating in this clinical trial. This trial was approved at the Tri-Star Institutional Review Board and by the institutional review boards at all participating sites.
Before enrolling in this trial, all patients were evaluated with a complete history and physical examination (including neurologic examination), complete blood counts and differential, chemistry profile, serum β2–microglobulin level, serum or urine electrophoresis, quantitative immunoglobulins, and meta- static bone survey. Patients underwent bone marrow aspiration/biopsy unless previous bone marrow examination had demonstrated myeloma involvement and response to bortezomib treatment was assessable by other studies. Women of childbearing potential had a pregnancy test before the initiation of treatment with bortezomib.
All patients received bortezomib at a dose of 1.6 mg/m2 by intravenous bolus for 4 consecutive weeks, followed by 1 week without treatment. A single treatment cycle was therefore considered to be of 5 weeks' duration. Treatment was continued until tumor progression occurred, 10 cycles (50 weeks) were completed, or unacceptable toxicity developed. Antiemetic prophylaxis with each dose of bortezomib was at the discretion of the treating physician. No other routine premedication was administered.
Modifications in bortezomib dosing were based on clinical assessment and blood counts determined on each day of scheduled treatment. Patients with a neutrophil count ≥750/μL and platelet count ≥50,000/μL received a full dose of bortezomib. If the blood counts were below these levels, the bortezomib dose was held for 1 week and blood counts were remeasured. If counts had risen above minimum levels, bortezomib dosing was resumed at 75% of the initial dose. If hematologic toxicity recurred with the 75% dose, bortezomib was continued at 50% of the original dose. Bortezomib was discontinued if unacceptable myelosuppression recurred after 2 dose reductions, or if blood counts failed to return to minimum levels after a 2-week delay.
Peripheral neuropathy was also monitored closely during this study; neurologic examinations were performed by the treating physician every 5 weeks. Patients with grade 2 sensory neuropathy or neuropathic pain had a 25% dose reduction in bortezomib. If grade 3 neuropathy developed, bortezomib dosing was discontinued until the neuropathy improved to ≤grade 1; bortezomib was then reinstituted at a 50% dose. If grade 4 peripheral neuropathy developed at any time, bortezomib was discontinued.
Patients experiencing reversible grade 3 or 4 nonhematologic toxicity had bortezomib dosing discontinued until the toxicity had improved to ≤ grade 1; at that time bortezomib was reinstituted at a 75% dose. If grade 3/4 toxicity recurred, a second dose reduction (to 50% of original dose) was allowed after the toxicity had improved to ≤ grade 1. If grade 3/4 toxicity recurred after 2 dose reductions or failed to improve to ≤ grade 1 after a delay of 3 weeks in dosing, bortezomib was discontinued.
Assessment of Treatment Effect
During therapy with bortezomib, patients were reassessed with complete blood counts, chemistry profile, serum β2–microglobulin, serum (or urine) electrophoresis, and quantitative immunoglobulins after each course (5 weeks) of therapy. Patients with obvious symptomatic disease progression and laboratory evidence of progression were removed from treatment after 5 weeks (1 cycle). Patients who were stable after 5 weeks continued to another course of bortezomib and were re-evaluated at 10 weeks. At that time, all patients were assigned a response category using the International Myeloma Working (IMW) Group Uniform Response Criteria.10 After the re-evaluation at 10 weeks, patients with objective response or stable disease with improved symptoms continued weekly bortezomib treatment until myeloma progression or unacceptable toxicity occurred. Patients with disease progression or those with stable disease who failed to demonstrate symptomatic improvement were recommended to proceed with bortezomib at a standard twice-weekly dosing schedule (1.3 mg/m2 on Days 1, 4, 8, and 11 of a 21-day cycle). However, this change in schedule was at the discretion of the physician, and if further bortezomib was believed to be unlikely to be of benefit patients could be removed from study and treated with other regimens.
This nonrandomized phase 2 study was performed to evaluate the efficacy and toxicity of a weekly schedule of bortezomib in patients with recurrent/refractory multiple myeloma. A secondary objective was to assess the efficacy of a standard twice-weekly bortezomib schedule in patients who failed to respond to weekly bortezomib.
Previous trials of twice-weekly bortezomib in patients with recurrent/refractory multiple myeloma have produced objective response rates of 35% to 43%. Therefore, in this trial a similar response rate was expected. Given our hypothesis that a weekly schedule will be of approximately the same efficacy as a twice-weekly schedule, the accrual of 40 patients to this trial would allow a response rate to be obtained within 95% confidence intervals (95% CIs) of ±7%, and also would allow adequate assessment of the toxicity of this treatment schedule.
In the current study, progression-free survival was defined as the time from the date of study entry until the date that myeloma progression was documented. Overall survival was measured from the date of study entry until the date of death. Survival curves were constructed using the method of Kaplan and Meier.11 All patients who received at least 1 dose of bortezomib were evaluated for toxicity using the National Cancer Institute Common Toxicity Criteria (version 3.0).
Between May 2004 and March 2006, 40 patients were enrolled in this clinical trial by 10 participating sites in the Minnie Pearl Cancer Research Network. Patient characteristics are summarized in Table 2. The median age of these patients was 69 years and the majority had good performance status (ECOG 0 or 1). β2–microglobulin was elevated (>3.5) in 45% of patients. The majority of patients (70%) had received 2 previous treatment regimens. One previously untreated patient entered this trial; although clearly ineligible by protocol inclusion criteria, he was included in the efficacy and toxicity analyses. Twenty-two of 39 patients (56%) had achieved at least 1 objective response to previous treatment. Fifteen patients (38%) had developed disease progression during or within 3 months of the most recent previous treatment regimen. The median duration of first remission in these patients was 8 months. Common previous treatment modalities included corticosteroids (95%), alkylating agents (50%), thalidomide/lenalidomide (48%), vinca alkaloids (33%), and anthracyclines (30%). Only 2 patients (5%) had previously been treated with high-dose therapy and peripheral stem cell support.
|Characteristic||No. of Patients (%)|
|Median age (range), y||69 (43-85)|
|ECOG performance status|
|β2-microglobulin >3.5||18 (45%)|
|Median time since diagnosis (range), y||4 (1-7)|
|No. of previous regimens|
|Any corticosteroid||38 (95%)|
|Any alkylating agent||20 (50%)|
|Any vinca alkaloid||13 (33%)|
|Any anthracycline||12 (30%)|
|Stem cell transplantation||2 (5%)|
|Sarah Cannon Research Institute||14 (35%)|
|Network sites||26 (65%)|
Thirty-five patients (88%) received at least 2 cycles (10 weeks) of weekly bortezomib and were evaluated for response. Two additional patients had rapid myeloma progression before completing 10 weeks of treatment and were included as nonresponders. Three other patients were removed from therapy before the completion of 10 weeks of treatment and are also included as nonresponders (treatment-related toxicity [grade 3 fatigue and diarrhea] in 1 patient and intercurrent illness in 2 patients [myocardial infarction and cerebrovascular accident]). The median number of treatment courses received was 5 (range, 1-10 treatment courses). Twenty-nine patients continued bortezomib after the first evaluation at 10 weeks. Eight of these patients went on to complete 10 cycles (50 weeks) of treatment, whereas 21 discontinued treatment for the following reasons: disease progression in 11 patients, treatment-related toxicity in 6 patients, poor compliance in 2 patients, and physician decision in 2 patients. At the time of last follow–up, no patient remained on bortezomib therapy.
Eight patients had stable myeloma after completing 2 courses (10 weeks) of weekly bortezomib, and were crossed over to treatment with a standard twice-weekly bortezomib schedule. These 8 patients received a median of 4 courses (range, 1-8 courses) of twice–weekly bortezomib after crossover.
Twenty-two of 40 patients who entered this trial (55%; 95% CI, 40%-70%) had objective responses to treatment with weekly bortezomib. Two patients (5%) achieved complete responses and 20 patients (50%) had partial responses. Six of the 20 partial responders had paraprotein decreases of 80% to 89%, but none met International Myeloma Working Group criteria for very good partial response (ie, >90% decrease). Twelve patients (30%) had stable disease as their best response to treatment, whereas 6 patients (15%) had progressive disease or failed to receive 10 weeks of treatment. The median duration of remission in patients with an objective response was 16 months (range, 4-35 months).
Eight patients who were stable after 10 weeks of weekly bortezomib subsequently received bortezomib by the standard twice-weekly dosing schedule. Four of these patients (50%) achieved partial responses (range of duration, 6-29 months), whereas 4 patients had stable disease for a median of 12 months (range, 4-27 months). Because slow responses are well documented in patients receiving bortezomib by standard schedule, the significance of these responses is difficult to assess. No patients with overt progression of myeloma while receiving weekly bortezomib were crossed over to the twice-weekly schedule.
The median time to treatment failure for the entire group of patients was 9.6 months (95% CI, 5.5-12 months), with 39% of patients free of disease progression at 1 year (Fig. 1). The median survival for the entire group had not been reached after a median follow-up of 24 months; the predicted 1-year and 2-year survival rates are 75% and 51%, respectively (Fig. 2).
Treatment-related toxicity with weekly bortezomib is summarized in Table 3. For most patients, weekly bortezomib was well tolerated, with only a few severe toxicities observed. Myelosuppression was mild with this schedule, and did not result in any infectious complications.
|No. of Patients (%)|
|Toxicity*||Grade 2||Grade 3||Grade 4|
|Neutropenia||10 (25%)||4 (10%)||1 (3%)|
|Thrombocytopenia||5 (13%)||5 (13%)||5 (13%)|
|Anemia||8 (20%)||3 (8%)||3 (8%)|
|Fatigue||8 (20%)||6 (15%)||0|
|Neuropathy||7 (18%)||4 (10%)||0|
|Diarrhea||5 (13%)||5 (13%)||0|
|Constipation||6 (15%)||1 (3%)||0|
|Peripheral edema||5 (13%)||0||0|
|Dyspnea||3 (8%)||2 (5%)||0|
|Arthralgia/myalgia||3 (8%)||1 (3%)||0|
|Anorexia||3 (8%)||1 (3%)||0|
|Skin rash||2 (5%)||0||0|
|Epigastric pain||0||1 (3%)||0|
The nonhematologic toxicities observed with weekly bortezomib included the same toxicities that have previously been reported with the twice-weekly schedule. Severe (grade 3) fatigue occurred in 6patients (15%) and was generally reversible with a treatment break from bortezomib. Four patients (10%) developed grade 3 neuropathy. All of these patients had received at least 4 courses of weekly bortezomib at the time neuropathy developed. Although bortezomib therapy was reinitiated in 2 of these 4 patients after a short treatment delay, eventually all 4 patients were forced to discontinue bortezomib due to neuropathy (a fifthpatient dis-continued bortezomib when grade 3 neuropathy developed after crossing over to the standard twice-weekly bortezomib schedule). Seven additional patients (23%) developed grade 2 neuropathy (painful neuropathy in 3 patients) after a median of 15 weeks of bortezomib therapy. Six of these patients were able to continue bortezomib (3 with dose reductions) without further worsening of neuropathy, whereas 1 patient discontinued bortezomib.
During treatment, a total of 6 patients (15%) required reductions in the dose of bortezomib. Six patients (15%) discontinued weekly bortezomib due to toxicity (grade 3 neuropathy in 4 patients, grade 3 diarrhea/grade 2 neuropathy in 1 patient, and grade 3 diarrhea/fatigue in 1 patient). There were no treatment-related deaths reported in this clinical trial.
During the last several years, bortezomib has been rapidly incorporated into the standard treatment of multiple myeloma. Although originally approved for use as a single agent in previously treated patients, major emphasis currently focuses on the development of bortezomib-containing combination regimens for use as first-line therapy.12–17 In the treatment of multiple myeloma, bortezomib continues to be administered by the twice-weekly schedule originally developed on the basis of pharmacodynamic considerations and preclinical data.4–6 More recently, the administration of a more convenient weekly bortezomib schedule demonstrated activity and suggested better tolerability in other tumor types.8, 9 However, to our knowledge only very limited experience exists in using weekly bortezomib in the treatment of patients with multiple myeloma.
In this nonrandomized, multicenter phase 2 trial, we documented a response rate of 55% (95% CI, 40%-70%) in a group of 40 patients with recurrent/refractory multiple myeloma who were treated with weekly bortezomib. The median response duration in patients with objective response was 16 months; progression-free survival for the entire group was 9.6 months, with a 1-year progression-free survival rate of 39%. These efficacy parameters are similar to those reported in the pivotal trial using a twice-weekly bortezomib schedule (Table 4).1–3 However, comparison of efficacy in various reported studies is difficult due to variations in patient characteristics. For example, our patients were a median 8 years older but had received less previous treatment (including high–dose therapy) than patients in the pivotal bortezomib study.1–3
|Twice-weekly Bortezomib (N=333)||Weekly Bortezomib (N=40)|
|Pivotal Study1, 2||Current Study|
|Median TTP, mo||6.2||9.6|
|Toxicity (grade 3/4)*|
Weekly bortezomib was generally well tolerated, with no unanticipated toxicity noted to develop in these patients with previously treated multiple myeloma. Grade 3/4 neutropenia and thrombocytopenia occurred in 13% and 26% of patients, respectively, but only 1 patient required hospitalization for neutropenic fever. Grade 3 neuropathy developed in 4 patients (10%); all of these patients had received at least 4 courses (20 weeks) of bortezomib when neuropathy developed. Two of the 4patients were able to resume bortezomib after a short treatment break, whereas 2 required discontinuation of therapy. An additional 9 patients (23%) developed grade 2 neuropathy, similar to the incidence reported with the standard schedule. Other severe nonhematologic toxicity was uncommon. Overall, the spectrum and incidence of toxicity in this trial are similar to toxicities reported in multiple myeloma patients treated with the standard twice-weekly dosing schedule (Table 4).
In 1 other small trial, 29 patients received weekly bortezomib (at a dose of 1.3 mg/m2) and methylprednisolone (at a dose of 500-2000 mg intravenously) on Days 1, 8, and 15 of a 28-day cycle.18 The majority of patients (70%) had received previous high-dose therapy, and most had received at least 2 previous regimens. In this group, a 62% overall response rate was achieved, with a median time-to-disease progression of 6.6 months. These efficacy results were believed to be similar to those previously reported with single-agent bortezomib on a twice-weekly schedule, and are also similar to the results achieved in our multicenter trial.
A small amount of experience with weekly bortezomib also exists in the treatment of patients with non-Hodgkin lymphoma. In a randomized phase 2 trial, weekly bortezomib was compared with the standard twice-weekly schedule; rituximab was included in both treatment regimens.9, 19 Although the inclusion of rituximab precludes the evaluation of bortezomib efficacy, bortezomib-related side effects, particularly myelosuppression, were less common with the weekly bortezomib schedule. However, less favorable results with weekly bortezomib in patients with non-Hodgkin lymphoma were recently reported by O'Connor et al.20 In an ongoing trial of weekly bortezomib (at a dose of 1.8 mg/m2 weekly for 4 of 6 consecutive weeks), only 2 of the first 18 patients (11%) achieved partial responses. This early response rate was lower than previously achieved by these investigators using a twice-weekly bortezomib schedule21; the somewhat lower dose intensity of bortezomib given by the weekly schedule was raised as a possible explanation.
In summary, our phase 2 study provides additional evidence that the weekly bortezomib schedule is active and well tolerated in the treatment of patients with recurrent/refractory multiple myeloma. In this trial (which included patients with a higher median age), the toxicity encountered was similar to that reported with the standard twice-weekly schedule. However, accumulated evidence from several trials suggests the frequency of grade 3 of 4 toxicities is somewhat decreased with the weekly schedule. Differences in toxicity may be schedule-related, or may be simply related to the slightly lower dose intensity of bortezomib administered with most weekly schedules (average weekly dose of 1.73 mg/m2 with the standard schedule vs 1.28 mg/m2 with the weekly schedule in the current study). Although the efficacy of the weekly and twice-weekly bortezomib schedules in patients with previously treated multiple myeloma appears to be similar, comparative trials are required to better define this issue, and existing data are not sufficient to justify the routine use of a weekly bortezomib schedule. However, this schedule has sufficient activity to be used as an alternative for patients who have logistic difficulties in receiving twice-weekly treatment. In addition, the weekly schedule may provide a more convenient and better-tolerated option for the development of bortezomib-containing combination regimens.
- 2Bortezomib continues to demonstrate superior efficacy compared with high-dose dexamethasone in relapsed multiple myeloma: updated results of the APEX trial [abstract]. Blood. 2005; 106: 715a. Abstract 2547., , , et al.
- 9Bortezomib plus rituximab in patients with indolent non-Hodgkin's lymphoma (NHL): a phase 2 study [abstract]. Blood. 2005; 106: 10a. Abstract 17., , , et al.
- 13Reduced dose PAD combination therapy (PS-341/bortezomib, adriamycin and dexamethasone) for previously untreated patients with multiple myeloma [abstract]. Blood. 2005; 106: 717a. Abstract 2554., , , et al.
- 14Rapid control of previously untreated multiple myeloma with bortezomib-thalidomide-dexamethasone followed by early intensive therapy [abstract]. Blood. 2005; 106: 231a. Abstract 784., , , et al.
- 15VELCADE/dexamethasone (Val/Dex) versus VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma: an interim analysis of the IFM 2005-01 randomized multicenter phase III trial [abstract]. Blood. 2006; 108: 21a. Abstract 56., , , et al.
- 16Long-term follow-up of PAD for untreated multiple myeloma [abstract]. Haematologica. 2007; 92: 725., , , et al.
- 17Bortezomib, thalidomide and dexamethasone as induction [abstract]. Haematologica. 2007; 92: 722., , , et al.
- 19Phase 2 study of bortezomib weekly or twice weekly plus rituximab in patients with follicular or marginal zone lymphoma: final results [abstract]. Blood. 2006; 108( suppl): 208a. Abstract 694., , , et al.
- 20Schedule of bortezomib administration may be an important determinant of single-agent activity in patients with relapsed or refractory follicular lymphoma and mantle cell lymphoma [abstract]. J Clin Oncol. 2007; 25( suppl): 453s. Abstract 8051., , , et al.