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Originally published as JCO Early Release 10.1200/JCO.2007.14.2372 on July 21 2008 © 2008 American Society of Clinical Oncology. Phase I-II Trial of Bortezomib Plus Oral Cyclophosphamide and Prednisone in Relapsed and Refractory Multiple Myeloma
From the Department of Medical Oncology and Hematology and Department of Biostatistics, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; and the Mayo Clinic, Scottsdale, AZ Corresponding author: Donna E. Reece, MD, Princess Margaret Hospital, 610 University Ave, Suite 5-207, Toronto, Ontario, M5G 2M9 Canada; e-mail: donna.reece{at}uhn.on.ca
Purpose The combination of oral weekly cyclophosphamide and alternate day prednisone is a convenient regimen for relapsed/refractory multiple myeloma (MM), and we sought to improve its efficacy by adding bortezomib, a proteasome inhibitor with proven antimyeloma activity. Patients and Methods We conducted a phase I-II trial evaluating six dose levels to define the maximum tolerated dose (MTD) of this combination in relapsed/refractory MM. An additional 10 patients were evaluated at the highest dose level reached. Results Thirty-seven patients were treated on this study. The MTD was not defined. Both of the highest dose levels of bortezomib tested (1.3 mg/m2 on days 1, 4, 8, and 11 and 1.5 mg/m2 on days 1, 8, and 15, each on a 28-day cycle) could be safely given with cyclophosphamide 300 mg/m2 per week and prednisone. At these dose levels, the overall response rate was 95% (complete responses [CR] plus partial response plus minimal response), with CR observed in more than 50% of patients. The weekly bortezomib regimen resulted in fewer instances of grade 3 thrombocytopenia and grade 1 to 2 peripheral neuropathy; the 1-year progression-free and overall survival probabilities with this dose level were 83% (95% CI, 73% to 96%) and 100%, respectively. Conclusion Weekly bortezomib 1.5 mg/m2 plus oral cyclophosphamide and prednisone produces an unprecedented response rate and encouraging 1-year survival in relapsed/refractory patients with MM. Further evaluation of this promising regimen is warranted both in relapsed and newly diagnosed disease.
Multiple myeloma (MM) can be controlled but remains largely incurable with current drug therapy. The introduction of new drugs with unique mechanisms of action has increased the number of treatment options beyond our previous armamentarium of high-dose corticosteroids, alkylating agents, and autologous stem cell transplantation (ASCT), and has substantially improved the survival of patients with relapsed/refractory disease.1-4 Novel agents produce higher response rates when given with other cytotoxic drugs, and many promising combination regimens have been reported, although the superiority of any one combination over another remains to be established.5-8 Bortezomib, a first-in-class proteasome inhibitor with impressive single-agent activity in relapsed/refractory myeloma, is an ideal drug to use in combination with other agents, as myelosuppression is usually mild, noncumulative, and readily reversible between cycles.2,3 Increased risk of venous thromboembolism, noted with many thalidomide- and lenalidomide-based combinations, has not been observed with bortezomib-based therapy. However, disadvantages have included the need for frequent intravenous doses and the potential for peripheral neuropathy. Oral cyclophosphamide regimens have been used more commonly for MM in Canada and Europe than in the United States. A 1987 National Cancer Institute of Canada trial reported that cyclophosphamide 150 to 250 mg/m2 (maximum 500 mg) per week, initially given intravenously, and prednisone 100 mg every second day produced a response rate of 30% in patients refractory to melphalan.9 Others have described variations of this regimen using oral cyclophosphamide,10,11 and our group has previously published a retrospective analysis of oral weekly cyclophosphamide at a fixed dose of 500 mg, plus 50 or 100 mg of prednisone on alternate days, in MM progressive after ASCT. Partial responses (PR) were seen in 41% and minimal responses (MR) in 20%; stable disease was noted in 20%.12 Despite the infrequency of complete response (CR), the progression-free survival (PFS) was 19 months, and median overall survival 28 months.12 This regimen was well tolerated; significant myelosuppression was uncommon, in contrast to the cumulative stem cell damage that often accompanies oral melphalan administration.13 The results of oral cyclophosphamide–containing regimens compare favorably with different salvage regimens. We sought to optimize a combination of oral cyclophosphamide and prednisone with bortezomib in a phase I-II trial in relapsed/refractory myeloma. In addition to identifying the maximum tolerated dose (MTD) of this regimen, we wished to evaluate schedules in which bortezomib was given once as well as twice per week.
Eligibility This was an open-label, dose-finding study. The eligibility criteria included: confirmed diagnosis of relapsed/refractory MM; age  18 years; one prior chemotherapy regimen; Eastern Cooperative Oncology Group performance status 0 to 2; serum creatinine level  186 µmol/L; hemoglobin 80 g/L, absolute neutrophil count (ANC) 1.0 x 109/L, and the ability to maintain a platelet count 50 x 109/L; no serious comorbid illness or other malignancy within 3 years (excluding skin cancer or cervical cancer in situ); and informed consent. After one patient who was given granulocyte colony-stimulating factor (G-CSF) to bring up his ANC to be eligible for the trial developed grade 3 neutropenia during cycle 1, the protocol was modified to exclude the use of G-CSF within 2 weeks of study entry.
Phase I Dose Escalation Schedule
Toxicity was assessed after cycle 1 using the National Cancer Institute Common Toxicity Criteria version 3. DLT was defined as A total of six dose levels were planned (Table 1). Prednisone was given every second morning while cyclophosphamide was given orally as a single morning dose, before bortezomib, on days 1, 8, 15, and 22 with granisetron or prochloperazine as an antiemetic. Bortezomib was either given on days 1, 4, 8, and 11 or days 1, 8, and 15 depending on the dose level. The cycle length was 28 days. One half of the usual weekly dose of cyclophosphamide was utilized in dose level 1, while the full dose of 300 mg/m2 was given thereafter.
All patients received antacid therapy with either an H2-blocker or proton pump inhibitor. After several patients experienced respiratory infections with cycle 1, the protocol was amended to require oral levofloxacin 500 mg per day in cycle 1. Hematopoietic growth factors were allowed after cycle 1, while transfusions were permitted to maintain the hemoglobin over 80 g/L and platelet count higher than 50 x 109/L.
Assessment of Response
Statistical Considerations
Patient Characteristics Table 2 summarizes the characteristics of the 37 patients entered into this trial. The median age was 60 years (range, 38 to 74 years). Two of nine patients with conventional bone marrow cytogenetics had abnormal metaphases. Fluorescence in situ hybridization studies were available for deletion 13q, t(4;14), t(11;14), and/or p53 deletion in 46% of patients. All but three patients had received induction with high-dose dexamethasone alone or vincristine, doxorubicin, and dexamethasone and ASCT. Thirty-four patients had received prior intravenous cyclophosphamide (2.5 g/m2) for stem cell mobilization. The median number of prior regimens was two (range, one to six). Eleven had been previously exposed to oral cyclophosphamide, and seven had progressed on oral alkylating agents.
Toxicity With Cycle 1 Table 3 lists the toxicities seen with the first cycle. The most frequent grade 3 and 4 toxicities were nausea with or without vomiting in three patients (8%), thrombocytopenia in five (13%) and neutropenia in three (8%). However, the criteria for DLT were not met and the MTD was not reached.
Several toxicities warrant further description, however. First, two patients developed community-acquired pneumonia at dose level 1; these infections occurred during the winter months, when many other patients in our center experienced similar respiratory infections. The data safety and monitoring board allowed the trial to continue with the subsequent use of prophylactic levafloxacin during cycle 1; no further episodes of pneumonia occurred during the initial cycle. Second, the patient given G-CSF to raise his ANC for the trial developed grade 3 neutropenia during the first cycle at dose level 4; this patient went on to receive a total of three cycles with further growth factor and platelet transfusion support before myeloma progression. Finally, one patient experienced grade 3 increases in AST and ALT during cycle 1 on day 4 at dose level 4; subsequent doses of cyclophosphamide were reduced and the studies rapidly normalized. The patient's myeloma progressed on day 28. This individual had a history of fluctuating liver tests with prior therapy, including ASCT.
Toxicities During Cycle 2 to 8
Infections
Dose Reductions After Cycle 1 At dose level 6, the weekly dose of bortezomib was reduced from 1.5 mg/m2 to 1.3 mg/m2 in two patients, one in cycle 3 due to hypokalemia in part associated with persistent nausea and vomiting requiring two reductions in cyclophosphamide dose; this patient had a long-standing history of gastrointestinal symptoms that antedated the trial; the other patient had the bortezomib dose reduced in cycle 5 after an episode of varicella zoster. The dose of prednisone was reduced to 50 mg on alternate days due to poor steroid tolerance in cycle 3 in two and cycle 4 in one patient.
Protocol Therapy Delivered
Treatment After Protocol Completion Of the 18 patients who have not progressed, eight are off all therapy, eight continued on cyclophosphamide and prednisone for a median of 9 months (range, 1 to 15 months) after finishing protocol therapy, one was on prednisone alone, and one in continuous PR had cyclophosphamide changed to thalidomide, with prednisone, at the discretion of the referring physician 15 months after completing dose level 1.
Response Rates
Disease Progression The median follow-up of all patients was 14 months (range, 14 to 30 months). Nineteen patients progressed or died; the actuarial 1-year PFS was 56% (95% CI, 38% to 71%) for all 37 patients, with a median PFS of 15 months (95% CI, 10.6 to 15.9 months; Fig 1A). Importantly, the 1-year PFS was 83% (95% CI, 47% to 96%) and the median PFS has not yet been reached in the group of patients treated at dose level 6—the dose selected for phase II study. Only two patients in this cohort progressed, at 3.5 and 7 months (Fig 1B).
Of the 18 patients who have not yet progressed, one was treated at dose level 1, two at dose level 4, four at dose level 5, and 11 at dose level 6. Eight are off all antimyeloma therapy, including one in PR at 1 month and seven in CR/nCR at a median of 6 months (range, 1 to 12 months) after stopping cyclophosphamide and prednisone alone. These patients remain free of progression at a median of 17 months (range, 11 to 24 months) after starting the trial.
Overall Survival
Influence of Cytogenetics The single patient with t(4;14) remained in continuous CR 17 months after protocol entry (dose level 5) and 8 months after stopping cyclophosphamide and prednisone. The two patients with deletion 13q were treated at dose level 6 and remained in nCR and PR for 8 and 11 months, respectively. One of the three patients with t(11;14) remained in PR at 15.5 months after treatment with dose level 4, while the other two, one of whom also had deletion 13q, remained in PR at 4 months and CR at 8 months, respectively, after commencing dose level 6.
This study demonstrates that full doses of bortezomib, 1.3 mg/m2 twice per week, can be combined with oral cyclophosphamide 300 mg/m2 per week and alternate day prednisone, at least using a 28-day cycle length, with acceptable toxicity and an excellent response rate. Although peripheral neuropathy, usually grade 1, and grade 3 thrombocytopenia occurred relatively frequently at this dose level, they were manageable, reversible, and not dose-limiting. However, two of six patients at this dose level completed only seven of eight planned cycles due to toxicity. Moreover, the antitumor effect appeared to be preserved when a somewhat higher dose of bortezomib—1.5 mg/m2—was given only once per week for three doses with the same oral combination. Myelosuppression was milder with less thrombocytopenia, and no significant peripheral neuropathy or neuropathic pain was observed with this dosing schedule. The use of prednisone, rather than dexamethasone, in our regimen also likely contributed to the excellent tolerance. Recently, prolonged use of high-dose dexamethasone therapy has been associated with more toxicity, at least when used as part of first-line therapy.18 Infectious complications were also manageable in this population of relapsed/refractory patients. As described in other bortezomib series, varicella zoster occurred in a significant proportion (30%) in the absence of routine antiviral prophylaxis.19 Such prophylaxis should be used with this regimen and will be incorporated into our future trials. There has been concern that myeloma may progress when the interval between bortezomib doses increases, as in certain maintenance schedules. Weekly bortezomib in our regimen was active, with a low rate of early progression, suggesting the need for twice weekly administration may be less when an alkylating agent and corticosteroid are used during the 2-week period without bortezomib.
Responses were achieved rapidly and were observed after the first cycle, with the best response achieved after two cycles in the majority of patients treated at the higher dose levels. The CR/nCR rate with dose levels 5 and 6, using the 1.3 and 1.5 mg/m2 doses of bortezomib, was Response duration is another critical factor in evaluating newer therapies for relapsed/refractory myeloma. In the initial trials of single-agent bortezomib, therapy could be continued on an extension program,22 particularly if CR had not been achieved. Despite this, the median time to progression was approximately 6 months. Moreover, some patients do not achieve the maximal response until many cycles have been given. Although the optimum duration of bortezomib therapy is uncertain, the ability to administer a regimen for prolonged periods without marked toxicity would likely be advantageous. One of our patients elected to continue all three drugs, at dose level 4, until disease progression was documented after a total of 16 cycles, without toxicity. The favorable toxicity profile of this regimen suggests that long-term therapy may be feasible. Although most of our patients received cyclophosphamide and prednisone alone, albeit for a relatively short period, after completing the eight cycles of protocol therapy, seven patients remain in unmaintained CR/nCR for periods of up to 1 year off all therapy. The absence of a formal bortezomib-based maintenance schedule over and above the oral combination does not allow us, in the context of this study, to adequately address the issue of prolonged therapy, however, and it should be evaluated as part of future studies. In summary, this pilot study found that a triple drug regimen incorporating weekly bortezomib with cyclophosphamide and prednisone was convenient, well tolerated, and effective. The efficacy of this regimen needs to be evaluated in a larger, controlled, comparative study, but our preliminary observations indicated that overall response rates were notable in terms of both quality and duration. Evaluation of this combination is warranted in studies involving newly diagnosed as well as relapsed/refractory patients. A Canadian trial comparing our weekly and twice weekly bortezomib combination is planned.
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: None Consultant or Advisory Role: Donna E. Reece, Ortho Biotech Canada (C); Christine Chen, Ortho Biotech Canada (C); Joseph Mikhael, Ortho Biotech Canada (C); A. Keith Stewart, Ortho Biotech Canada (C) Stock Ownership: None Honoraria: Donna E. Reece, Ortho Biotech Canada, Millennium Pharmaceuticals Inc, Johnson and Johnson; Christine Chen, Ortho Biotech Canada; Joseph Mikhael, Ortho Biotech Canada; A. Keith Stewart, Ortho Biotech Canada Research Funding: Donna E. Reece, Ortho Biotech Canada, Millennium Pharmaceuticals Inc; Christine Chen, Ortho Biotech Canada Expert Testimony: None Other Remuneration: None
Conception and design: Donna E. Reece, Giovanni Piza Rodriguez, A. Keith Stewart Administrative support: Giovanni Piza Rodriguez Provision of study materials or patients: Donna E. Reece, Giovanni Piza Rodriguez, Christine Chen, Suzanne Trudel, Vishal Kukreti, Joseph Mikhael, A. Keith Stewart Collection and assembly of data: Donna E. Reece, Giovanni Piza Rodriguez, Mariela Pantoja, A. Keith Stewart Data analysis and interpretation: Donna E. Reece, Giovanni Piza Rodriguez, Christine Chen, Suzanne Trudel, Vishal Kukreti, Joseph Mikhael, Wei Xu, A. Keith Stewart Manuscript writing: Donna E. Reece, A. Keith Stewart Final approval of manuscript: Donna E. Reece, Giovanni Piza Rodriguez, Christine Chen, Suzanne Trudel, Vishal Kukreti, Joseph Mikhael, Mariela Pantoja, Wei Xu, A. Keith Stewart
published online ahead of print at www.jco.org on July 21, 2008 Supported by Ortho Biotech Canada. Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005; the 48th Annual Meeting of the American Society of Hematology, Orlando, FL, December 9-12, 2006; and the XIth International Myeloma Workshop, Kos Island, Greece, June 25-30, 2007. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Weber DM, Chen C, Niesvizky R, et al: Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): Results of a North American phase III study (MM-009). J Clin Oncol 24:427s, 2006 (suppl; abstr 7521) 2. 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 3. 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 4. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999 5. Garcia-Sanz R, Gonzalez-Porras JR, Hernandez JM, et al: The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia 18:856-863, 2004[CrossRef][Medline] 6. Offidani M, Bringhen S, Corvatta L, et al: Thalidomide-dexamethasone plus pegylated liposomal doxorubicin vs. thalidomide-dexamethasone: A case-matched study in advanced multiple myeloma. Eur J Haematol 78:297-302, 2007[CrossRef][Medline] 7. Richardson PG, Mitsiades C, Ghobrial I, et al: Beyond single-agent bortezomib: Combination regimens in relapsed multiple myeloma. Curr Opin Oncol 18:598-608, 2006[Medline] 8. Orlowski RZ, Nagler A, Sonneveld P, et al: Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: Combination therapy improves time to progression. J Clin Oncol 25:3892-3901, 2007 9. Wilson K, Shelley W, Belch A, et al: Weekly cyclophosphamide and alternate-day prednisone: An effective secondary therapy in multiple myeloma. Cancer Treat Rep 71:981-982, 1987[Medline] 10. Brandes LJ, Israels LG: Weekly low-dose cyclophosphamide and alternate-day prednisone: An effective low toxicity regimen for advanced myeloma. Eur J Haematol 39:362-368, 1987[Medline] 11. de Weerdt O, van de Donk NW, Veth G, et al: Continuous low-dose cyclophosphamide-prednisone is effective and well tolerated in patients with advanced multiple myeloma. Neth J Med 59:50-56, 2001[CrossRef][Medline] 12. Trieu Y, Trudel S, Pond GR, et al: Weekly cyclophosphamide and alternate-day prednisone: An effective, convenient, and well-tolerated oral treatment for relapsed multiple myeloma after autologous stem cell transplantation. Mayo Clin Proc 80:1578-1582, 2005 13. Berenson JR, Yang HH, Sadler K, et al: Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. J Clin Oncol 24:937-944, 2006 14. Blade 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. Br J Haematol 102:1115-1123, 1998[CrossRef][Medline] 15. Durie BG, Harousseau JL, Miguel JS, et al: International uniform response criteria for multiple myeloma. Leukemia 20:1467-1473, 2006[CrossRef][Medline] 16. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 17. Lonial S, Waller EK, Richardson PG, et al: Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 106:3777-3784, 2005 18. Rajkumar SV, Jacobus S, Callander N, et al: Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 25:447s, 2007 (suppl; abstr LBA8025)[CrossRef] 19. Chanan-Khan AA, Sonneveld P, Schuster MW, et al: Analysis of varicella zoster virus reactivation among bortezomib-treated patients in the APEX study. Blood 108:1009a, 2006 (abstr 3535) 20. Chang H, Trieu Y, Qi X, et al: Bortezomib therapy response is independent of cytogenetic abnormalities in relapsed/refractory multiple myeloma. Leuk Res 31:779-782, 2007[CrossRef][Medline] 21. Sagaster 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] 22. Berenson JR, Jagannath S, Barlogie B, et al: Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma. Cancer 104:2141-2148, 2005[CrossRef][Medline] Submitted September 10, 2007; accepted May 27, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
