Annals of Oncology Advance Access originally published online on September 15, 2006
Annals of Oncology 2006 17(12):1766-1771; doi:10.1093/annonc/mdl313
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© 2006 European Society for Medical Oncology
hematologic malignancies |
Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy
1 Cleveland Clinic Cancer Center Myeloma Research Program, Cleveland Clinic, Cleveland
2 Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland
3 Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland
4 Hematology and Medical Oncology, Sparrow Cancer Center, Lansing, Celgene Corporation, Summit, USA
Correspondence to: Dr M. A. Hussein, M.D., Director, Myeloma Research Program, Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk R35, Cleveland, OH 44195, USA. Tel: +1(216) 445 6830; Fax: +1(216) 445 3434; E-mail: mashussein{at}runbox.us
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Abstract |
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Background: Lenalidomide is active and well tolerated in relapsed and refractory multiple myeloma. We conducted a phase I/II trial of the combination of lenalidomide and chemotherapy to evaluate the safety and efficacy of the combination.
Methods: The 62 patients enrolled received liposomal doxorubicin 40 mg/m2 i.v. and vincristine 2 mg i.v. on day 1, dexamethasone 40 mg p.o. on days 1–4 (DVd), and lenalidomide on days 1–21 in 28-day cycles. Primary end points were maximum tolerated dose (MTD) of lenalidomide with DVd chemotherapy and overall response rate (ORR) by Southwest Oncology Group criteria of the combination.
Findings: The median age was 62 years, 70% of patients were males and 65% had refractory multiple myeloma. The MTD of lenalidomide with DVd chemotherapy was 10 mg and the dose-limiting toxicity was non-neutropenic sepsis. After 7.5 months of median follow-up, the ORR of the combination was 75%, with 29% of patients achieving a complete or near complete remission. The median progression-free survival was 12 months, while the median overall survival has not yet been reached.
Interpretation: The combination of lenalidomide and DVd chemotherapy was well tolerated and resulted in high response rates in this mostly refractory patient population. Evaluation of this combination in newly diagnosed patients is warranted.
Key words: Multiple Myeloma, Refractory, Lenalidomide, reduced dose dexamethasone, Doxil
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background |
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TopAbstractbackgroundpatients and methodsresultsdiscussioncontributorsReferences |
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Multiple myeloma is a plasma-cell disorder characterized by the production of a monoclonal protein from plasma cells in the bone marrow. Despite initial responses to therapy, multiple myeloma ultimately progresses and the treatment of patients with relapsed and refractory multiple myeloma remains challenging [1, 2]. This is especially true for patients with refractory multiple myeloma who have a progression-free survival (PFS) of 6 months and median survival of a year [3, 4]. The optimal combination of chemotherapeutic agents has not been defined in this setting. The introduction of novel agents, such as bortezomib, arsenic trioxide, thalidomide, and more recently lenalidomide, to the medical armamentarium marks the beginning of a new era in the management of patients with multiple myeloma [5–7].
The combination of liposomal doxorubicin (DOX), vincristine (VCR), decreased frequency dexamethasone, and thalidomide (DVd-T) results in a high response rate (>80%) in patients with newly diagnosed and relapsed/refractory multiple myeloma [7, 8]. However, it is associated with 20% grades 3 and 4 peripheral neuropathy.
Lenalidomide has immunomodulatory properties and is more potent than thalidomide in stimulating T-cell proliferation, decreasing the production of tumor necrosis factor-
(TNF-) and interleukin 6 (IL-6) [9–12]. Lenalidomide also inhibits the binding of malignant plasma cells to bone marrow stromal cells resulting in decreased production of IL-6, vascular endothelial growth factor, TNF-, and angiogenesis [13, 14]. In addition, lenalidomide is well tolerated in patients with multiple myeloma without the known side-effects of thalidomide [15]. While myelosuppression and venous thromboembolic events are the most significant adverse events, peripheral neuropathy and sedation are not associated with lenalidomide use [16, 17]. The combination of DVd chemotherapy and lenalidomide promises to result in an increased response rate without significant neuropathy or sedation.
We conducted a phase I/II clinical trial at the Cleveland Clinic Taussig Cancer Center to determine the safety, tolerability, and maximum tolerated dose (MTD) of lenalidomide with DVd, and to evaluate the response rate and PFS of this combination in patients with relapsed or refractory multiple myeloma.
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patients and methods |
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eligibility
Eligible patients must have been older than 18 years of age, had active relapsed or refractory multiple myeloma with a measurable serum or urine paraprotein, and must have been able to understand and sign an informed consent document. Patients must have had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero to two, a serum bilirubin less than two times the upper limits of normal, serum transaminases (alanine aminotransferase/aspartate aminotransferase) less than three times the upper limits of normal, adequate bone marrow function [absolute neutrophil count (ANC) >1000 per µl, platelet count >100 000 per µl, and hemoglobin >8 g/dl], a serum creatinine
2.5 mg/dl, and a left ventricular ejection fraction >50% by echocardiogram. Patients with ECOG PS of three and four were allowed if the decline in PS was related to bony disease. Patients were considered to have refractory disease if they demonstrated progression on active myeloma therapy. Relapsed multiple myeloma was defined as the evidence of progression (increased monoclonal protein and end organ damage) after the end of active therapy. Patients with >50% plasma cells in the bone marrow were allowed to have baseline ANC <1000 per µl and baseline platelet count <100 000 per µl (i.e. no particular minimum low count mandated). Women of childbearing potential must have had a negative serum or urine pregnancy test within 1 week of receiving the study drug and must have agreed to use an adequate contraceptive method and be subjected to monthly pregnancy testing. Exclusion criteria included the presence of a severe ongoing infection requiring i.v. antibiotics, a life expectancy of <3 months, a history of prior malignancy, a history of cardiac dysfunction with New York Heart Association classification II or greater, and patients who have received >500 mg/m2 of DOX alone, Doxil® (Sequus Pharmaceuticals Inc., Menlo Park, CA) alone, or DOX plus Doxil®. In addition, patients with uncontrolled medical problems or conditions that would have placed the subject at an unacceptable risk from study participation were excluded. Pregnant or lactating females at screening, and patients who had developed grade 2 or greater [National Cancer Institute, Common Toxicity Criteria (NCI CTC)] allergic reaction/hypersensitivity, or grade 3 or greater (NCI CTC) rash or any desquamation during prior thalidomide therapy were excluded as well. Patients who had previously received lenalidomide were excluded. A history of prior malignancy with the exception of adequately treated basal cell carcinoma of the skin and cervical in situ carcinoma was only allowed if the patient has been disease free for at least 5 years. Patients with solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma-cell dyscrasias were excluded. The study was approved by The Cleveland Clinic Foundation Internal Review Board.
role of the funding source
The funding sources were not involved in the design of the study, in the collection of data or its analysis, in the interpretation of results, in the writing of the report, or in the decision to submit the paper for publication.
treatment
DVd chemotherapy was repeated every 4 weeks for a minimum of four cycles and two cycles beyond best response in the induction phase of the study. DVd consisted of pegylated liposomal DOX given at 40 mg/m2 Intra-Venous (Piggy-Back) (IVPB) on day 1, VCR at 2 mg IVP on day 1, and dexamethasone at 40 mg p.o. on days 1–4. A standard phase I dose escalation of lenalidomide was carried out to identify the MTD of lenalidomide in combination with DVd chemotherapy. Three to six patients were enrolled on each dose level. On the first cycle of the phase I portion of the study, lenalidomide was started at 5 mg p.o. daily 1 week before the start of chemotherapy and continued for 28 days of the 35-day cycle. On subsequent cycles and on the phase II portion of the study, lenalidomide was started on the first day of the cycle for 21 of the 28 days. Subsequent planned dose levels of lenalidomide were 10, 15, 20, and 25 mg orally as tolerated. In the maintenance phase of the study, patients received lenalidomide, at their highest tolerated dose for 21 of every 28 days with prednisone 50 mg every other day until disease progression (PD).
dosage modifications
Pegylated liposomal DOX was reduced by 25% in the event of grade 3 or 4 myelosuppression, palmar–plantar erythrodysaesthesia, grade 1 or 2 stomatitis, and grade 1 hyperbilirubinemia. A 50% dose reduction was applied for grade 
2 hyperbilirubinemia and grade 3 stomatitis. Pegylated liposomal DOX was discontinued with grade 4 stomatitis. Lenalidomide was dose reduced by 5 mg daily from the prior dose level with the occurrence of the following: a cardiac arrhythmia, grade 3 rash, grade 3 constipation, grade 2 or 3 allergic reactions, and grade 3 neuropathy. For grade 3 or 4 neutropenia or thrombocytopenia, the dose of the pegylated liposomal DOX was modified first and if the event reoccurred, lenalidomide was reduced by 5 mg daily from the previous dose. Lenalidomide was discontinued if any of the following occurred: grade 4 rash or allergic reaction and grade 4 peripheral neuropathy. VCR was dose reduced by 25% with the occurrence of grade 3 constipation and grade 2 or 3 neuropathy. Dexamethasone was dose reduced by 50% with the occurrence of grade 2 or greater confusion or muscle weakness, grade 3 edema, grade 3 or 4 hyperglycemia, and grade 3 dyspepsia.
A new cycle of treatment was administered on day 1 of the new cycle if the following conditions were satisfied: the platelet count was >75 000 per µl (lower platelet counts were allowed in patients with >50% plasma cells in the bone marrow), the serum bilirubin was <3 mg/dl, the patient had recovered from stomatitis, and therapy-related adverse events had improved to grade 1 or less severity.
supportive care
All patients received amoxicillin (250 mg b.i.d. orally), aciclovir (400 mg b.i.d. orally), and aspirin (81 mg daily orally). Low-dose daily aspirin prophylaxis for thromboembolic events was instituted in view of its effectiveness and safety in decreasing thromboembolic events in patients receiving chemotherapy and thalidomide and was used regardless of the platelet count [18]. The use of bisphosphonates, erythropoietic, and myeloid growth factor was allowed per the accepted standard of care.
safety and responses
Assessment of response and safety included monthly history, physical examination, and laboratory testing for the following: complete blood counts and metabolic panel, serum protein electrophoresis, ß2-microglobulin, and a 24-h urine collection for urine protein electrophoresis in the patient with prior urinary monoclonal protein. Bone marrow aspirate and biopsy were carried out at the enrollment, after four cycles of therapy and at the completion of chemotherapy if complete remission was to be confirmed. Skeletal survey was carried out every 6 months or earlier if clinically indicated. An echocardiogram was done at the start of study and was repeated when the total dose of anthracyclines has exceeded 500 mg/m2 or at the discretion of the investigator as clinically indicated. Toxicity was assessed using the common toxicity criteria version 2.0. The Southwest Oncology Group (SWOG) staging system was utilized for staging [19].
The modified SWOG response criteria were used to assess responses [20]. A complete response (CR) is defined by the disappearance of the paraprotein in serum and urine by immunofixation as well as by <5% plasma cell in the bone marrow. Near complete remission (NCR) was adopted from the Intergroupe Francais du Myelome studies [21]. A NCR was defined by >90% decrease in the paraprotein. A partial response (PR) was defined as 50% decrease in the serum paraprotein. Stable disease (SD) was defined as <50% decrease and <25% increase in the paraprotein. Finally, PD was defined by the development of two worsening parameters. Patients were taken off study in the event of PD, unacceptable toxicity, patient wishes, and/or at the discretion of the principal investigator if patient reliability resulted in compromise to patient safety. Patients who had not completed two cycles of therapy were considered non-assessable for response. Non-assessable patients are not included in response assessment but are included in mortality and adverse event assessment.
study design
During the phase I portion of the study, dose-limiting toxicity (DLT) was defined as a grade 3 or greater non-hematologic toxicity or grade 4 hematologic toxicity within the first cycle of DVd-R therapy. The phase I portion of the study followed a sequential dose escalation, '3 + 3' design. Initially, three subjects were started on treatment with dose regimen 1. After the third subject completed one cycle (4 weeks) of treatment, if no DLT occurred, then the next group of three subjects were treated at the next dose level of lenalidomide. If one of the three initial subjects experienced a DLT, the cohort of subjects was expanded to six subjects. If less than two out of the six subjects experienced a DLT, then the next higher dose group was initiated. If two or more (of a cohort of up to six) subjects experienced a DLT, no higher dose levels would be tested and the MTD would have been exceeded. Intra-patient dose escalation was not permitted. The MTD was defined as the highest dose studied for which the incidence of DLT was less than two out of the six subjects during the first cycle of DVd-R therapy. Fifty additional patients were enrolled at the MTD on the phase II portion of the trial.
statistical analysis
Descriptive statistics were computed for demographic as well as baseline variables. PFS and overall survival (OS) were analyzed using Kaplan–Meier curves. The analyses were done using JMP 5.1 (SAS Institute).
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patient characteristics
Sixty-two patients were enrolled on the present phase I/II study. The median follow-up was 7.6 months [interquartile range (IQR): 5.0–18.1]. The median age was 62 years (IQR: 57–70). Forty-four patients (71%) were males and 53 were Caucasian (85%). Forty patients (64%) had refractory multiple myeloma, while 22 patients had relapsed multiple myeloma. The median time from diagnosis to study participation was 36 months (IQR: 19–64). The median serum ß2-microglobulin was 5.2 mg/dl (IQR: 3.4–7.8). The median number of prior chemotherapeutic regimens was three (IQR: 1–7). Forty-one patients (66%) had received a prior thalidomide-containing regimen and 11 patients had prior high-dose therapy with autologous stem-cell transplantation. In addition, two patients had failed after allogeneic stem-cell transplantation. Patient characteristics are summarized in Table 1.
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DLT and MTD
The phase I study enrolled 12 patients. Three, three, and four patients were enrolled on dose levels 1, 2, and 3 of lenalidomide (5, 10, and 15 mg), respectively. The DLT (non-neutropenic sepsis) occurred at a lenalidomide dose of 15 mg daily in three patients. Accordingly, the MTD of lenalidomide with DVd chemotherapy was 10 mg.
An additional 50 patients were enrolled on the phase II portion of the study. Pegylated liposomal DOX was dose reduced in 19 patients, and the median total dose was 200 mg/m2 (mean 168 ± 75 mg/m2). VCR was dose reduced in 25 patients and withdrawn in 10 patients because of neuropathy. Dexamethasone was dose reduced in only two patients. In the phase II portion of the study, lenalidomide was dose reduced to 5 mg in one patient during the maintenance phase. The median daily lenalidomide dose was 10 mg for 21 of 28 days for the entire cohort of patients.
maintenance therapy
Thirty-five patients received maintenance therapy with lenalidomide (10 mg days 1–21) and prednisone (50 mg every other day) for a median of 7 months (range 1–19 months). Maintenance therapy was overall well tolerated and only one patient required dose reduction of the lenalidomide by one level (i.e. to 5 mg) for recurrent grade 2 myelosuppression. No grade 3-related adverse events were noted during maintenance therapy.
adverse events
Adverse events are reported for the entire cohort of patients. The most common adverse events were pancytopenia, asthenia, muscle cramps, rash, and peripheral neuropathy. The most frequent grades 3 and 4 adverse event was myelosuppression. Despite 32% grade 3 or 4 neutropenia, only four patients (7%) developed febrile neutropenia. Thromboembolic events (deep venous thrombosis or pulmonary embolus) occurred in 9% of patients and this is consistent with the rate of thromboembolic events in patients with plasma-cell dyscrasias at our institution and other institutions [22, 23]. One patient experienced upper gastrointestinal bleeding during therapy, this was successfully treated with H2 blocker therapy. Grades 3 and 4 peripheral neuropathy occurred in only 5% of patients. Table 2 summarizes the adverse events for the entire cohort of patients.
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response rates
After a median follow-up of 7.5 months, 52 of the 62 enrolled patients were assessable for response. Non-assessable patients received less than two cycles of DVd-R for the following reasons: early death in three, withdrawal of consent in five, and screen failure in two patients. Early deaths occurred after 5, 12, and 18 days and were likely infectious in etiology. The median number of cycles of DVd-R delivered was five (IQR: 3–6). The best responses were as follows: 15 patients (29%) had CR or NCR, 24 (46%) PR, nine (17%) SD, and four (8%) PD. The overall response rate (ORR = PR + NCR + CR) was 75% (Table 3). Three responders had extramedullary plasmacytomas as part of their disease presentation. The three patients responded to therapy with one achieving CR. The first response was noted at a median of 45 days and a median one cycle of DVd-R therapy. Best response occurred after a median of 115 days and four cycles of therapy. Eleven patients had received high-dose therapy and peripheral blood stem cells, of which seven had a response. Sixteen patients had bortezomib-based therapy, of which eight had a response to DVd-R. Forty-one patients had relapsed or were refractory to thalidomide (no patient was intolerant to thalidomide), of which 22 responded to DVd-R.
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After a median follow-up of 7.5 months, 34 patients had PD, of which 20 patients died. Kaplan–Meier estimates for PFS and OS are illustrated in Figures 1 and 2, respectively. The median PFS was 12 months, while the median OS has not yet been reached.
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discussion |
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The combination of lenalidomide (10 mg daily on days 1–21) and DVd (every 28 days) is well tolerated and results in a high response rate in a group of mostly refractory multiple myeloma patients. Notably, the combination resulted in acceptable myelosuppression with only 7% incidence of febrile neutropenia. Non-neutropenic infectious complications (mostly pneumonia, cellulitis, and candidosis) occurred in about 17% of patients despite prophylactic amoxicillin and aciclovir. Grade 3 peripheral neuropathy occurred only in 5% of patients with this regimen. This contrasts favorably with the DVd-T and other thalidomide-containing regimens which resulted in
20% grades 3 and 4 peripheral neuropathy [7]. The combination of lenalidomide and dexamethasone was associated with an increased risk of thromboembolic events [24]. Low-dose aspirin has been successfully used prophylactically for this complication [18]. Thromboembolic events (deep venous thrombosis and pulmonary embolism) were noted in 9% of patients receiving DVd with lenalidomide with low-dose aspirin (81 mg daily) prophylaxis. This rate is comparable to the background rate of thromboembolic events in patients with multiple myeloma at our institution [18, 23].
DVd combined with lenalidomide resulted in a high ORR (75%) in this mostly refractory group of patients. The combination of lenalidomide and high-frequency dexamethasone resulted in an ORR of 58% and a time to progression of about 13 months [25]. It should be noted, however, that our study population consists of a high percentage of refractory patients (64%) with known poor outcomes regardless of the therapeutic regimen used.
How does DVd-R compare with regimens that did not include lenalidomide for relapsed refractory patients? The Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma. The ORR was 38% and the time to progression was 6 months in the bortezomib arm. In addition, grades 3 and 4 adverse events occurred in 75% of patients [26].
Two-thirds of the patients (41 patients) in this study had received and failed a thalidomide-containing regimen. Twenty-two of these patients (54%) responded to the DVd-R regimen, suggesting continued efficacy of lenalidomide in combination with DVd chemotherapy for thalidomide refractory patients. In addition, 42 patients (68%) had received prior DVd-like chemotherapy, of which 28 responded to DVd-R and three out of three patients who had progressed on single-agent lenalidomide have responded to this combination.
DVd-R resulted in a high number of quality responses (29% CR and NCR) in this patient population. We have previously reported that high-quality responses in patients receiving a thalidomide-containing regimen resulted in a survival benefit. It remains unclear whether higher quality responses will result in improvement in the OS of patients with multiple myeloma treated with a lenalidomide-containing regimen.
These responses noted with the DVd-R regimen in a majority of refractory multiple myeloma patients are comparable to the quality of responses noted with high-dose therapy followed by autologous stem-cell transplantation. Moreover, the high incidence of grades 3 and 4 neutropenia did not translate into clinical neutropenic fever and the incidence of thrombotic events with the use of 81 mg of aspirin was <10% despite aggressive proactive monitoring for deep venous thrombosis. As such, the use of DVd-R in the treatment of newly diagnosed patients should be considered.
In conclusion, the DVd-R regimen was safe, well tolerated, and effective in patients with refractory and relapsed multiple myeloma and trials of this regimen in newly diagnosed patients are warranted.
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contributors |
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All authors performed the research. E. Walker, R. Baz, M.A. Hussein, and M. Kelly analyzed the data. R. Baz, E. Walker, and M.A. Hussein wrote the manuscript and M.A. Hussein designed the research.
Received for publication April 3, 2006. Revision received June 5, 2006. Accepted for publication July 24, 2006.
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References |
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