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First Published Online October 15, 2008
The Oncologist, Vol. 13, No. 10, 1120-1127, October 2008; doi:10.1634/theoncologist.2008-0077
© 2008 AlphaMed Press

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Regulatory Issues: FDA

Lenalidomide in Combination with Dexamethasone for the Treatment of Multiple Myeloma After One Prior Therapy

Maitreyee Hazarikaa, Edwin Rocka, Gene Williamsc, Ramzi Daghera, Rajeshwari Sridharab, Brian Boothc, Ann Farrella, Robert Justicea, Richard Pazdura

aOffice of Oncology Drug Products, Office of New Drugs, bOffice of Biostatistics, Office of Translational Sciences, and cOffice of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA

Key Words. Lenalidomide • Multiple myeloma • Approval

Correspondence: Ann T. Farrell, M.D., Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993-0002, USA. Telephone: 301-796-2330; Fax: 301-796-9845; e-mail: ann.farrell{at}fda.hhs.gov

Received March 28, 2008; accepted for publication September 15, 2008; first published online in THE ONCOLOGIST Express on October 15, 2008.

Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.


   ABSTRACT
Top
 Abstract
Introduction
 Phase III Trial Designs
 Results
 Discussion
 Conclusions
 Author Contributions
 References
 
Purpose. Lenalidomide (CC-5013, Revlimid®; Celgene Corporation, Summit, NJ), a thalidomide analogue, was granted approval by the U.S. Food and Drug Administration (FDA) on June 29, 2006, for use in combination with dexamethasone in patients with multiple myeloma (MM) who have received at least one prior therapy. The FDA approved lenalidomide with a restricted distribution program, RevAssist®.

Experimental Design. In two randomized, double-blind, multicenter studies, the combination of lenalidomide and dexamethasone (LD) was compared with placebo and dexamethasone (PD) in patients with MM who had received at least one prior therapy. The primary endpoint was time to progression (TTP).

Results. Following a prespecified interim analysis of TTP, an independent data-monitoring committee advised the sponsor to halt the two studies. For both studies, the interim analysis for efficacy revealed a statistically significant longer TTP with LD than with PD.

The most clinically relevant grade 3 and 4 adverse events that occurred more frequently in the LD arm were neutropenia, thrombocytopenia, deep vein thrombosis, pulmonary embolism, and atrial fibrillation. Thrombotic or thromboembolic events, including deep vein thrombosis, pulmonary embolism, thrombosis, and intracranial venous sinus thrombosis were reported more frequently in patients treated with LD than with PD.

Conclusions. The FDA approved lenalidomide based on interim results from two multicenter, placebo-controlled, randomized trials comparing the combination of LD with PD that revealed a longer TTP with LD than with PD. The major toxicity observed during these trials was myelosuppression. The serious toxicities included thromboembolic events. Lenalidomide is only available under the RevAssist® Program.


   INTRODUCTION
Top
 Abstract
 Introduction
Phase III Trial Designs
 Results
 Discussion
 Conclusions
 Author Contributions
 References
 
Lenalidomide (CC-5013, Revlimid®; Celgene Corporation, Summit, NJ), a thalidomide analogue, is an immunomodulatory agent. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione.

Lenalidomide was first approved on December 27, 2005, for the treatment of patients with transfusion-dependent anemia resulting from low or intermediate-1 risk myelodysplastic syndromes with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. The original approval included 5-mg and 10-mg capsules. The U.S. Food and Drug Administration (FDA) approved lenalidomide under Subpart H regulations (21 Code of Federal Regulations 314.500) with a restricted distribution program, RevAssist®. The current approval includes 15-mg and 25-mg capsules.

On June 29, 2006, the FDA granted approval to lenalidomide under Subpart H regulations under a restricted distribution program, RevAssist®, for use in combination with dexamethasone in patients with multiple myeloma (MM) who have received at least one prior therapy. Celgene submitted interim results from two identically designed, multicenter, randomized, double-blind, placebo-controlled trials that compared the lenalidomide plus dexamethasone (LD) combination with the placebo plus dexamethasone (PD) combination in patients with relapsed MM who had received at least one prior therapy. Study 1 was conducted in the U.S. and Canada; study 2 was conducted in Europe, Israel, and Australia. In both studies, the primary endpoint was time to progression (TTP). Secondary endpoints included overall survival (OS), myeloma response rate, safety, time to first skeletal-related event, and time to first decrease in Eastern Cooperative Oncology Group (ECOG) performance status (PS) score.


   PHASE III TRIAL DESIGNS
Top
 Abstract
 Introduction
 Phase III Trial Designs
Results
 Discussion
 Conclusions
 Author Contributions
 References
 
Population
The eligibility criteria included patients diagnosed with Durie-Salmon stage II or III MM and considered to have disease progression after at least two cycles of antimyeloma treatment or to have relapsed with progressive disease after treatment. Patients were required to have measurable levels of myeloma paraprotein in serum (≥0.5 g/dl) or urine (≥0.2 g excreted in a 24-hour collection sample). Women of child-bearing potential were required to have a negative pregnancy test and to use two adequate contraceptive methods. Other patient eligibility requirements included an ECOG PS score of 0, 1, or 2, an absolute neutrophil count >1,000 cells/mm3 (1.0 x 109/l), a platelet count >75,000/mm3 (75 x 109/l), serum creatinine <2.5 mg/dl (221 µmol/l), serum aspartate aminotransferase or alanine aminotransferase <3.0x the upper limit of normal, and serum total bilirubin <2.0 mg/dl (34 µmol/l). Patients with known hypersensitivity to thalidomide or dexamethasone, a history of a desquamating rash while taking thalidomide, or a history of prior lenalidomide use were excluded. Also, patients were ineligible if they had received high-dose dexamethasone (total monthly dose of dexamethasone >200 mg) within 6 months prior to randomization.

Treatment
Patients were randomized to receive oral treatment regimens of either LD or PD. Randomization was centralized and stratified by three factors: baseline serum β2-microglobulin level (≤2.5 mg/l versus >2.5 mg/l), prior treatment with high-dose chemotherapy and stem cell transplant (SCT) or no prior treatment with high-dose chemotherapy or SCT, and number of prior antimyeloma regimens (one versus more than one). Patients in the LD arm took 25 mg of lenalidomide orally once daily on days 1–21 and a placebo on days 22–28 of each 28-day cycle. Both groups took 40 mg of dexamethasone orally once daily on days 1–4, 9–12, and 17–20 of each 28-day cycle for the first four cycles and 40 mg daily on days 1–4 every 28 days after the fourth cycle. The protocols had dose modifications based on toxicity. Physicians and patients were blinded to treatment assignment.

Endpoints
The primary endpoint was TTP. TTP was defined as the time from randomization to the first occurrence of any one of the following events: (a) progressive disease based on standardized myeloma response criteria; (b) discontinuation resulting from progressive disease according to investigator assessment whether or not confirmed by the standardized criteria; and (c) death resulting from progressive disease. The criteria for MM progression (or relapse from complete response) were those defined by the European Group for Blood and Marrow Transplant using clinical and laboratory findings [1].

Secondary endpoints included response rate, overall survival (OS), safety, time to first symptomatic skeletal-related event, and time to first decrease in ECOG PS score. The definition of the complete response rate was similar to that used by the EBMT, but the definition of the partial response rate in the protocol differed from the EBMT criteria. Serum and urine protein electrophoresis were performed at screening, on day 1 of cycle 1, on day 15 of cycles 1, 2 and 3, and at the end of treatment. Quantitative immunoglobulins were determined and serum and urine immunofixation studies were performed at the screening visit and on day 1 of each cycle beginning with cycle 2.

The statistical analysis plan included a one-sided unstratified log-rank test at the overall 0.025 level (allowing for one interim analysis) for TTP. A secondary analysis was planned to compare OS after at least 194 deaths, which was expected to occur after 18 months of follow-up. The study had 85% power to detect a hazard ratio of 1.5 for TTP between the two arms (an increase of 6 to 9 months in the median TTP; a total of 222 TTP events was required for the final analysis) and 80% power to detect a hazard ratio of 1.5 for OS (an increase of 12 to 18 months in the median OS duration). The intent-to-treat (ITT) population was the primary efficacy population analyzed. Progression was based on the independent reviewer or investigator assessment. An interim analysis in both the studies was planned at 50% of the required TTP events.


   RESULTS
Top
 Abstract
 Introduction
 Phase III Trial Designs
 Results
Discussion
 Conclusions
 Author Contributions
 References
 
Baseline demographic and disease-related characteristics are presented in Table 1. In both studies, the baseline demographic and disease-related characteristics were comparable between the LD and PD groups. Patients were predominantly male and white, with a good PS score. The median age was 63 years (range, 33–86 years). Most patients had Durie-Salmon stage II or III MM. More North American study patients had received prior bortezomib, dexamethasone, or thalidomide than patients from Europe, Israel, and Australia. By contrast, fewer North American study patients had received melphalan. Prior SCT and doxorubicin use were comparable between the two trials.


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  		Table 1. Baseline demographics and disease characteristics (study 1 and 2)

 
In study 1, eight minor protocol violations were present but balanced between the two arms. Seven patients had stage I myeloma and one patient had stage not recorded (four patients in each treatment group); these patients were included in the ITT population because there was no doubt about the diagnosis of MM. Eight patients had event dates before randomization dates, four in each arm. These patients were censored at day 0 in the ITT analysis. In study 2, eight patients were censored for analysis of the primary endpoint at the date of randomization because of eligibility violations. A sensitivity analysis excluding patients with inclusion and exclusion criteria protocol violations did not alter the results of the primary ITT population.

Efficacy
After approximately 50% of the patients in each trial had a TTP event, the prespecified planned interim analysis based on the ITT population was conducted. After review of each trial's interim TTP analysis, the independent data monitoring committee recommended that the sponsor halt and unblind the physicians and patients remaining on study and offer patients in the control arm lenalidomide.

In studies 1 and 2, TTP was significantly longer in the LD arm than in the PD arm (Table 2). Although relatively few progression events were recorded, TTP results in each study exceeded the O'Brien Fleming stopping boundaries. The Kaplan–Meier estimates of TTP for studies 1 and 2 are shown in Figures 1 and 2. Response rates based on the best response assessments are also shown in Table 2.


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  		Table 2. Efficacy data (studies 1 and 2)

 


Figure 1
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  		Figure 1. Kaplan–Meier estimate of time to progression (study 1).

Abbreviations: LD, lenalidomide and dexamethasone; PD, placebo and dexamethasone.

 


Figure 2
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  		Figure 2. Kaplan–Meier estimate of time to progression (study 2).

Abbreviations: LD, lenalidomide and dexamethasone; PD, placebo and dexamethasone.

 
For most patients, the basis of progression was increasing paraprotein measurements. Of the patients who had progressive disease, 55% in the LD arm versus 67% in the PD arm had a rising paraprotein level in study 1. In study 2, 69% of progression events were a result of an increased paraprotein level in the LD arm versus 80% in the PD arm. There were several patients who progressed on more than one parameter. For these patients, the earliest date of progression was taken as the date of progression. Fewer patients had progression resulting from increases in the percentages of bone marrow plasma cells, lytic bone lesions, and plasmacytoma measurements.

The median follow-up at the time of this analysis was approximately 5 months (20.1 weeks for study 1 and 22.3 weeks for study 2).

Safety
The trials used the National Cancer Institute Common Toxicity Criteria for grading adverse events (AEs). More patients in the LD arm reported grade 3 or 4 AEs than patients in the PD arm. Reported grade 3 or 4 AEs with an incidence >5% were more than double and included neutropenia, thrombocytopenia, anemia, and deep vein thrombosis (DVT) (Table 3).


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  		Table 3. Grade 3 or 4 AEs in at least 2% of patients in both treatment groups (studies 1 and 2)

 
Thrombotic or thromboembolic events, including DVT, pulmonary embolism, thrombosis, and intracranial venous sinus thrombosis were reported more frequently in patients treated with LD than in patients treated with PD. The proportion of patients experiencing a thrombotic event in the LD arm was 43 of 346 (12%), compared with 14 of 345 (4%) in the PD arm.

In study 1, the number of on-study deaths was 16 in the LD arm and 15 in the PD arm. In study 2, both arms had 16 deaths reported. Celgene submitted two pharmacokinetic studies. The first was a drug interaction study examining the effect of lenalidomide administration on the pharmacokinetics of digoxin. Lenalidomide slightly increases the digoxin maximum concentration (Cmax) (14% increase; 90% confidence interval [CI], 99%–131%) but has no significant effect on the digoxin area under the concentration–time curve (AUC) (8% increase; 90% CI, 100%–117%). The package insert advises periodic monitoring of digoxin plasma levels in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication during administration of lenalidomide.

The second study compared the pharmacokinetics of the new 15-mg capsule with those of the previously approved 5-mg capsule. These formulations are bioequivalent. The ratio of test to reference for the Cmax was 1.03 (90% CI for Cmax, 92%–116%) and the ratio of the AUC was 0.97 (90% CI for Cmax, 93%–101%).

Both studies 1 and 2 used a new 25-mg capsule formulation to provide the lenalidomide starting dose. However, pharmacokinetics following administration of this 25-mg capsule have not been studied and the applicant has agreed to conduct a postmarketing study to address this issue.


   DISCUSSION
Top
 Abstract
 Introduction
 Phase III Trial Designs
 Results
 Discussion
Conclusions
 Author Contributions
 References
 
Approval was based on the results of two large, randomized, double-blinded, placebo-controlled trials demonstrating that the addition of lenalidomide to dexamethasone yields an improvement in TTP. Previously, bortezomib received regular approval based on the endpoint of TTP in patients with MM progressing on prior therapy [2].

The design of these studies incorporated several elements to reduce potential systematic sources of bias that could confound the trials' results. A placebo plus dexamethasone control arm was ethical in this trial because: (a) at the time these studies were conducted, dexamethasone alone was a standard therapy for patients with MM that had progressed on a prior regimen [3] and (b) patients in both treatment arms received best supportive care in addition to study treatment. The blinded independent data review was done to eliminate potential bias in the interpretation of progression. Standardized and prespecified scheduled assessments for progression minimized the likelihood that differences in the timing of the progression determination in either arm might account for any observed beneficial effect of treatment.

The myeloma complete response rate complements the primary endpoint in that myeloma complete responses can be considered a result of treatment alone, whereas time-to-event endpoints including TTP integrate the effect of therapy with disease natural history. Response rates were consistent across both trials.

OS in a randomized placebo-controlled trial is a particularly compelling secondary endpoint because it avoids measurement bias. Survival data from studies 1 and 2 are not mature. Updated survival data are awaited.

Several factors bolster the credibility of the efficacy results from these two studies. The treatment groups were well balanced at baseline. Results for the primary endpoint of TTP were statistically robust and complemented by the higher response rate observed following the addition of lenalidomide to dexamethasone. Finally, results were consistent across the two studies.

The randomized trial design enabled direct comparison of AE rates in the two groups and attribution of a lenalidomide effect. Pooled data, for the most part, corroborated the distribution of AEs recorded in the two individual studies assessed. The most notable difference was seen in the frequency of thrombotic events, which was higher in study 1 than in study 2. It has been noted that most of the thromboembolic events in study 1 were reported among patients who had an erythropoietic agent listed as a concomitant medication, and that, in both treatment groups, the incidence of thromboembolic events was significantly higher in those who were using erythropoietin-stimulating agents than in those who were not. The sponsor stated that this may have been a result of the higher number of patients on erythropoietin [4, 5]. However, the potential role of lenalidomide cannot be ruled out. Therefore, the applicant has agreed to a postmarketing commitment to assess the prophylaxis and treatment regimens of thromboembolic events seen with lenalidomide. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. The decision to take prophylactic measures should be considered carefully after an assessment of an individual patient's underlying risk factors.

Sufficient data exist to assess the safety of LD, as well as to provide directions for safe use in the approved indication. However, the submitted safety data present notable limitations. First, lenalidomide has not been formally studied in patients with either hepatic or renal impairment. Second, QT interval prolongation assessments have not been performed. Third, effective prophylactic and treatment measures for thromboembolic disease associated with lenalidomide remain incompletely defined. In addition to these issues, lenalidomide is an analogue of thalidomide, a known human teratogen that causes severe life-threatening human birth defects. Women should be advised to avoid pregnancy while taking lenalidomide or if their partners are taking lenalidomide. Because of this potential toxicity and to avoid fetal exposure, lenalidomide is only available under a special restricted distribution program called RevAssist®. The boxed warning in the label reflects the special restricted distribution under the RevAssist® program, as well as warnings regarding the risk for neutropenia, thrombocytopenia, DVT, and pulmonary embolism [6].

Postmarketing commitments agreed to by the sponsor include the following. First, epidemiologic studies to assess prophylaxis and treatment regimens of thromboembolic events seen with lenalidomide will be conducted. Second, a phase IV bioequivalence study comparing the pharmacokinetics of the 25-mg capsule (test formulation) with those of the previously approved 5-mg capsule (reference formulation) will be performed. Third, an assessment of the QT interval prolongation following from the use of the 25-mg formulation of lenalidomide in the clinical setting will be conducted. Finally, the sponsor will follow through on their previous commitment to provide an evaluation of lenalidomide teratogenicity in an appropriate test species.


   CONCLUSIONS
Top
 Abstract
 Introduction
 Phase III Trial Designs
 Results
 Discussion
 Conclusions
Author Contributions
 References
 
Lenalidomide was approved by the U.S. FDA on June 29, 2006, for use in combination with dexamethasone in patients with MM who have received at least one prior therapy. Because of concerns about possible developmental toxicity, the FDA approved lenalidomide under Subpart H regulations with a continued restricted distribution program for this additional indication. Approval was based on an improvement in TTP. Two independently conducted trials generated results that were consistent, statistically significant, and clinically meaningful. The benefit of the combination of lenalidomide and dexamethasone in prolonging TTP is accompanied by additional toxicity. Prominent safety issues include cytopenias, thromboembolic risk, neuropathy, gastrointestinal symptoms, and metabolic abnormalities. The recommended dose is 25 mg/day of lenalidomide orally as a single 25-mg capsule on days 1–21 of each 28-day cycle with dexamethasone at a dose of 40 mg/day on days 1–4, 9–12, and 17–20 of each 28-day cycle for the first four cycles of therapy and then 40 mg/day orally on days 1–4 every 28 days.

Lenalidomide, an analogue of thalidomide, is only available under a special restricted distribution program called RevAssist® because of unresolved uncertainty concerning teratogenicity. Complete prescribing information is available on the FDA website at http://fda.gov/cder/approval/index.htm.


   AUTHOR CONTRIBUTIONS
Top
 Abstract
 Introduction
 Phase III Trial Designs
 Results
 Discussion
 Conclusions
 Author Contributions
References
 
Conception/Design: Maitreyee Hazarika, Edwin Rock, Ramzi Dagher, Ann Farrell

Data analysis: Maitreyee Hazarika, Edwin Rock, Gene Williams, Ramzi Dagher, Rajeshwari Sridhara, Brian Booth, Ann Farrell

Manuscript writing: Maitreyee Hazarika, Edwin Rock, Gene Williams, Ramzi Dagher, Rajeshwari Sridhara, Brian Booth, Ann Farrell, Robert Justice, Richard Pazdur

Final approval of manuscript: Maitreyee Hazarika, Edwin Rock, Ramzi Dagher, Rajeshwari Sridhara, Ann Farrell, Robert Justice, Richard Pazdur


   REFERENCES
Top
 Abstract
 Introduction
 Phase III Trial Designs
 Results
 Discussion
 Conclusions
 Author Contributions
 References
 

  1. 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. European Group for Blood and Marrow Transplant. Br J Haematol 1998;102:1115–1123.[CrossRef][Medline]
  2. Kane RC, Bross PF, Farrell AT et al. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. The Oncologist 2003;8:508–513.[Abstract/Free Full Text]
  3. Alexanian R, Barlogie B, Dixon D. High-dose glucocorticoid treatment of resistant myeloma. Ann Intern Med 1986;105:8–11.[Abstract/Free Full Text]
  4. Knight R, DeLap RJ, Zeldis JB. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med 2006;354:2079–2080.[Free Full Text]
  5. Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med 2006;354:2079–2080.[Free Full Text]
  6. Revlimid® label [U.S. package insert]. Available at http://www.fda.gov/cder/approval/index.htm. accessed October 10, 2008.




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