Regulatory Decision Summary for REVLIMID

The decision to authorize the use of Revlimid in combination with dexamethasone in the transplant non-eligible newly diagnosed multiple myeloma (TNE NDMM) population was based on the results of Study MM-020. This study was a phase III, randomized, multicentre, open-label, 3 arm study conducted to evaluate the efficacy and safety of Revlimid and low-dose dexamethasone (Rd) given for 2 different durations of time (until disease progression [Arm Rd] or for up to eighteen 28-day cycles [Arm Rd18]), compared to that of melphalan, prednisone, and thalidomide (Arm MPT) for a maximum of twelve 42-day cycles (72 weeks) in the transplant non-eligible newly diagnosed multiple myeloma (TNE NDMM) population. A total of 1,623 patients were enrolled in this large study, 35% of whom were over 75 years of age. Sixteen percent of the study population were Canadian.

A statistically significant and clinically relevant improvement in the primary endpoint, progression free survival (PFS) as assessed by blinded, independent review, was demonstrated for Rd versus MPT. The probability of remaining free from progression or death was significantly greater in Arm Rd compared with Arm MPT (hazard ratio [HR], 95% confidence interval = 0.72 [0.61, 0.85]; p-value <0.0001) indicating a 28% decrease in the risk of progression or death. Median PFS in Arm Rd was 25.5 months, a 4.3 month improvement over the median PFS demonstrated in Arm MPT of 21.2 months. Overall response rates were higher in Arm Rd (75.1%) compared with Arm MPT (62.3%) with a median duration of response of 35.0 months in Arm Rd and 22.3 months in Arm MPT.

Two interim overall survival (OS) analyses (at 64% and 78% of the pre-specified number of deaths for the final analysis) from Study MM-020 have demonstrated a consistent trend in HRs (0.78 and 0.75) suggesting an improvement in OS for Rd as compared with MPT. The most recent interim OS analysis demonstrated a median 10 month survival benefit with Rd compared to MPT. The final OS analysis was not available at the time of submission filing.

The safety population for Study MM-020 included a total of 1613 patients, 1072 of whom were treated with Revlimid in Arms Rd and Rd18. The safety profile of Rd was acceptable. Toxicities were manageable with specified dose modifications. The most commonly reported adverse events (AEs) for patients treated in Arms Rd and Rd18 were generally consistent with those that have been reported with use in the previously treated MM population. Grades 3 and 4 hematologic toxicities were more commonly reported with MPT than with Rd and Rd18 while grades 3 and 4 infections were more common in the Revlimid arms. There were more serious AEs reported in the Revlimid arms, primarily related to infections. The incidence of peripheral neuropathy was greater in Arm MPT than in Arms Rd and Rd18 while the incidence of venous thromboembolic events was greater in Arms Rd and Rd18 than Arm MPT.

In both Arms Rd and Rd18, the frequencies of onset of adverse events were generally highest in the first 6 months of treatment and then decreased over time or remained stable throughout treatment. An exception was cataracts which had a higher incidence with prolonged exposure to Rd. There were no major concerns of increased toxicity of common AEs as duration of Rd treatment was continued up to 36 months.

Rd until disease progression provides an efficacious treatment regimen for the transplant non-eligible newly diagnosed multiple myeloma (TNE NDMM) population with a manageable safety profile. The Rd regimen provides an oral treatment beneficial in the typically elderly, often frail multiple myeloma population. The recommended doses and dosage modifications are fully supported by the pivotal study and supporting data. The overall benefit/risk balance is positive for Revlimid use in the proposed indication under the conditions of use specified in the Product Monograph.

Revlimid 2.5 mg capsules have been granted market authorization based on comparable bioavailability to the currently marketed Revlimid 5 mg capsules. Revlimid 2.5 mg capsules were incorporated into the dosing modifications for phase III studies in the transplant non-eligible newly diagnosed multiple myeloma (TNE NDMM) population, including Study MM-020.