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Positive EMA CHMP opinion for two new triplet regimens in multiple myeloma
By Emily Smith
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The triplet regimens of lenalidomide, bortezomib and dexamethasone (VRd) and pomalidomide, bortezomib and dexamethasone (PVd) have both received a positive opinion from the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) for the treatment of multiple myeloma (MM). A final decision by the European Commission is expected to take another two months, though usually follows the CHMP opinion.1
Indications
- VRd: patients with previously untreated MM who are ineligible for transplant
- Based on the results of the SWOG S0777 trial (Table 1)2
- PVd triplet: lenalidomide-exposed patients with relapsed/refractory MM (RRMM) who have received 1–3 prior lines of treatment
- Based on the results of the OPTIMISMM trial (Table 2)3,4
Background
Lenalidomide and pomalidomide are both immunomodulatory drugs (IMiDs) that are administered orally and are hypothesized to have multiple mechanisms of action. Both drugs have previously been approved in other combinations:5
- Lenalidomide is approved for use in patients with newly diagnosed MM who are ineligible for transplant, in combination with low-dose dexamethasone.
- Pomalidomide has been approved in combination with dexamethasone and is indicated in the 3rd line treatment of adults with RRMM.
VRd triplet2
Table 1: Summary of the SWOG S0777 trial
|
CR, complete response; HR, hazard ratio; IV, intravenous; ORR, overall response rate; OS, overall survival; PFS, progression free survival; VRd, bortezomib, lenalidomide and dexamethasone |
|
|
Trial name |
SWOG S0777 |
|---|---|
|
NCT reference |
|
|
Phase |
III |
|
Number of patients (N) |
525 |
|
Randomization |
1:1 - VRd:Rd |
|
Dosing VRd
|
Eight 21-day cycles IV bortezomib 1.3 mg/m2, on days 1, 4, 8 and 11 Oral lenalidomide 25 mg, on days 1–14 Oral dexamethasone 20 mg, on days 1, 2, 4, 5, 8, 9, 11 and 12 |
|
Dosing Rd |
Six 28-day cycles Oral lenalidomide 25 mg, on days 1–21 Oral dexamethasone 40 mg on days 1, 8, 15 and 22 |
|
Maintenance |
Oral lenalidomide 25 mg once daily for 21 days Oral dexamethasone 40 mg once daily for days 1, 8, 15 and 22 of each 28-day cycle |
|
Efficacy (given as VRd vs Rd) |
Median PFS: 43 vs 30 months (HR 0.712, 96% CI, 0.56–0.906, P = 0.0018) Median OS: 75 vs 64 months (HR 0·709, 95% CI 0·524–0·959, P = 0.025) ORR: 82% vs 72% CR: 16% vs 8% |
|
Safety |
Consistent with the individual safety profiles of each drug alone Most common grade ≥3 events that were partially attributable to treatment:
Neurological events: more frequent in VRd group compared to Rd group (33% vs 11%, P < 0.0001) |
PVd triplet1,3,4
Table 2: Summary of the OPTIMISMM trial
|
HR, hazard ratio; PFS, progression free survival; PVd, pomalidomide, bortezomib and dexamethasone |
|
|
Trial name |
OPTIMISMM |
|---|---|
|
NCT reference |
|
|
Phase |
III |
|
Number of patients (N) |
559 71% vs 69% of patients were refractory to lenalidomide (PVd vs Vd arm) |
|
Randomization |
1:1 - PVd:Vd – patients were stratified based on age, anti-myeloma treatment and β-microglobulin levels |
|
Dosing PVd
|
21-day cycles: Pomalidomide 4 mg daily on days 1–14 Bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of cycles 1–8 and on days 1 and 8 of cycle 9 onwards: Dexamethasone 20 mg (dose was 10 mg for patients > 75 years old) on the same day and the day after bortezomib in all 21-day cycles |
|
Efficacy (given as PVd vs Vd) |
Median follow-up: 16 months Median PFS: 11.2 vs 7.1 months 39% reduction in the risk of disease progression or death (HR 0.61, 95% CI, 0.49–0.77, P ≤ 0.001) |
|
Subgroup analysis in patients with one prior line of therapy |
Median PFS: 20.73 vs 11.63 months (HR 0.54, P = 0.0027) Benefit of PVd was independent of whether patients were refractory or non-refractory to prior lenalidomide |
|
Safety |
Consistent with the individual safety profiles of each drug alone |
- OncLive. EU Panel Backs Lenalidomide- and Pomalidomide-Based Triplets for Myeloma https://www.onclive.com/web-exclusives/eu-panel-backs-lenalidomide-and-pomalidomide-based-triplets-for-myeloma [accessed 2019 April 01]
- Durie B.G. et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2016 Dec 22. DOI: 10.1016/S0140-6736(16)31594-X
- Richardson P.G. et al. Pomalidomide (POM), bortezomib, and low‐dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): Phase 3 OPTIMISMM trial. J Clin Onc. 2018 June 01. DOI: 10.1200/JCO.2018.36.15_suppl.8001
- Multiple Myeloma Hub. EHA 2018 | The phase III OPTIMISMM study of pomalidomide, bortezomib and dexamethasone https://multiplemyelomahub.com/medical-information/eha-2018-the-phase-iii-optimismm-study-of-pomalidomide-bortezomib-and-dexamethasone [accessed 2019 April 01]
- BioSpace. Celgene Receives CHMP Positive Opinions for Both REVLIMID® (lenalidomide) and IMNOVID® (pomalidomide)-Based Triplet Combination Regimens for Patients with Multiple Myeloma. https://www.biospace.com/article/releases/celgene-receives-chmp-positive-opinions-for-both-revlimid-lenalidomide-and-imnovid-pomalidomide-based-triplet-combination-regimens-for-patients-with-multiple-myeloma/ [accessed 2019 Apr 03]
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