Patients non-eligible for transplant

European commission approves lenalidomide and pomalidomide triplets for multiple myeloma

The European Commission has approved two triplet regimens for the treatment of multiple myeloma. The first is lenalidomide + bortezomib + dexamethastone (RVd) and the second is pomalidomide + bortezomib + dexamethasone (PVd). Both regimens previously received a positive opinion from the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP).1

The approved indication for RVd is in patients with newly diagnosed multiple myeloma (NDMM) who are non-transplant eligible. This is based on the results of SWOG S0777 phase III trial results shown in Table 1.1,2

Table 1: Summary of the SWOG S0777 trial2

Trial name

SWOG S0777

NCT reference

NCT00644228

Phase

III

Number of patients (N)

525

Randomization

1:1 - VRd:Rd

Dosing VRd

 

Eight 21-day cycles

Intravenous (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 progression-free survival (PFS): 43 vs 30 months (HR 0.712, 96% CI, 0.56–0.906, P = 0.0018)

Median overall survival (OS): 75 vs 64 months (HR 0·709, 95% CI 0·524–0·959, P = 0.025)

Overall response rate (ORR): 82% vs 72%

Complete response (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:

-          Hematological: anemia, lymphopenia, neutropenia and thrombocytopenia

-          Non-hematological: fatigue, sensory neuropathy, hyperglycemia, thrombosis or embolism, hypokalemia, muscle weakness, diarrhea and dehydration

 

Neurological events: more frequent in VRd group compared to Rd group (33% vs 11%, P < 0.0001)

The approved indication of PVd is in patients with MM who have received ≥1 prior treatment including lenalidomide. This approval is based on the OPTIMISMM phase III trial results, shown in Table 2.1,3

Table 2: Summary of the OPTIMISMM trial3

Trial name

OPTIMISMM

NCT reference

NCT01734928

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

These approvals will increase the options available to patients with NDMM in Europe. 

References
  1. Celgene receives European commission approvals for Revlimid and Imnovid-based triplet combination regimens for patients with multiple myeloma https://finance.yahoo.com/news/celgene-receives-european-commission-approvals-123000318.html?guccounter=1&guce_referrer=aHR0cHM6Ly9lbmRwdHMuY29tL2ZvdXIteWVhcnMtYWZ0ZXItZXUtYXBwcm92YWwtbmljZS1maW5hbGx5LWJhY2tzLXJldmxpbWlkLXVzZS1pbi1jZXJ0YWluLWZpcnN0LWxpbmUtbXVsdGlwbGUtbXllbG9tYS1wYXRpZW50cy8&guce_referrer_sig=AQAAAF1kQG1aii_DMG66bUj2SwHVbIZOFkQG7DXPXK19DmGRZyPCf90Fc0d_K0HKECoWUQckAfkmWdKikMy6uN2VZT24V_A4-YA_45NqSgmSyULvUODti8A8eVBEkyrUR1B6CfKD8hnvUQucJMc8yq6xBbtzxOkYleLyvyv68GDu0m__ [accessed 2019 May 17]
  2. 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
  3. 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
     
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