Results from the OPTIMISMM phase III trial: Pomalidomide for lenalidomide-refractory patients

Treatment of patients with relapsed/refractory multiple myeloma (MM) is challenging, with the management of patients refractory to initial treatments particularly difficult. Lenalidomide is the preferred option for patients with newly diagnosed MM, and as such, patients refractory to this drug present a treatment challenge.

Paul Richardson from the Jerome Lipper MM Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, US, and colleagues, conducted an open-label, randomized, phase III trial (NCT 01734928) to investigate the efficacy and safety of the triplet combination pomalidomide, bortezomib and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd).

The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response (OR), duration of response, and safety. Exploratory endpoints were time to response, PFS after next-line treatment, health-related quality of life (HRQOL) and subgroup efficacy.

Patient characteristics

• N = 559; n = 281 assigned to PVd; n = 278 assigned to Vd
• All patients had prior treatment with lenalidomide, n = 391 (70%) were lenalidomide-refractory
• Patients were eligible if they met the following conditions:
  • Measurable disease based on serum, >5 g/dL or urine protein levels, >200 mg/24 hours
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0—2
  • At least two or more cycles of lenalidomide treatment
• Baseline characteristics were well-balanced:
  • Cytogenic profile by fluorescence in situ hybridization (FISH)
    • PVd: standard risk, 137 (49%), high risk, 61 (22%)
    • Vd: standard risk, 132 (47%), high risk, 49 (18%)
  • > 3 lines of treatment: PVd arm, 19%; Vd arm, 21%

Treatment schedule

• Treatment cycles of 21 days until progressive disease or unacceptable toxicity
• IV or SC bortezomib (1.3 mg/m²):
  • Cycles 1—8: administered on days 1, 4, 8, and 11
  • Cycle 9+: administered on days 1 and 8
• Oral dexamethasone (20 mg if aged < 75 years, otherwise 10 mg)
  • Cycles 1—8: administered on days 1, 2, 4, 5, 8, 9, 11 and 12
  • Cycle 9+: administered on days 1, 2, 8 and 9
• Oral pomalidomide (for those patients assigned the drug)
  • 4 mg on days 1—14 of each cycle

Results

• PVd, n = 278 received allocated intervention (n = 93 still receiving treatment)
  • Majority of patients (39%) stopped treatment due to disease progression
  • There were 87 study withdrawals due to death
• Vd, n = 270 received allocated intervention (n = 45 still receiving treatment)
  • Majority of patients (49%) stopped treatment due to disease progression
  • There were 89 study withdrawals due to death
• At median follow-up of 15.9 months (range, 9.9—21.7):
  • PVd: n = 154 (55%) had disease progression or death
  • Vd, n = 162 (58%) had disease progression or death
• PFS was significantly improved with PVd (median 11.2 months; 95% CI, 9.66—13.73) vs Vd (median 7.1 months; 95% CI, 5.88—8.48; HR 0.61, p <0.0001)

Key findings

Table 2: Key comparisons between PVd, and Vd

	PVd % (n = 281)	Vd % (n = 278)
Overall response	82.2	50.0
Stringent complete response	3.2	0.7
Complete response	12.5	3.2
Very good partial response	37.0	14.4
Partial response	29.5	31.7
Stable disease	11.4	38.1
Progressive disease	3.9	5.8
Not accessible	2.5	6.1

• The most common grade III or IV treatment emergent side effects were (PVd vs Vd):
  • Neutropenia (42% vs 9%)
  • Infections (31% vs 18%)
  • Thrombocytopenia (28% vs 29%)

Conclusion

Patients with relapsed or refractory MM who previously received lenalidomide showed significantly better PFS when treated with PVd, compared to Vd. As such, data from the OPTIMISMM trial supports the use of a triplet pomalidomide-based treatment regimen after lenalidomide treatment failure for the management of relapsed/refractory MM.