Pomalidomide-Based Regimen Associated With Durable Response in Lenalidomide-Refractory Myeloma

Treatment with a regimen consisting of pomalidomide, low-dose dexamethasone, and daratumumab as either second- or third-line therapy induced durable responses in a high proportion of lenalidomide-pretreated patients with relapsed or refractory myeloma, according to findings from the phase II MM-014 trial. Clinical benefit was seen across all patient populations, including those with high-risk cytogenetics.

According to the study authors, led by David Siegel, MD, of Hackensack University Medical Center in New Jersey, these findings could alter clinicians’ treatment decisions, as practitioners currently “may be inclined to switch away from the immunomodulatory agent drug class after lenalidomide-based treatment failure.”

The study – conducted across 49 sites in the U.S., Canada, and Japan – included 3 treatment cohorts:

  • cohort A: pomalidomide plus low-dose dexamethasone
  • cohort B: pomalidomide, low-dose dexamethasone, and daratumumab (North American arm)
  • cohort C: pomalidomide, low-dose dexamethasone, and daratumumab (currently enrolling, Japanese-only arm)

Dr. Siegel and colleagues reported only on findings from 112 patients enrolled in cohort B. Participants in this treatment arm had a documented diagnosis of myeloma, measurable disease (serum M-protein ≥0.5 g/dL or urine M-protein ≥200 mg/24 hours), an Eastern Cooperative Oncology Group performance status of ≤2, and documented progressive disease; they had recently received a lenalidomide-based regimen for ≥2 consecutive cycles.

Participants received 28-day cycles of:

  • oral pomalidomide 4 mg (administered on days 1-21)
  • oral low-dose dexamethasone 40 mg (20 mg for patients >75 years of age; administered on days 1, 8, 15, and 22)
  • intravenous daratumumab 16 mg/kg (administered on days 1, 8, 15, and 22 of cycles 1 and 2; days 1 and 15 of cycles 3-6; and day 1 for subsequent cycles)

The median age of patients in cohort B was 66.5 years, and the majority of patients (67.9%) were men. The median time from myeloma diagnosis to study entry was 3.4 years (range = 0.5-11.6).

Seventy participants had received 1 prior line of therapy, and the remaining 42 had received 2. Per study inclusion criteria, all 112 patients received lenalidomide); other prior therapies included a proteasome inhibitor (n=89), alkylating agents (n=89), hematopoietic cell transplant (n=78), or other agents (n=8). The median duration of most recent prior lenalidomide-based regimen was 23.9 months (range = 0.4-116.8).

Most patients (59.8%) had an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 1, whereas more than one-third (39.3%) of patients had an ECOG PS of 0. More than three-quarters of patients (78.5%; n=73) were classified as standard cytogenetic risk at study entry, whereas 21.5% of patients (n=20) were classified as high risk.

“These findings [indicate] that pomalidomide-based regimens … can overcome early-line resistance or refractoriness to lenalidomide.”

—David Siegel, MD

Patients were followed for a median of 17.2 months, during which 63 patients discontinued treatment. The other 49 patients remained on active treatment as of data cutoff (February 8, 2019). The most common cause of treatment discontinuation was progressive disease (n=33), followed by patient withdrawal (n=17), adverse events (n=4), other reasons (n=4), death (n=2), and transition to another therapy (n=1).

The median treatment durations for each drug in the regimen were:

  • pomalidomide: 14.6 months
  • low-dose dexamethasone: 13.2 months
  • daratumumab: 14.4 months

Infections were the most common treatment emergent adverse events (TEAEs; 75.9%), and neutropenia was the most common hematologic any-grade TEAE (66.1%). The most common grade 3/4 hematologic TEAEs included neutropenia (62.5%) and anemia (17.9%).

Approximately 77.7% of patients (n=87) in the intent-to-treat population responded to treatment. Half of responders (n=57; 50.9%) achieved at least a very good partial response, while nearly one-quarter (n=27; 24.1%) achieved a complete response. The authors noted that the median time to best response was 3.7 months (range = 0.9-20.7), and 42.5% of patients did not achieve a best response until 6 months or later.

The median duration of response was not reached as of last follow-up. At 1 year, 77.7% of participants were responding to treatment. While the investigators observed a higher overall response rate (ORR) among patients with standard-risk cytogenetics compared with those with high-risk cytogenetics (79.5% vs. 55.0%), they wrote that the fact that more than one-half of high-risk patients responded “indicates activity with this pomalidomide-based regimen in this difficult-to-treat population.”

Duration of prior lenalidomide treatment also appeared to be associated with response rates: The ORR was higher in patients who were treated with lenalidomide for >24 months (90.9%) compared with those treated with lenalidomide for ≤24 months (64.9%).

The median progression-free survival (PFS) was not reached at last follow-up, but the 1-year PFS rate was 75.1% for the entire population. For patients who had relapsed disease following lenalidomide or who had lenalidomide-refractory disease, the 1-year PFS rates were 83.2% and 72.4%, respectively. The authors reported that there were 20 documented deaths during follow-up, but the data on overall survival were not yet mature and were not included in this analysis, representing a potential study limitation.

“The higher 1-year PFS rate and ORR reported in patients who were treated with lenalidomide for >2 years versus those treated for ≤2 years, as well as the fact that responses deepened over time, may be suggestive of the benefits of uninterrupted treatment with immunomodulatory agents and tolerance to their related AEs,” the researchers concluded. “In clinical practice, physicians may be inclined to change class following progressive disease on or after lenalidomide. However, these findings add to the growing body of evidence indicating that pomalidomide-based regimens, including pomalidomide with daratumumab, can overcome early-line resistance or refractoriness to lenalidomide.”

Study authors report relationships with Bristol-Myers Squibb, which sponsored this trial.

Reference

Siegel DS, Schiller GJ, Samaras C, et al. Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment. Leukemia. 2020 May 6. [Epub ahead of print]