Pomalidomide Combo Sustains Improved Outcomes in Pretreated R/R Myeloma

"The findings from OPTIMISMM provide valuable insights that help translate clinical trial data into real-world practice and continue to support sequencing of a pomalidomide-based regimen immediately after lenalidomide treatment failure in patients with [relapsed/refractory multiple myeloma]," according to the study authors.

Combining pomalidomide (Pomalyst) with bortezomib (Velcade) and dexamethasone (PVd) numerically prolonged overall survival (OS) and yielded other improved outcomes vs bortezomib plus dexamethasone alone (Vd) among patients with lenalidomide (Revlimid)-exposed relapsed/refractory multiple myeloma, according to final OS analysis findings from the phase 3 OPTIMISMM trial (NCT01734928).¹

After a median follow-up of 64.5 months, the median OS was 35.6 months (95% CI, 28.6-41.2) with PVd vs 31.6 months (95% CI, 26.1-37.2) with Vd (HR, 0.94; 95% CI, 0.77-1.15; P = .5707). In an analysis accounting for the use of subsequent therapies as a time-dependent covariate, data showed a statistically significant OS improvement with the addition of pomalidomide (HR, 0.76; 95% CI, 0.619-0.931; P = .008). PVd yielded the largest OS benefits among patients with high-risk cytogenetics (HR, 0.68; 95% CI, 0.45-1.03; P = .065) and those with a baseline β2-microglobulin level of 3.5 to 5.5 mg/L (HR, 0.74; 95% CI, 0.52-1.06; P = .097).

Data showed a median progression-free survival (PFS) of 11.7 months (95% CI, 9.7-14.6) with PVd and 6.9 months (95% CI, 5.6-8.3) with Vd (HR, 0.56; 95% CI, 0.46-0.68; P <.0001). PVd prolonged PFS across clinically relevant prespecified subgroups such as those with high-risk cytogenetics (HR, 0.59; 95% CI, 0.39-0.90) and prior treatment with proteasome inhibitors (HR, 0.50; 95% CI, 0.40-0.63).

The median PFS after next-line therapy (PFS2) was 22.1 months (95% CI, 18.9-26.1) in the PVd arm vs 16.9 months (95% CI, 14.6-20.0) in the Vd arm (HR, 0.77; 95% CI, 0.64-0.94; P = .0077). Additionally, the median time to treatment failure (TTF) was 8.8 months (95% CI, 7.4-10.2) vs 4.6 months (95% CI, 3.8-5.5) in each respective arm (HR, 0.54; 95% CI, 0.46-0.65; P <.001).

“[T]hese results from OPTIMISMM are consistent with previous reports, showing improved outcomes with PVd versus Vd in patients with [relapsed/refractory multiple myeloma] who had received prior lenalidomide-based treatments, including patients with lenalidomide-refractory disease. The findings from OPTIMISMM provide valuable insights that help translate clinical trial data into real-world practice and continue to support sequencing of a pomalidomide-based regimen immediately after lenalidomide treatment failure in patients with [relapsed/refractory multiple myeloma],” lead study author Paul G. Richardson, MD, clinical program leader and director of Clinical Research at Jerome Lipper Multiple Myeloma Center of Dana-Farber Cancer Institute and an RJ Corman Professor of Medicine at Harvard Medical School, wrote with coauthors.¹ “Overall, these

data reinforce that a switch in class of agent may not be necessary for patients who have become lenalidomide-refractory, although decisions should be made on an individual basis with consideration given to the patient's response to first-line lenalidomide.”

In the open-label phase 3 OPTIMISMM trial, patients were randomly assigned to receive PVd (n = 278) or Vd (n = 270). Investigators administered bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11 of cycles 1 to 8 and on days 1 and 8 of every cycle thereafter. Additionally, dexamethasone was given at 20 mg if the patient was 75 years or younger or 10 mg if the patient was older than 75 on days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 cycles and then on days 1, 2, 8, and 9 of every cycle thereafter. Patients in the PVd arm also received pomalidomide at 4 mg orally on days 1 to 14 of each cycle.

The trial’s primary end point was PFS. OS was a prespecified secondary end point. Other secondary end points included overall response rate, duration of response, and safety. TTF and PFS2 were prespecified exploratory end points.

Patients 18 years and older with documented multiple myeloma and measurable disease per serum and urine protein electrophoresis were eligible for enrollment on the trial.² Other eligibility criteria included having 1 to 3 prior lines of therapy and documented disease progression on or after the last line of treatment. Those with non-secretory multiple myeloma or severe renal impairment requiring dialysis were ineligible for study entry.

The median patient age was 68.0 years in the overall population, 67.0 years in the PVd arm, and 68.0 years in the Vd arm. Most patients had International Staging System stage I (51.3%) or II disease (31.3%). A majority of the PVd (71.2%) and Vd (68.7%) arms had lenalidomide-refractory disease.

The median time to subsequent therapy for multiple myeloma was 19.9 months in the PVd arm vs 8.5 months in the Vd arm (HR, 0.48; 95% CI, 0.39-0.59; P <.001). Additionally, 68.3% and 79.1% of patients in each arm required at least 1 subsequent line of treatment, and subsequent pomalidomide was administered to 19.2% and 58.3%, respectively.

Any-grade treatment-emergent adverse effects (TEAEs) affected 100% of the PVd arm and 97.8% of the Vd arm, with the most common toxicities including infections and infestations (83.1% vs 66.3%), general disorders and administration site conditions (78.4% vs 64.4%), nervous system disorders (75.5% vs 61.1%), and gastrointestinal disorders (74.8% vs 63.0%). Grade 3/4 TEAEs occurred in 93.2% of the PVd arm and included neutropenia in 47.1% of patients; 71.9% in the Vd arm experienced such toxicities, which included thrombocytopenia in 29.3%.

Serious TEAEs were reported in 63.7% of the PVd arm and 44.1% of the Vd arm. Additionally, 33.1% and 19.6% of patients from each respective arm discontinued any study drug due to TEAEs. Secondary primary malignancies occurred in 8.6% and 5.2% of patients, respectively.

References

1. Richardson P, Beksaç M, Oriol A, et al. Pomalidomide, bortezomib, and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: final survival and subgroup analyses from the OPTIMISMM trial. Eur J Haematol. Published online January 8, 2025. doi:10.1111/ejh.14365.
2. Safety and efficacy of pomalidomide, bortezomib and low-dose dexamethasone in subjects with relapsed or refractory multiple myeloma (OPTIMISMM). ClinicalTrials.gov. Updated June 6, 2023. Accessed March 11, 2025. https://tinyurl.com/3naebmkt