Newly diagnosed multiple myeloma (NDMM) treatment typically involves induction chemotherapy, potentially followed by autologous stem cell transplantation (ASCT), and maintenance therapy. While bortezomib, lenalidomide, and dexamethasone (VRd) are standard frontline options, newer agents like pomalidomide, approved for relapsed/refractory multiple myeloma (RRMM), aim to improve response rates. Pomalidomide's mechanism involves binding to cereblon, demonstrating higher potency than lenalidomide and activity in lenalidomide-resistant models. However, data on pomalidomide's use in NDMM is limited. This open-label, single-arm, phase 2 POMACE study investigated the efficacy and safety of a bortezomib, pomalidomide, and dexamethasone (VPd) regimen in NDMM patients to address this knowledge gap and explore its potential as a superior induction therapy compared to the standard VRd regimen.

The standard of care for NDMM patients includes induction chemotherapy followed by ASCT (if eligible) and maintenance. The goal is to maximize tumor reduction, improving progression-free survival (PFS) and overall survival (OS). VRd is a common frontline regimen, with PETHEMA/GEM2012 showing 33.4% CR and 63.8% ≥VGPR rates after four cycles. Drugs initially used for RRMM, such as daratumumab and carfilzomib, have been incorporated into frontline treatment to increase response rates. Pomalidomide, a third-generation immunomodulatory drug, demonstrates potent immune-enhancing activity by binding to cereblon, showing higher potency than lenalidomide and effectiveness in lenalidomide-resistant models. However, prior to this study, limited data existed on its use in NDMM patients.

This single-center, open-label, phase 2 study enrolled treatment-naïve NDMM patients aged 18-75 years with ECOG PS ≤2 from July 2020 to December 2021. Patients received four cycles of VPd induction (bortezomib 1.3 mg/m²/day on days 1, 8, 15, 22; capped at 2 mg; pomalidomide 2 mg/day in cycle 1, 4 mg/day from cycle 2; dexamethasone 40 mg/day on days 1, 8, 15, 22). Transplant-eligible patients achieving ≥VGPR could proceed to ASCT after four cycles. Transplant-ineligible patients continued VPd for up to nine cycles. Maintenance therapy varied based on R-ISS stage. The primary endpoint was the ≥VGPR rate after four VPd cycles; secondary endpoints included safety, PFS, and OS. Baseline assessments included SPEP, IF, SFLC, bone marrow biopsy, and PET-CT. Response was assessed using IMWG criteria. Toxicity was graded using NCI CTCAE v5.0. Sample size was determined using Fleming's two-stage design, aiming for 80% ≥VGPR rate. Data analysis used SPSS version 21.

Thirty-four patients were enrolled, with 31 completing four VPd cycles. The median age was 52 years (range 32-72). The overall response rate was 100%. Ten patients (32%) achieved stringent CR, nine (29%) CR, eight (26%) VGPR, and four (13%) PR. Twenty-seven (87%) patients achieved ≥VGPR (primary endpoint). Fifteen (48%) patients had a complete metabolic response (CMR) on PET-CT. At a median follow-up of 14 months, nine patients died, and five experienced disease progression. Twelve-month PFS and OS in the intent-to-treat population were 67.7% and 70.7%, respectively. Patients with ≥VGPR had significantly better 12-month PFS (87.1% vs. 50%, p=0.03) and OS (90.3% vs. 50%, p=0.002) than those with PR. Patients with CMR on PET-CT showed significantly better 12-month OS (100% vs. 40.6%, p=0.03) compared to those with partial response. The most common hematological toxicities were neutropenia (24%), anemia (21%), and thrombocytopenia (15%). Common non-hematological toxicities included peripheral sensory neuropathy (27%), fatigue (27%), and constipation (24%). Two patients experienced grade 5 adverse events. Of 27 transplant-eligible patients, 11 underwent ASCT; stem cell mobilization and engraftment were successful.

This study demonstrates VPd induction's high efficacy and manageable toxicity in NDMM, achieving a 100% response rate and 87% ≥VGPR, comparable to results seen with carfilzomib and daratumumab regimens. The high CMR rate on PET-CT (48%) correlates with improved OS, highlighting the potential of PET-CT in assessing minimal residual disease. The toxicity profile was manageable, with anemia being the most frequent hematological AE, and peripheral neuropathy being the most prominent non-hematological AE. The lower rates of hematological toxicities compared to other studies, particularly the OPTIMISSM study, might be attributed to the lower starting dose of pomalidomide in the first cycle and capping the bortezomib dose at 2 mg. The 12-month PFS and OS rates were lower than those reported in more recent studies, potentially due to the relatively short follow-up period. While two deaths were considered SAEs, other deaths occurred post-trial and were not directly attributable to treatment.

Bortezomib, pomalidomide, and dexamethasone induction chemotherapy is safe and efficacious in NDMM, showing superior response rates compared to the standard VRd regimen. However, longer follow-up is needed to assess long-term survival benefits fully. Future phase 3 trials are warranted to confirm the superiority of VPd over established regimens for NDMM induction.

The study's limitations include the relatively small sample size, single-center design, and inability to conduct FISH analysis or MRD assessment via multiparameter flow cytometry in all patients. The short follow-up period may have influenced the overall survival data. Further studies with larger sample sizes and longer follow-up are needed to confirm these findings and to explore the long-term effects of this regimen.