Efficacy and safety of pomalidomide, bortezomib, and dexamethasone combination chemotherapy for newly diagnosed multiple myeloma: POMACE Phase II Study

Newly diagnosed multiple myeloma (NDMM) is typically treated with induction chemotherapy followed by autologous stem cell transplantation (ASCT) and maintenance. Maximizing depth of response correlates with improved progression-free (PFS) and overall survival (OS). The standard VRd regimen (bortezomib, lenalidomide, dexamethasone) achieves high response rates, but curability remains challenging. Pomalidomide, a third-generation immunomodulatory drug with higher cereblon-binding potency than lenalidomide and activity in lenalidomide-resistant models, is approved for relapsed/refractory disease. Data on pomalidomide in frontline NDMM are limited. The POMACE Phase II study prospectively evaluates the efficacy and safety of replacing lenalidomide with pomalidomide in a VPd regimen for NDMM.

Prior frontline regimens such as VRd have demonstrated robust responses, with PETHEMA/GEM2012 reporting CR 33.4% and ≥VGPR 63.8% after four induction cycles. The field has incorporated agents first approved in RRMM—e.g., daratumumab and carfilzomib—to deepen responses in NDMM. Pomalidomide binds cereblon with higher potency than lenalidomide and shows distinct gene activation and substrate degradation kinetics, retaining activity in lenalidomide-resistant cell lines and animal models. However, clinical experience with pomalidomide as part of initial therapy for NDMM remains limited, prompting prospective evaluation of a VPd regimen.

Design: Single-center, single-arm, open-label, phase 2 clinical trial (POMACE). Enrollment period: July 2020–December 2021. Ethics and registration: Institutional ethics approval (JIP/IEC/2020/059) and CTRI registration (CTRI/2020/09/027547); conducted per Declaration of Helsinki and ICMR GCP. Written informed consent obtained. Eligibility: Treatment-naïve NDMM patients aged 18–75 years with ECOG PS ≤2. Key exclusions: ≥grade 2 peripheral neuropathy, ANC <1000/µL, platelets <50,000/µL, bilirubin/transaminases ≥3× ULN, creatinine clearance <15 mL/min, significant active comorbidities or infections, plasma cell leukemia, amyloidosis, POEMS. Intervention (VPd induction): 4-week cycles of bortezomib 1.3 mg/m2 SC on days 1, 8, 15, 22 (dose capped at 2 mg), pomalidomide orally days 1–21 (2 mg/day in cycle 1; 4 mg/day from cycle 2 onward), and dexamethasone 40 mg orally on days 1, 8, 15, 22. Transplant-eligible patients achieving ≥VGPR could proceed to ASCT after ≥4 cycles; up to six VPd cycles permitted, then Vd until ASCT. Stem cell mobilization with G-CSF ± plerixafor; conditioning with melphalan 140–200 mg/m2. Post-ASCT maintenance continued. Transplant-ineligible patients received 9 cycles of VPd followed by maintenance: pomalidomide for R-ISS I; bortezomib for R-ISS II–III. Prophylaxis: aspirin 75 mg daily (unless contraindicated), acyclovir 400 mg BID, and bisphosphonates (zoledronic acid). Assessments and endpoints: Primary endpoint—rate of ≥VGPR after four VPd cycles. Secondary endpoints—safety, PFS, OS. Baseline: SPEP with M-protein quantification, IF, serum free light chains, beta-2 microglobulin, bone marrow aspiration/biopsy with FISH cytogenetics, PET-CT skeletal imaging; routine labs before each cycle. Interim M-protein quantification after two cycles (if elevated at baseline). End of four cycles: full response assessment (SPEP, IF, sFLC, marrow biopsy, PET-CT). Responses per IMWG Uniform Criteria; AEs graded by CTCAE v5.0. Data cutoff: July 2022. Sample size and statistics: Fleming’s two-stage design assuming VRd ≥VGPR ~65% and expecting VPd ≥VGPR 80%; type I error 0.05, power 0.8. Stage 1 accrual 31; stopping rules predefined; potential total 59 if criteria not met. Response rates and toxicities summarized as percentages; survival analyzed with Kaplan–Meier (SPSS v21).

Cohort: 34 enrolled; 31 completed ≥4 induction cycles and were evaluable for response. Median age 52 years (32–72); 55% male; ECOG 0–1 in 61%. ISS I/II/III: 27%/27%/46%. High-risk cytogenetics in 9%. Median follow-up 14 months. Efficacy: Overall response rate 100%. After four VPd cycles: sCR 32% (10/31), CR 29% (9/31), VGPR 26% (8/31), PR 13% (4/31); ≥VGPR 87% (primary endpoint achieved). PET-CT: complete metabolic response (CMR) 48% (15/31); partial metabolic response 52% (16/31). At 12 months (intent-to-treat): PFS 67.7%, OS 70.7%. By depth of response: 12-month PFS 87.1% in ≥VGPR (n=27) vs 50% in PR (n=4) (p=0.03); 12-month OS 90.3% in ≥VGPR vs 50% in PR (p=0.002). By PET-CT: 12-month PFS 93.3% with CMR (n=15) vs 42.4% without (partial response; n=16) (p=0.06); 12-month OS 100% with CMR vs 40.6% without (p=0.03). Safety: Most common hematologic AEs (any grade): neutropenia 24% (8/33), anemia 21% (7/33), thrombocytopenia 15% (5/33). Grade ≥3: anemia 9% (3/33), neutropenia 3% (1/33). Febrile neutropenia occurred in 3% (grade 5: 3%). Non-hematologic AEs (any grade): peripheral sensory neuropathy 27% (9/33; grade ≥3: 6%), fatigue 27% (9/33), constipation 24% (8/33), sedation 9% (3/33), myalgia 6% (2/33), CINV 6% (2/33). Non-neutropenic infection 3% (grade 5: 3%). Two serious adverse events and two early deaths in cycle 1 were noted; one death attributed to treatment (febrile neutropenia with sepsis in a diabetic patient), another due to pre-renal AKI from gastroenteritis (non-neutropenic). Transplant and mobilization: 27/31 (87%) were transplant-eligible by age/fitness; 11 (35%) underwent ASCT. Median time from induction start to ASCT 8.5 months (5.4–12). Median cycles before ASCT: 8 (typically 6 VPd then Vd). G-CSF used in all, plerixafor in 55% (6/11). No second apheresis required. Median CD34+ yield 6.3×10^6/kg (range 2.8–21.1×10^6). Median neutrophil engraftment 9 days (8–11); platelet engraftment 11 days (10–12).

VPd induction in NDMM achieved deep responses (≥VGPR 87%, sCR/CR 61%) and high PET-CT CMR rates (48%) after four cycles, comparable to outcomes reported with carfilzomib- or daratumumab-containing frontline regimens. Depth of response and PET-CT CMR correlated with improved 12-month PFS and OS, supporting the prognostic value of metabolic MRD negativity. Toxicity was manageable; hematologic AEs were lower than those reported in RRMM VPd studies, potentially due to a lower pomalidomide dose in cycle 1 and capping bortezomib at 2 mg, which may have reduced thrombocytopenia and neuropathy. Pomalidomide did not impair stem cell mobilization or engraftment. Although 12-month PFS and OS appeared lower than contemporary benchmarks, this may reflect short follow-up and deaths unrelated to study therapy. The findings support VPd as an effective induction option warranting confirmation in randomized phase 3 trials with longer follow-up and formal MRD assessments.

VPd induction (bortezomib, pomalidomide, dexamethasone) is safe and efficacious in newly diagnosed multiple myeloma, delivering high rates of ≥VGPR and complete responses, with favorable PET-CT metabolic responses and acceptable toxicity. The regimen did not compromise stem cell collection or engraftment. Larger randomized phase 3 studies with extended follow-up and MRD evaluation are needed to establish superiority over standard VRd and confirm survival benefits.

Single-center, single-arm phase 2 design with small sample size and short median follow-up (14 months) limit generalizability and survival interpretation. Cytogenetic FISH testing was not performed in all patients, and MRD assessment by multiparameter flow cytometry was not done due to logistical issues. Early deaths and events not directly attributable to study therapy and financial/social barriers reducing ASCT rates may have influenced outcomes.