Consolidation Treatment with VRd Followed By Maintenance with Lenalidomide in Multiple Myeloma Improves Overall Survival: Long-Term Follow-up of the EMN02/HOVON95 Randomized Phase 3 Trial

Speaker: Pieter Sonneveld, Erasmus MC Cancer Institute, Netherlands

Key Highlights

Study Overview:

1. The EMN02/HOVON95 trial enrolled 1,500 transplant-eligible, newly diagnosed multiple myeloma (MM) patients.
2. The trial assessed the role of consolidation therapy with VRd (bortezomib, lenalidomide, dexamethasone) followed by lenalidomide maintenance.
3. Two randomizations: All participants received VCd (bortezomib, cyclophosphamide, dexamethasone) as their initial induction regimen.
   1. First randomization: single or tandem autologous stem cell transplant (ASCT) vs chemotherapy-based intensification.
   2. Second randomization (focus of the current analysis): consolidation with VRd (2 cycles) vs no consolidation, followed by lenalidomide maintenance until progression.
4. Follow-up duration: Median of 130 months (10.8 years).

Key Findings:

1. Improved Survival with VRd Consolidation:
   1. 10-year OS rate: 64% in VRd consolidation vs. 51% without consolidation.
   2. VRd consolidation increased restricted mean survival time by 9.4 months.
   3. Complete Response (CR) at any time post-randomization was strongly linked to improved OS (HR = 0.39).
2. Cytogenetic Risk Impacts:
   1. Standard-risk cytogenetics (no 17p deletion/t(4;14)) showed significant OS benefit.
   2. High-risk cytogenetics (17p deletion or t(4;14)) did not show a survival benefit with VRd consolidation alone.
3. Maintenance Therapy's Role:
   1. Median duration of lenalidomide maintenance: 35 months with VRd vs. 33 months without consolidation.
   2. Extended maintenance (≥3 or 5 years) was associated with superior overall survival.
4. Second Primary Malignancies: Rates of non-skin SPMs were similar in both groups (~10%), indicating no additional risk linked to prolonged lenalidomide use.

Clinical Implications:

• VRd consolidation + lenalidomide maintenance improves long-term survival, especially in standard-risk MM and earlier ISS stages.
• Achieving CR remains a strong predictor of survival.
• High-risk cytogenetic patients [17p deletion or t(4;14)] may require more intensive therapies.

Daratumumab Plus Lenalidomide (D-R) Versus Lenalidomide (R) Alone as Maintenance Therapy in Newly Diagnosed Multiple Myeloma (NDMM) after Transplant: Analysis of the Phase 3 AURIGA Study Among Clinically Relevant Subgroups

Speaker: Laahn Foster, University of Virginia

Key Highlights

Study Overview:

The Phase 3 AURIGA trial compared daratumumab plus lenalidomide (D-R) vs. lenalidomide alone (R) as maintenance therapy in MRD-positive, transplant-eligible, newly diagnosed multiple myeloma (NDMM) patients post-transplant.

• Participants: Anti-CD38 naïve patients achieving VGPR or better post-transplant.
• Primary endpoint: MRD negative conversion rate at 12 months (10⁻⁵ sensitivity).
• Median follow-up: 32.3 months.

Key Findings:

1. Higher MRD-Negative Conversion with D-R:
   1. D-R showed higher MRD-negative conversion rates across all demographics and risk subgroups.
   2. 47% reduction in disease progression or death compared to R alone.
2. Ultra-High-Risk Subgroups: D-R achieved MRD negativity in 6/11 ultra-high-risk patients, while none achieved MRD negativity with R alone.
3. Subgroup Insights:
   1. Age, race, cytogenetic risk, and ISS stage: D-R consistently improved MRD conversion and PFS regardless of demographics.
   2. Cytogenetic groups with gain/amplification of 1q showed significant PFS benefit with D-R maintenance.
4. Safety & Tolerability:
   1. Older adults (≥65 years): No increase in severe infections or cytopenias with D-R vs. younger patients.
   2. Black patients: D-R was well tolerated, with no new safety concerns.

Clinical Implications:

• MRD negativity as a goal: Achieving MRD negativity with D-R is critical for improving PFS and potentially OS in MRD-positive patients post-transplant.
• High-risk patients: D-R maintenance showed the most benefit in ultra-high-risk groups and patients with multiple cytogenetic abnormalities.
• Safety across demographics: D-R demonstrated favourable safety and tolerability, supporting its use across diverse populations.

Results of the Phase II Randomized Trial EMN15/HOVON147: Carfilzomib-Lenalidomide-Dexamethasone Vs Lenalidomide-Dexamethasone in Patients with High-Risk Smoldering Multiple Myeloma

Speaker: Annemiek Broijl, Erasmus MC Cancer Institute, Netherlands

Key Highlights

Study Overview:

1. Objective: Evaluate KRd (carfilzomib-lenalidomide-dexamethasone) vs Rd (lenalidomide-dexamethasone) in patients with high-risk SMM (defined by Mayo Clinic 2008 criteria).
2. Why KRd? Recent data suggest early intervention benefits in high-risk SMM patients.
3. Study Design: Participants: 57 total (35 KRd, 22 Rd); median age 61–63.
4. Treatment arms:
   1. KRd group: 4 cycles of KRd → optional stem cell mobilization → 5 additional cycles → lenalidomide maintenance.
   2. Rd group: 4 cycles of Rd → optional stem cell mobilization → 5 additional cycles → lenalidomide maintenance for 2 years.
5. Primary Endpoint: MRD negativity (sensitivity 10⁻⁵) after 9 cycles.
6. Secondary endpoints: PFS, ORR, duration of response, and safety.

Key Findings

1. MRD Negativity:
   1. KRd: 57% achieved MRD negativity.
   2. Rd: 5% achieved MRD negativity (p<0.001).
2. Progression-Free Survival (PFS):
   1. KRd: 94% at 3 years.
   2. Rd: 40% at 3 years.
   3. Hazard Ratio: 0.18, translating to an 82% risk reduction for progression or death.
3. Overall Response Rate (ORR):
   1. KRd: ~100%.
   2. Rd: 68%.
4. Safety:
   1. Grade 3 toxicities: KRd (24%) vs. Rd (5%).
   2. Common toxicities with KRd:
      1. Cardiac events (hypertension, palpitations, VTE).
   3. Peripheral neuropathy and infections.
   4. Toxicities manageable with intervention.

Clinical Implications:

• Efficacy: KRd leads to significantly deeper responses and prolonged PFS compared to Rd.
• Toxicity concerns: The higher adverse event rate with KRd necessitates careful patient selection to minimize overtreatment.
• Biochemical progression: Identifying progression earlier with biochemical markers may lead to earlier intervention but limits comparisons with other trials focusing on symptomatic myeloma onset.

Mezigdomide (MEZI) in Novel-Novel Combinations for Relapsed or Refractory Multiple Myeloma (RRMM): Preliminary Results from the CA057-003 Trial

Speaker: Luciano Costa, University of Alabama, Birmingham

Key Highlights

Background & Rationale

Mezigdomide (MEZI): A novel oral CELMoD (cereblon E3 ligase modulator) with superior immunomodulatory and tumoricidal effects compared to traditional IMIDs.

Goal: Investigate MEZI combinations with novel targeted agents to overcome resistance mechanisms in relapsed/refractory multiple myeloma (RRMM): EZH2 inhibition (tazemetostat) & MEK inhibition (trametinib)

Study Design: Type: Phase 1b/2 trial (CA057-003).

1. Participants: 56 heavily pretreated RRMM patients (median of 5 prior therapies).
   1. 100% triple-class exposed; 82% triple-refractory.
   2. 33% with prior CAR-T therapy, 30% with bispecific antibodies, 33% with extramedullary disease.
2. Cohorts:
   1. Cohort A: MEZI + dexamethasone + tazemetostat (EZH2 inhibitor).
   2. Cohort B: MEZI + dexamethasone + BMS-96158 (BAT inhibitor).
   3. Cohort C: MEZI + dexamethasone + trametinib (MEK inhibitor).
3. Endpoints:
   1. Primary: Safety, tolerability, and RP2D (recommended phase 2 dose).
   2. Secondary: Efficacy (ORR), pharmacokinetics (PK), and exploratory biomarkers.

Efficacy Highlights:

1. MEZI + Tazemetostat: ORR: 50%, rising to 60% at dose level 3.
2. MEZI + BMS-96158: ORR: 35% overall with deeper responses at dose level 3.
3. MEZI + Trametinib: ORR: 75% across all doses.

Biomarkers & Pharmacodynamics: Dose-dependent effects:

• Observed Ikaros/Aiolos degradation and B-cell depletion.
• Significant T-cell activation and CD4/CD8+ proliferation occurred, irrespective of combination partners.

Safety & Tolerability Findings:

• MEZI + Tazemetostat (Cohort A): RP2D established with 1 DLT in 16 patients.
• MEZI + BMS-96158 (Cohort B): 5 DLTs observed at the highest dose. Tolerability was a concern.
• MEZI + Trametinib (Cohort C): RP2D established with 2 DLTs.

Clinical relevance:

• MEZI combinations show promise for high-risk RRMM patients, including extramedullary disease and prior T-cell therapy failures.
• Biomarker-driven strategies may enhance outcomes by identifying optimal responders.

GEM-2017FIT Phase 3 Trial in FIT Elderly Patients (Aged 65-80) with Newly Diagnosed Myeloma: Impact of Daratumumab at Induction and/or Consolidation

Speaker: Maria-Victoria Mateos, Spanish Myeloma Group

Key Highlights

The GEM-2017FIT Phase 3 trial evaluated daratumumab (Dara) in fit elderly patients (aged 65–80) with NDMM. The aim was to assess the role of Dara during induction and/or consolidation therapy to optimize efficacy and safety.

Study Design:

1. Population: FIT elderly patients determined by Geriatric Assessment in Hematology (GAH) scores.
2. Arms:
   1. Control: VMP-Rd (18 cycles).
   2. Experimental:
      1. KRd (18 cycles).
      2. Dara-KRd (18 cycles).
   3. Consolidation: 4 cycles of Dara-Rd in arms without Dara during induction.
   4. Endpoints:
      1. Primary: MRD negativity rate at 10⁻⁵ after 18 cycles.
      2. Secondary: MRD after consolidation, PFS, and safety.

Key Findings:

1. MRD Negativity Rates:
   1. Control (VMP-Rd): 27% MRD negativity at 10⁻⁵.
      1. KRd Arm: 54%.
   2. Dara-KRd Arm: 61% (highest efficacy).
   3. Impact of Consolidation:
      1. VMP-Rd: Improved MRD from 39% → 60% with Dara-Rd consolidation.
      2. KRd: Improved MRD from 74% → 79%.
      3. Dara-KRd induction alone: Achieved 85–81% MRD negativity, even without consolidation.
   4. PFS: 4-year median follow-up showed superior PFS in experimental arms:
      1. Dara-KRd: 67%.
      2. KRd: 71%.
      3. Both superior to VMP-Rd.
   5. Toxicity Profile:
      1. Neutropenia (Grade 3–4): ~33%.
      2. Infection rates remained low despite Dara.
   6. Lenalidomide dose reduction was needed in 36–45% of patients.

Conclusions & Clinical Impact:

• Key Insight: Dara-KRd and KRd showed superior MRD negativity and PFS compared to VMP-Rd.
• Consolidation with Dara-Rd Compensated for the absence of Dara during induction, significantly improving MRD rates.

ASH Annual Meeting and Exposition, 7-10 December 2024, San Diego, California