Summary

• DARZALEX FASPRO for subcutaneous (SC) use is not approved by the regulatory agencies for use in patients with smoldering multiple myeloma (SMM). Janssen does not recommend the use of DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
• AQUILA is a phase 3 study evaluating the safety and efficacy of DARZALEX FASPRO monotherapy vs active monitoring in patients with high-risk SMM. The trial has enrolled 390 patients in 23 countries.^1-5
  • Dimopoulous et al (2024)^4-6 reported the primary results of a phase 3 AQUILA study of DARZALEX FASPRO monotherapy vs active monitoring in patients with high-risk SMM. DARZALEX FASPRO significantly reduced the risk of progressing to MM or death by 51% compared to active monitoring (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.36-0.67; P<0.001) and the benefit continued beyond 36 months. At a median follow-up of 65.2 months, the median progression free survival (PFS) was not reached in the DARZALEX FASPRO group, while it was 41.5 months in the active monitoring group. Patients identified as high-risk per Mayo 2018 criteria experienced greater PFS improvement with DARZALEX FASPRO. Notably, PFS benefits were also observed in other prespecified subgroups. The 5-year PFS rate was 63.1% vs 40.8% in the DARZALEX FASPRO vs active monitoring group, respectively. The DARZALEX FASPRO group was associated with an overall response rate (ORR) rate of 63.4% (relative risk ratio, 31.00; 95% CI, 13.05-101.03; P<0.001), with 29.9% patients achieving a very good partial response or better (≥VGPR) and 8.8% patients achieving a complete response or better (≥CR). In contrast, the active monitoring group had an overall response rate (ORR) of 2.0%. DARZALEX FASPRO prolonged time to first-line treatment for MM vs active monitoring (HR, 0.46; 95% CI, 0.33-0.62) and improved PFS on first-line treatment for MM vs active monitoring (HR, 0.58; 95% CI, 0.35-0.96). The 5-year estimate for initiation of first-line treatment was 29.7% vs 55.9% for the DARZALEX FASPRO vs active monitoring group, respectively. Early intervention with fixed duration of DARZALEX FASPRO extended overall survival (OS) vs active monitoring (HR, 0.52; 95% CI, 0.27-0.98). The 5-year OS rate was 93.0% vs 86.9% in the DARZALEX FASPRO group vs active monitoring group, respectively. The DARZALEX FASPRO group was associated with a low rate of discontinuation due to treatment-emergent adverse events (TEAEs) and no new safety events were identified. Grade 3/4 adverse events (AEs) occurred in 40.4% of patients from the DARZALEX FASPRO group vs 30.1% of patients from the active monitoring group. The frequency of second primary malignancies was similar between the DARZALEX FASPRO vs active monitoring group (9.3% vs 10.2%), respectively.

PRODUCT LABELING

• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf.

CLINICAL studies

DARZALEX FASPRO Monotherapy Phase 3 Study

AQUILA (SMM3001; clinicaltrials.gov identifier: NCT03301220) is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of DARZALEX FASPRO vs active monitoring in patients with high-risk SMM.^1-5

Study Design/Methods

• This phase 3, open-label, multicenter, randomized trial enrolled 390 patients from 124 sites in 23 countries.⁵ 
• Randomization was stratified based on the number of factors associated with progression to MM (<3 vs ≥3); which included⁵ :
  • Serum involved:uninvolved free light chain (FLC) ratio ≥8 (yes vs no)
  • Serum-M protein ≥30 g/L (yes vs no)
  • Immunoglobulin A (IgA) SMM (yes vs no)
  • Immunoparesis (reduction of 2 uninvolved immunoglobulin vs reduction of <2 uninvolved immunoglobulins)
  • Bone marrow plasma cells (BMPCs; >50% to <60% vs ≤50%)
• Patients were stratified and randomized in a 1:1 ratio to receive either DARZALEX FASPRO or active monitoring⁵ :
  • DARZALEX FASPRO:
    • Patients received 1,800 mg DARZALEX FASPRO monotherapy QW (cycle 1-2), Q2W (cycle 3-6), and Q4W (thereafter in 28-day cycles) until 39 cycles, or up to 36 months, or until confirmed progressive disease (PD), whichever occurred first.
  • Active monitoring:
    • No disease-specific treatment was administered. Active monitoring was conducted for up to 36 months or until confirmed PD, whichever occurred first.
• Key inclusion criteria⁵ :
  • ≥18 years of age
  • Confirmed diagnosis of SMM (per International Myeloma Working Group [IMWG] criteria) for ≤5 years
  • Measurable disease
  • Eastern Cooperative Oncology Group (ECOG) performance status of ≤1
  • Factors indicating a high risk of progression, including clonal BMPCs ≥10% and ≥1 of the following risk factors:
    • Serum M-protein ≥30 g/L
    • IgA SMM
    • Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes
    • Serum involved: uninvolved FLC ratio ≥8 to <100
    • Clonal BMPCs >50% to <60%
• All patients were required to have computed tomography (CT)/ positron emission tomography (PET)-CT and magnetic resonance imaging (MRI) during screening
• Key exclusion criteria⁶ :
  • MM per SLiM-CRAB criteria or primary systemic light chain amyloidosis
  • Prior exposure to approved or investigational treatments for SMM or MM
• Primary endpoint: PFS by independent review committee (IRC) per IMWG SLiM-CRAB diagnostic criteria for MM.⁵ 
• Secondary endpoints: Overall response (partial response or better), complete response rate, disease progression as assessed with IMWG biochemical or SLiM–CRAB criteria, time to first-line treatment for active MM, death from any cause, PFS on first-line treatment for MM, and OS.^4,5 

Dimopoulous et al (2024)^4-6 reported the primary results of a phase 3 AQUILA study of DARZALEX FASPRO monotherapy vs active monitoring in patients with high-risk SMM.

Results

Baseline Demographics and Disease Characteristics

• The baseline characteristics were generally balanced between both groups and are presented in Table: Baseline Demographics and Clinical Characteristics – ITT Population.

Treatment or Active Monitoring and Study Disposition

• Treatment or active monitoring details are presented in Table: Treatment or Active Monitoring Disposition.
  • By the cut-off date of 01 May 2024, 127 (65.5%) of patients vs 80 (40.8%) of patients completed 39 cycles or 36 months of treatment with DARZALEX FASPRO vs. 36 months of active monitoring, respectively.⁵ 
• The median follow-up was 65.2 (range, 0-76.6) months. The trial follow-up is ongoing.⁵ 
• Most patients in both groups remained in ongoing follow-up on study (DARZALEX FASPRO group, 163 [84.0%] patients vs active monitoring group, 145 [74%] patients).⁴ 
• A total of 30 (15.5%) vs 51 (26.0%) of patients from the DARZALEX FASPRO vs active monitoring group discontinued the study due to the following reasons.⁴ 
  • Death: 15 (7.7%) vs 26 (13.3%).⁵ 
  • Withdrawal by patient: 12 (6.2%) vs 23 (11.7%).⁵ 
  • Lost to follow-up: 1 (0.5%) vs 1 (0.5%).⁴ 
  • Other reasons: 2 (1.0%) vs 1 (0.5%).⁴ 

Efficacy

• Details regarding progression to active MM by IMWG SLiM-CRAB criteria (IRC assessment) are presented in Table: Summary of Progression Events – ITT Population.
  • DARZALEX FASPRO significantly reduced the risk of progressing to MM or death by 51% vs active monitoring (HR, 0.49; 95% CI, 0.36-0.67; P<0.001) and the benefit continued beyond 36 months.⁴ 
  • At a median follow-up of 65.2 months, the median PFS was not reached in the DARZALEX FASPRO group vs 41.5 months in the active monitoring group.⁴
  • The 5-year PFS rate was 63.1% vs 40.8% in the DARZALEX FASPRO vs active monitoring group, respectively.⁵ 
  • The median time to occurrence of PD (IMWG biochemical or SLiM–CRAB criteria) was 44.1 months vs 17.8 months in the DARZALEX FASPRO vs active monitoring group (HR, 0.51; 95% CI, 0.40-0.66).⁵ 
  • Retrospective review of high-risk per Mayo 2018 criteria showed that the median PFS was not reached for DARZALEX FASPRO group vs 22.1 months for the active monitoring group (HR, 0.36; 95% CI, 0.23-0.58).⁴
  • Patients identified as high-risk per Mayo 2018 criteria experienced greater PFS improvement with DARZALEX FASPRO.⁴  Notably, benefits were also observed in other prespecified subgroups and are summarized in Table: Progression to Active MM by IMWG SLiM-CRAB Criteria in Prespecified Subgroups.
• The DARZALEX FASPRO group was associated with an ORR rate of 63.4% (relative risk ratio, 31.00; 95% CI, 13.05-101.03; P<0.001). In contrast, the active monitoring group had an ORR of 2.0%.⁶ 
  • ≥CR was observed in 17 (8.8%) patients vs no patients from the DARZALEX FASPRO vs active monitoring group, respectively.⁵ 
  • PR was observed in 33.5% patients and 1.0% patients from the DARZALEX FASPRO vs active monitoring group, respectively.^4,6 
  • ≥VGPR was observed in 58 (29.9%) patients vs 2 (1.0%) patients from the DARZALEX FASPRO vs active monitoring group, respectively.^4,5 
  • VGPR was observed in 21.1% patients and 1.0% patients from the DARZALEX FASPRO vs active monitoring group, respectively.^4,6 
  • CR and stringent complete response (sCR) were observed in 6.2% patients and 2.6% patients, from the DARZALEX FASPRO group exclusively.^4,6 
• DARZALEX FASPRO prolonged time to first-line treatment for MM vs active monitoring (HR, 0.46; 95% CI, 0.33-0.62).⁴ 
  • First-line treatment for MM was initiated by 33.2% (64/193) patients in the DARZALEX FASPRO group vs 53.6% (105/196) patients in the active monitoring group.⁴ 
  • The 5-year estimate for initiation of first-line treatment was 29.7% vs 55.9% for the DARZALEX FASPRO vs active monitoring group, respectively.⁵ 
• DARZALEX FASPRO improved PFS on first-line treatment for MM vs active monitoring (HR, 0.58; 95% CI, 0.35-0.96).⁴ 
  • The most common first-line treatment for MM was bortezomib + lenalidomide + dexamethasone (VRd) (DARZALEX FASPRO, 29.7% [19/64] vs active monitoring, 27.6% [29/105]).
  • Anti-cluster of differentiation (CD)38 monoclonal antibody-based regimens were administered to 25.0% (16/64) patients from the DARZALEX FASPRO group vs 33.3% (35/105) patients from the active monitoring group.
• Early intervention with fixed duration of DARZALEX FASPRO extended OS vs active monitoring (HR, 0.52; 95% CI, 0.27-0.98).⁴ 
  • The 5-year OS rate was 93.0% vs 86.9% in the DARZALEX FASPRO group vs active monitoring group, respectively.⁵ 
  • Deaths occurred in 7.7% (15/194) patients and 13.3% (26/196) patients from the DARZALEX FASPRO vs active monitoring group, respectively. The primary causes included disease progression (3 vs 9 patients), AE (2 vs 4 patients), and deaths due to an event occurring after the AE reporting window or deaths with unknown reason (10 vs 13 patients).⁴ 
• Per the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) global health status score, baseline values for patient-reported outcomes were maintained over the study duration in both groups. Further, there was no significant difference in scores obtained during treatment or active monitoring between the groups.^4,5  

Safety

• The DARZALEX FASPRO group was associated with a low rate of discontinuation due to TEAEs and no new safety events were identified.⁴  The safety overview is presented in Table: Summary of Adverse Events – Safety Population.
  • The median duration of AE reporting was 35 months and 26 months in the DARZALEX FASPRO vs active monitoring group, respectively.⁴ 
  • Grade 3 or 4 infections were of short duration (median duration: DARZALEX FASPRO group, 9 days vs active monitoring group, 5 days), and the majority were recovered or resolved.⁴ 
  • The frequency of second primary malignancies was similar between the DARZALEX FASPRO vs active monitoring group (9.3% vs 10.2%).⁴ 

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 10 December 2024.