Summary

• Janssen does not recommend the use of DARZALEX or 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 versus active monitoring in patients with high-risk smoldering multiple myeloma (HR-SMM).^1,2,3
  • Dimopoulos et al (2024)^4-6 reported primary results of the phase 3 AQUILA study of DARZALEX FASPRO monotherapy vs active monitoring in patients with HR-SMM. DARZALEX FASPRO significantly reduced the risk of progression to multiple myeloma (MM) or death by 51% vs 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 and was 41.5 months in the active monitoring group. Grade 3/4 adverse events (AEs) occurred in 40.4% vs 30.1% of patients from the DARZALEX FASPRO vs active monitoring group, respectively.
• Nadeem et al (2021)⁷ presented updated safety and efficacy results of an ongoing open-label, multicenter, phase 2 study evaluating the safety and efficacy of DARZALEX monotherapy in patients with high-risk monoclonal gammopathy of undetermined significance (HR-MGUS) and low-risk SMM (LR-SMM). Of the 41 patients treated, grade 3 toxicities were reported in 5 patients: diarrhea (n=1), flu like symptoms (n=1), headache (n=1), and hypertension (n=2). The primary endpoint of ≥VGPR was observed in 12.5% of the 40 patients who completed ≥16 cycles.
• CENTAURUS is a phase 2 study evaluating the safety and efficacy of 3 dose schedules (long intense, intermediate, and short intense) of DARZALEX monotherapy in patients with previously untreated intermediate-risk SMM or HR-SMMs.⁸
  • Landgren et al (2025)^9,10 reported the final analysis of CENTAURUS study at a median follow-up of 85.2 months. The investigator-assessed overall response rate (ORR) and complete response or better (≥CR) rate were higher in the long intense (58.5% and 4.9%, respectively) and intermediate (53.7% and 9.8%, respectively) treatment arms than in the short intense treatment arm (37.5% and 0%, respectively).
• ASCENT is a phase 2 study evaluating the safety and efficacy of DARZALEX + carfilzomib, lenalidomide, and dexamethasone (D-KRd) in patients with HR-SMM.¹¹
  • Kumar et al (2022)¹² reported safety and efficacy results of the D-KRd given for a fixed duration of 2 years. At a median follow-up of 26.2 months, the ORR was 97%, stringent complete response (sCR) was 38%, complete response (CR) was 26%, and very good partial response (VGPR) was 30%. Median PFS was not reached. Any grade toxicity possibly related to treatment occurred in 92% of patients, grade ≥3 hematological toxicities occurred in 18% of patients and non-hematological toxicities occurred in 51% of patients.
  • Kumar et al (2020)¹³ provided an initial analysis of safety data.
• B-PRISM is an ongoing, open-label, multicenter, phase 2 study evaluating the safety and efficacy of DARZALEX FASPRO + bortezomib, lenalidomide, and dexamethasone (VRd) in patients with HR-SMM.
  • Nadeem et al (2024)¹⁴ presented results of the B-PRISM study. The ORR in patients who completed at least 2 cycles of therapy was 98%. Among the 45 patients treated, the most common grade 3 toxicities included the following: neutropenia (22%), increased alanine transaminase (ALT; 9%), diarrhea (7%), and lung infection (7%).
  • Nadeem et al (2022)¹⁵ presented preliminary results of this study. Of the 20 patients treated, the most common grade 3 toxicities that were reported included: neutropenia (15%), ALT increased (5%), thrombocytopenia (5%), hyperglycemia (5%), hypertension (5%), diarrhea (5%), and syncope (5%). MRD was evaluable in 16 patients and 8 patients have undergone MRD testing, with MRD-negativity rate of 50% and 25% at thresholds of 10^-5 and 10^-6, respectively.
• Patel et al (2025)¹⁶ presented the primary results of a phase 2, Simon 2-stage, investigator-initiated study evaluating the efficacy and safety of DARZALEX FASPRO + carfilzomib + dexamethasone (DKd) in patients with HR-SMM. The ORR achieved was 100%. Two patients had undetectable MRD-negativity with a VGPR. The grade 3 AEs reported were lymphopenia (n=1), hypertension (n=1), lung infection (n=1), and myocardial infarction (n=1). No grade 4 AEs were reported.

PRODUCT LABELING

• DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf. 
• 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; NCT03301220) is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of DARZALEX FASPRO versus active monitoring in patients with HR-SMM.^{1, 2,3} Dimopoulos et al (2024)^4-6 reported primary results of the phase 3 AQUILA study of DARZALEX FASPRO monotherapy vs active monitoring in patients with HR-SMM.

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:
  • 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 isotypes vs other)
  • Bone marrow plasma cells (BMPCs; >50% to <60% vs ≤50%)
• Patients were stratified and randomized 1:1 to receive either DARZALEX FASPRO or undergo active monitoring⁵:
  • DARZALEX FASPRO:
    • Patients received 1800 mg DARZALEX FASPRO monotherapy weekly (QW; cycles 1-2), every 2 weeks (Q2W; cycles 3-6), and every 4 weeks (Q4W; 28-day cycles thereafter) up to 39 cycles, or up to 36 months, or until confirmed progressive disease (PD), whichever occurred first.
  • Active monitoring:
    • No disease-specific therapy was administered. Active monitoring was conducted for up to 36 months or until confirmed PD, whichever occurred first.
• Key eligibility 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 score of 0 to 1
  • Clonal BMPCs ≥10% and ≥1 of the following risk factors:
    • Serum myeloma protein (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 undergo computed tomography (CT) or positron emission tomography (PET)-CT and magnetic resonance imaging (MRI) during screening.⁴
• Primary endpoint: PFS by independent review committee (IRC) per IMWG SLiM-CRAB diagnostic criteria for MM.⁵
• Secondary endpoints: ORR (≥PR), CR rate, disease progression as assessed per 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

Results

Baseline Demographics and Disease Characteristics

• Baseline characteristics were generally balanced between DARZALEX FASPRO and active monitoring groups.⁵
  • Across groups, the median age was 64 years (range, 31-86), the median time from initial diagnosis of SMM to randomization was 0.72 years (range, 0-5.0) and Black patients made up 2.8% of the trial population.

Study Disposition During Treatment and Active Monitoring

• Treatment and active monitoring details are presented in Table: Treatment and Active Monitoring Disposition.
  • By the cutoff date of May 1, 2024, 127 (65.5%) vs 80 (40.8%) 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 months (range, 0-76.6). The trial follow-up is ongoing.⁵
• Most patients in both groups have remained in the ongoing follow-up of the study (DARZALEX FASPRO group, 163 [84.0%] patients; active monitoring group, 145 [74%] patients).⁴
• A total of 30 (15.5%) vs 51 (26.0%) patients from the DARZALEX FASPRO vs active monitoring group, respectively, were discontinued from the study due to the following reasons⁴:
  • Death: 15 (7.7%) vs 26 (13.3%) patients, respectively⁵
  • Withdrawal by patient: 12 (6.2%) vs 23 (11.7%) patients, respectively⁵
  • Lost to follow-up: 1 (0.5%) vs 1 (0.5%) patients, respectively⁴
  • Other reasons: 2 (1.0%) vs 1 (0.5%) patients, respectively⁴

Efficacy

• DARZALEX FASPRO significantly reduced the risk of progression 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 and was 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
• Patients identified as having a high risk per Mayo 2018 criteria experienced a greater PFS improvement with DARZALEX FASPRO.⁴
• A retrospective review of high risk per Mayo 2018 criteria showed that the median PFS was not reached for the DARZALEX FASPRO group and was 22.1 months for the active monitoring group (HR, 0.36; 95% CI, 0.23-0.58).⁴
• The median time to occurrence of PD (IMWG biochemical or SLiM-CRAB criteria) was 44.1 vs 17.8 months in the DARZALEX FASPRO vs active monitoring group, respectively (HR, 0.51; 95% CI, 0.40-0.66).⁵
  • Per the IMWG SLiM-CRAB criteria, 34.5% of patients (n=67) in the DARZALEX FASPRO group vs 50.5% of patients (n=99) in the active monitoring group experienced disease progression or death.
    • In each arm, 5 patients experienced death without disease progression.
• A summary of progression to active MM by IMWG SLiM-CRAB criteria in prespecified subgroups was reported.⁵
• The DARZALEX FASPRO group had an ORR 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% vs 1.0% of patients from the DARZALEX FASPRO vs active monitoring group, respectively.^4,6
  • ≥VGPR was observed in 58 (29.9%) vs 2 (1.0%) patients from the DARZALEX FASPRO vs active monitoring group, respectively.^4,5
  • VGPR was observed in 21.1% vs 1.0% of patients from the DARZALEX FASPRO vs active monitoring group, respectively.^4,6
  • CR and sCR were observed in 6.2% and 2.6% of patients, respectively, from the DARZALEX FASPRO group exclusively.^4,6
• DARZALEX FASPRO prolonged the 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 in 33.2% (64/193) vs 53.6% (105/196) of patients in the DARZALEX FASPRO vs active monitoring group, respectively.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 VRd (DARZALEX FASPRO, 29.7% [19/64]; active monitoring, 27.6% [29/105]).
  • Anti-cluster of differentiation (CD)38 monoclonal antibody-based regimens were administered to 25.0% (16/64) vs 33.3% (35/105) of patients from the DARZALEX FASPRO vs active monitoring group, respectively.
• Early intervention with a 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 vs active monitoring group, respectively.⁵
  • Death occurred in 7.7% (15/194) vs 13.3% (26/196) of patients from the DARZALEX FASPRO vs active monitoring group, respectively: primary causes included disease progression (3 vs 9 patients, respectively), AEs (2 vs 4 patients, respectively), and events occurring after the AE-reporting window or unknown (10 vs 13 patients, respectively).⁴
• Regarding patient-reported outcomes, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) global health status score was maintained over the study duration from baseline in both groups. Further, there was no significant difference in the scores obtained during intervention (treatment or active monitoring) between the groups.^4,5

Safety

• No new safety events were identified in the DARZALAEX FASPRO group.⁴ The safety overview is presented in Table: Summary of AEs - Safety Population.
  • The median duration of AE reporting was 35 vs 26 months in the DARZALEX FASPRO vs active monitoring group, respectively.⁴
  • Grade 3/4 infections were of a short duration (median duration: DARZALEX FASPRO group, 9 days; 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 and active monitoring groups (9.3% and 10.2%, respectively).⁴
• Serious AEs occurred in 29.0% of patients in the DARZALEX FASPRO arm vs 19.4% of patients in the active monitoring arm.⁵
  • The most common serious AE was pneumonia (3.6% of patients in the DARZALEX FASPRO arm vs 0.5% in the active monitoring arm).
• AEs of special interest are summarized in Table: AEs of Special Interest - Safety Population.

DARZALEX Monotherapy Phase 2 Study

Nadeem et al (2019)¹⁷ presented the preliminary safety and efficacy results of an ongoing, phase 2, single-arm study (NCT03236428)¹⁸ evaluating the safety and efficacy of DARZALEX monotherapy in patients with HR-MGUS or LR-SMM. Nadeem et al (2021)⁷ presented updated results of this study.

Study Design/Methods

• DARZALEX 16 mg/kg was administered:
  • Cycles 1-2: QW
  • Cycles 3-6: Q2W
  • Cycles 7-20: monthly
• Key inclusion criteria:
  • HR-MGUS defined as <10% BMPCs and <3 g/dL M-protein as well as ≥2 of the following 3 criteria: M-protein ≥1.5 g/dL; non-IgG M-protein; abnormal serum free light chain (SFLC) ratio of <0.26 or >1.65.
  • LR-SMM with either ≥10% BMPCs, SFLC ratio of <0.125 or >8, or M-protein ≥3 g/dL.
• Primary endpoint: ≥VGPR after 20 cycles of DARZALEX.
• Secondary endpoints: safety, duration of response and MRD-negativity rates in patients that experienced ≥VGPR.

Results

• Forty-two patients (22 males, 20 females) were enrolled with a median age of 60 years (range, 38-76); 41 patients have initiated treatment and are included in the safety assessment; 40 patients have completed ≥16 cycles (range, 6-20).
• Thirty-seven (88.1%) patients had a classification of LR-SMM and 5 patients (11.9%) patients had HR-MGUS.

Efficacy

• Best overall responses were CR (n=4, 9.8%), VGPR (n=1, 2.4%), partial response (PR; n=16, 39%), minimal response (n=13, 31.7%), and stable disease (n=7, 17.1%).
• Minimal response or better was reported in 82.9% (34/41) of patients and ≥PR in 51.2% (21/41) of patients.
• The following response rates were reported in the 40 patients that completed ≥16 cycles:
  • Minimal response or better in 85% of patients.
  • ≥PR in 52.5% of patients.
  • ≥VGPR in 12.5% of patients.
• Median time to VGPR was 7 months.
• Median OS and PFS have not been reached.
• No patients have progressed to MM.

Safety

• Of the 41 patients treated, grade 3 toxicities were reported in 5 patients: diarrhea (n=1, [2%]), flu like symptoms (n=1, [2%]), headache (n=1, [2%]), and hypertension (n=2, [5%]).
• Of the 41 patients treated, the most common any-grade toxicities were fatigue (n=24, [51%]), cough (n=19, [46%]), nasal congestion (n=18, [44%]), headache (n=14, [34%]), hypertension (n=11, [27%]), nausea (n=13, [32%]), and leukopenia (n=13, [32%]). No discontinuations due to toxicity have been reported.

DARZALEX Monotherapy Phase 2 Study

CENTAURUS (SMM2001: NCT02316106) is an ongoing study evaluating the safety and efficacy of 3 dose schedules of DARZALEX monotherapy in patients with previously untreated intermediate-risk SMM or HR-SMM. Landgren et al (2025)^9,10 reported the final analysis of CENTAURUS

Study Design/Methods

• Phase 2, randomized, open-label, multicenter study in which randomization of patients at screening was stratified based on the number of risk factors (<2 vs ≥2) for progression to symptomatic MM.⁸
• Patients received 1 of 3 DARZALEX dosing schedules: extended intense (intense), extended intermediate (intermediate), and short.⁸
• Intense: Patients were administered DARZALEX 16 mg/kg IV⁸:
  • Cycle 1: QW
  • Cycle 2-3: Q2W
  • Cycles 4-7: Q4W
  • Cycles 8-20: every 8 weeks
• Intermediate: Patients were administered DARZALEX 16 mg/kg IV⁸:
  • Cycle 1: QW
  • Cycle 2-20: every 8 weeks
• Short: Patients were administered DARZALEX 16 mg/kg IV⁸:
  • Cycle 1: QW
• Pre-infusion medications administered were methylprednisolone 60-100 mg, diphenhydramine 25-50 mg, acetaminophen 650-1000 mg, and montelukast 10 mg (optional).⁸
• Median range (median) follow-up was 25.9 (0-33.2) months.⁸
• Key inclusion criteria⁸:
  • Diagnosis of SMM for <5 years and an ECOG performance score of 0 or 1.
  • BMPCs ≥10% to <60% and ≥1 of the following:
    • Serum M-protein ≥3 g/dL (IgA ≥2 g/dL)
    • Urine M-protein >500 mg/24 hours
    • Abnormal FLC ratio (<0.126 or >8) and serum M-protein <3 g/dL but ≥1 g/dL
    • Absolute involved serum FLC ≥100 mg/L with an abnormal FLC ratio (<0.126 or >8, but not ≤0.01 or ≥100; added following a protocol amendment)
• Key exclusion criteria⁸:
  • Presence of ≥1 SLiM-CRAB myeloma-defining event defined as ≥60% BMPCs, FLC involved/uninvolved ratio ≥100 (involved FLC ≥100 mg/L), >1 focal bone lesion (≥5 mm) on MRI, calcium elevation, renal insufficiency by creatinine clearance, anemia, or bone disease (CRAB) due to lytic bone lesions.
• Key study design updates⁹:
  • As per the protocol amendment dated January 28, 2019, patients in the long intense and intermediate arms were offered the option to enter an extension phase and continue DARZALEX treatment after completion of 20 treatment cycles.
    • Transition to the extension phase was permitted only if there was a positive benefit/risk ratio per the investigator’s assessment, no grade ≥3 treatment-related toxicity had been reported, and at least stable disease had been achieved.
  • As per the protocol amendment dated April 01, 2020, patients were given the option to switch from DARZALEX to DARZALEX FASPRO administration during the extension phase, aiming to prioritize patients’ safety during the coronavirus disease 2019 (COVID-19) pandemic.
  • As per the final protocol amendment (March 29, 2021), patients had the option for extension of the study duration up to a maximum of 7 years after the last patient’s first dose, allowing for evaluation of the long-term safety and efficacy of DARZALEX.
• Coprimary endpoints: CR rate in each trial arm, and rate of PD/death per patient-year.⁹
• Secondary endpoints: ORR, PFS, OS, subsequent MM treatment, response to first subsequent MM treatment, biochemical progression, and safety.⁹

Results

Baseline Characteristics and Patient Disposition

• A total of 123 patients were randomly assigned to treatment, with 41 patients assigned to each of the 3 treatment arms.^9,10 
  • The baseline characteristics were well balanced across the 3 arms. Baseline demographics and disease characteristics are summarized in Table: Baseline Demographics and Disease Characteristics.
  • Patient disposition in the 3 treatment arms is summarized in Table: Patient Disposition.¹⁰
• Among the 123 patients, 55 (44.7%) patients (long intense, n=30/41 [73.2%]; intermediate, n=25/41 [61.0%]) who achieved at least stable disease, had no grade ≥3 treatment-related toxicity, and had a positive benefit/risk ratio were eligible to enter the extension phase.⁹
  • In the long intense and intermediate treatment arms, 16 of 30 patients (53.3%) and 10 of 25 patients (40.0%), respectively, switched from DARZALEX to DARZALEX FASPRO in the extension phase.⁹
• The median duration of study treatment including the extension phase was 44.0 months (range, 1.0-91.6), 35.2 months (range, 1.9-90.6), and 1.6 months (range, 0.1-1.9) in the long intense, intermediate, and short intense treatment arms, respectively.⁹
• In the extension phase, the median treatment duration was 45.2 months (range, 1.9-48.6) and 46.1 months (range, 11.1-49.2) in the long intense and intermediate treatment arms, respectively.⁹

Efficacy

• The ORR was higher in the long intense and intermediate treatment arms compared with the short intense treatment arm.⁹ Response rates are summarized in Table: Response Rates.
• At the final analysis, patients across all 3 treatment arms had experienced PD and progression events as detailed in Table: Summary of Progression Events.
  • PD/death rates patient-year for the long intense, intermediate, and short intense treatment arms were 0.096, 0.102, and 0.109, respectively (P<0.0001 for all).⁹
• The median follow-up was 85.2 months (range, 0-94.3).⁹
• The PFS and OS across the 3 treatment arms are summarized in Table: PFS and OS.
• In the per-protocol phase including the extension phase, time to next treatment was not reached in either the long intense or intermediate treatment arms and was 76.3 months (90% CI, 40.4-80.3) in the short intense arm.⁹
• A total of 93 (75.6%) patients across all 3 treatment arms experienced biochemical progression and of these, 57 (61.3%) patients progressed to active MM.⁹
  • One patient had PD per the investigator’s diagnosis 1 month before biochemical progression and 35 of 93 patients (37.6%) had no documented PD.
  • Among these, 20 patients (13 in the long intense and 7 in the intermediate treatment arms) continued DARZALEX while awaiting progression to active MM.
  • The median time to biochemical progression in the long intense, intermediate, and short intense treatment arms was 38.6 months (90% CI, 35.0-47.0), 31.4 months (90% CI, 25.4-60.8), and 14.8 months (90% CI, 11.1-20.4), respectively.

• Of the 123 patients included in the study, 50 (40.7%) received first-line subsequent systemic therapy for MM as summarized in Table: Summary of Subsequent First-line Systemic Therapy.^9,10
• Of the 57 patients with biochemical progression who progressed to active MM, 45 (78.9%) received subsequent therapy; 36 patients were alive at the end of the study.
• Among the 35 patients who did not progress to active MM, 1 (2.9%) received further treatment, and all were alive at study completion.⁹

Safety

• No new safety concern was reported with extended DARZALEX exposure and follow-up.⁹
  • At the final analysis, the safety population consisted of 122 patients. An overview of safety with extended follow-up is presented in Table: Safety Overview With Extended Follow-up.
• One patient in the long intense treatment arm died due to chronic renal failure (75 days after the last dose of the study treatment) and 2 patients in the intermediate treatment arm died due to heart failure (36 days after the last dose of the study treatment) and myocardial infarction (1 day after the last dose of the study treatment).⁹
  • No death was associated with DARZALEX treatment.
  • One patient each in the long intense and intermediate treatment arms and 2 patients in the short intense treatment arm died due to PD.

Biomarkers

• DARZALEX treatment consistently decreased the frequency and absolute count of natural killer (NK) cells (CD45⁺CD3⁻CD16⁺CD56⁺) across all 3 treatment arms.⁹
• Simultaneously, DARZALEX treatment increased the frequency and absolute number of T cells (CD45⁺CD3⁺) in each treatment arm.⁹

DARZALEX in Combination with Carfilzomib, Lenalidomide and Dexamethasone

ASCENT (MMY2009; NCT03289299) is an ongoing, open-label, multicenter, phase 2 study evaluating the safety and efficacy of DARZALEX + KRd in patients with high-risk-SMM.¹¹ Kumar et al (2020)¹³ provided an initial analysis of safety data for ASCENT. Kumar et al (2022)¹² reported safety and efficacy results of ASCENT study after all patients completed 2 years of treatment.

Study Design/Methods

• This study will include 3 treatment phases: induction, consolidation, and maintenance.
  • Induction phase (4-week cycle for 6 cycles): Patients were administered:
    • Carfilzomib: 56 mg/m² IV on days 1, 8 and 15 of each cycle
    • Lenalidomide: 25 mg oral (PO) on days 1-21 of each cycle
    • Dexamethasone: 40 mg PO on days 1, 8, 15, and 22 of each cycle
    • DARZALEX: 16 mg/kg IV on days 1, 8, 15, and 22 of cycles 1-2; days 1 and 15 of cycles 3-6
  • Consolidation phase (6 cycles): Patients were administered:
    • Same as above for carfilzomib and lenalidomide
    • Dexamethasone: 20 mg on days 1, 8, 15, and 22 of each cycle
    • DARZALEX: 16 mg/kg IV on day 1 of each cycle
  • Maintenance phase (4-week 12 cycles): Patients were administered:
    • Lenalidomide 10 mg PO daily on days 1-21 of each cycle
    • DARZALEX: 16 mg/kg IV on day 1 of every odd cycle
• Key inclusion criteria: patients with adequate marrow and organ function, and untreated HR-SMM with the presence of any 2 of the following (as defined by the IMWG criteria):
  • Serum M spike >2 g/dL or an involved to uninvolved FLC ratio >20 or BMPCs >20%
  • Score of ≥9 using the risk scoring system using FLC ratio, serum M spike, marrow plasma cell percentage and presence of high-risk fluorescence in situ hybridization (FISH)
• Key exclusion criteria: significant comorbidities (e.g., uncompensated heart or lung disease, uncontrolled infection), evidence of current uncontrolled cardiovascular conditions, standard risk smoldering myeloma, light chain amyloidosis with organ involvement, monoclonal gammopathy of undetermined significance, or extramedullary disease
• Primary endpoint: sCR rate
• Secondary endpoints: MRD-negativity after induction, consolidation, and maintenance phase; MRD-negativity at 1 year post treatment; OS; PFS; AEs

Results

Baseline Characteristics and Patient Disposition

• A total of 87 patients were included in this study. A summary of baseline patient characteristics is summarized in Table: Baseline Patients Characteristics.
• Median duration of follow-up was 26.2 (95% CI, 23.8-33.2) months with 31% (n=27) ongoing treatment.
• Median number of cycles administered were 23 (range, 1-24). A total of 55% (n=48) patients completed all 24 cycles.
• Twelve (14%) patients discontinued treatment prior to completion of 24 cycles due to withdrawal by consent (n=3), AEs (n=3), physician decision (n=3), disease progression (n=2), and death (n=1).

Efficacy

• The efficacy outcomes are summarized in the Table: Response Outcomes.
• MRD-negativity was achieved by 84% (n=73) of patients of whom 61% (n=53) were in MRD-negative CR (as per IMWG criteria).
• In the total population (N=87), the median time to MRD-negativity was 6.6 months; of these 53 patients achieved MRD-negativity at the end of induction, 16 after consolidation, and 4 at the completion of maintenance.
• Overall, 3 patients had progressed and the median PFS was not reached.
• The rate of PFS at 3 years was 89.9% (95% CI, 82.3-98.3%).

Safety

• Any grade toxicity possibly related to treatment occurred in 92% (n=81) of patients.
• Grade ≥3 hematological toxicities occurred in 18% (n=16) of patients and non-hematological toxicities occurred in 51% (n=44) of patients. See Table: Grade 3 and 4 Adverse Events.
• The median dose per cycle was 1600 mg for DARZALEX, 210 mg for lenalidomide, 80 mg for dexamethasone, and 312 mg for carfilzomib.

DARZALEX FASPRO in Combination with Bortezomib, Lenalidomide and Dexamethasone

B-PRISM (clinicaltrials.gov identifier: NCT04775550) is an ongoing, open-label, single-arm, multicenter, phase 2 study evaluating the safety and efficacy of DARZALEX FASPRO + VRd (D-VRd) in patients with HR-SMM.¹⁹ Nadeem et al (2024)¹⁴ have reported efficacy analysis results and safety data for B-PRISM, which are summarized below.

Study Design/Methods

• In part 1 of the study, patients will receive the following¹⁴:
  • DARZALEX FASPRO 1800 mg SC on days 1, 8, 15, and 22 for cycles 1 and 2; days 1 and 15 for cycles 3 through 6; and day 1 for each cycle thereafter
  • Bortezomib 1.3 mg/m² SC on days 1, 8, and 15 for cycles 1 through 6 and on days 1 and 15 for each cycle thereafter
  • Lenalidomide 25 mg PO on days 1 to 21 for cycles 1 through 6 and 15 mg PO on days 1 to 21 for each cycle thereafter
  • Dexamethasone 20 mg QW for cycles 1 through 6 and 20 mg on days 1 and 15 for each cycle thereafter
• In part 2 of the study, patients who are MRD-positive after 2 years will be randomized to undergo observation or receive continued therapy with DARZALEX FASPRO and lenalidomide for an additional 24 months.¹⁴
• All eligible patients will undergo stem cell collection after 6 cycles of therapy.¹⁴
• Inclusion criteria ¹⁴:
  • Bone marrow clonal plasma cells ≥10% and any 1 or more of the following:
    • Serum M protein ≥3.0 g/dL
    • Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes
    • Serum involved:uninvolved FLC ratio ≥8 to <100
    • Progressive increase in the M protein level (evolving type of SMM)
    • Bone marrow clonal plasma cells 50-60%
    • Abnormal plasma cell immunophenotype (≥95% of BMPCs are clonal) and reduction of 1 or more uninvolved immunoglobulin isotypes
    • High-risk FISH findings, characterized by the presence of any 1 or more of the following: t(4;14), t(14;16), t(14;20), del 17p, or 1q gain
    • Diffuse abnormalities or 1 focal lesion (≥5 mm) on MRI
    • One focal lesion (≥5 mm) with increased uptake but without underlying osteolytic bone destruction on PET-CT
  • High risk per Mayo 2018 “20-2-20” criteria with 2 of the following 3 criteria:
    • Bone marrow plasmacytosis ≥20%, M protein ≥2 g/dL, and involved:uninvolved serum FLC ratio ≥20
• Primary endpoint: rate of MRD conversion (proportion of patients with HR-SMM who are MRD-negative at 2 years after receiving D-VRd).¹⁴
• Secondary endpoints: Sustained MRD-negativity rate (at 6, 12, 24, and 36 months); PFS; duration of response and OS.¹⁴
• In addition to the primary and secondary endpoints, exploratory endpoints include mass spectrometry quantification of M protein, examination of molecular evolution of tumor cells, and determination of the role of immune cells in SMM progression.¹⁴

Results

Baseline Characteristics

• A total of 45 patients have been enrolled in this study.¹⁴ Patient baseline characteristics are summarized in Table: B-PRISM: Baseline Patient Characteristics.

Efficacy

• Efficacy results were evaluated for patients who completed at least 2 cycles of therapy¹⁴; these are summarized in Table: B-PRISM: Efficacy Results.
• Stem cells were successfully collected from all patients, with a mean stem cell yield of 4.89×10⁶ CD34+ cells/kg.¹⁴
• Granulocyte-colony stimulating factor and plerixafor were used for mobilization.¹⁴
• At a median follow-up of 25 months, the median OS was not reached.¹⁴

Safety

• Among the 45 patients treated, the most common grade 3 toxicities were neutropenia (22%), increased ALT levels (9%), diarrhea (7%), and lung infection (7%).¹⁴
• A summary of all-grade toxicities is presented in Table: B-PRISM: Toxicities.
• One patient was discontinued from therapy due to intolerance.¹⁴

Exploratory Endpoints

• None of the patients experienced SLiM-CRAB progression.¹⁴
• One patient experienced biochemical progression.¹⁴

Phase 2 Study of DARZALEX FASPRO in Combination with Carfilzomib and Dexamethasone

Patel et al (2025)¹⁶ presented the primary results of a phase 2, Simon 2-stage, investigator-initiated study evaluating the efficacy and safety of DKd in patients with HR-SMM.

Study Design/Methods

• This study enrolled patients with HR-SMM diagnosed based on the Mayo Clinic; PETHEMA; and/or Rajkumar, Mateos, and Landgren criteria.¹⁶
• Patients received 8 cycles (28 days) of DKd, which included the following¹⁶
  • DARZALEX FASPRO 1800 mg SC per the United States prescribing information (USPI)
  • Carfilzomib 20 or 56 mg/m² on days 1, 8, and 15
  • Dexamethasone 40 mg on days 1, 8, 15, and 22
• Patients with detectable MRD after 8 cycles of DKd received an additional 4 cycles.¹⁶
• All patients received monthly DARZALEX FASPRO maintenance for 24 cycles.¹⁶
• Responses were assessed by the IMWG criteria, VGPR was confirmed by mass spectrometry, and MRD (10^-5 sensitivity) was assessed using multicolor flow cytometry after cycle 8, cycle 12 (if applicable), and yearly.¹⁶
• A pre-planned interim analysis assessed futility based on MRD-negative sCR rates of ≥55%.¹⁶
• Primary endpoint: MRD-negative sCR.¹⁶

Results

Baseline Characteristics and Patient Disposition

• A total of 14 patients were enrolled between October 21, 2022, and January 22, 2024. Nine (64%) patients met the Mayo 2018 high-risk criteria.¹⁶ Baseline characteristics and patient disposition are presented in Table: Baseline Characteristics.

Efficacy

• At a median follow-up of 2.13 years, 1 patient died of sudden death (cycle 4) and 1 patient withdrew consent (cycle 1).¹⁶
• The ORR in 13 evaluable patients was 100%, with a VGPR of 85% and sCR of 15%.
• Among patients who completed the additional 4 cycles, 1 patient became MRD-negative but remained in VGPR.¹⁶
• One patient had a deepened response after a year of DARZALEX FASPRO maintenance and 2 patients were MRD-negative with a VGPR.¹⁶
• Of the 13 evaluable patients, 5 (38%; 95% CI, 18-65) patients had at least 1 MRD-negative bone marrow result.¹⁶
• Biochemical progression was observed in 1 patient.¹⁶
• No patient developed the SLiM CRAB criteria.¹⁶

Safety

• The grade 3 AEs reported were lymphopenia (n=1), hypertension (n=1), lung infection (n=1), and myocardial infarction (n=1).¹⁶
• No grade 4 AEs were observed.¹⁶

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 24 October 2025.