DARZALEX + DARZALEX FASPRO - Use in High-Risk Smoldering Multiple Myeloma

Summary

• Johnson & Johnson 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
  • Dimopoulos et al (2024)^1,2 reported primary results of the AQUILA study. 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. Grade 3/4 adverse events (AEs) occurred in 40.4% vs 30.1% of patients from the DARZALEX FASPRO vs active monitoring group, respectively.
• 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-SMM.³
  • Landgren et al (2025)⁴ 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). Grade 3/4 treatment-emergent AEs (TEAEs) occurred in 65.9%, 41.5%, and 15.0% of patients in the long intense, intermediate, and short intense groups, respectively.
• GEM-CESAR is a phase 2 study evaluating biochemical progression following treatment with carfilzomib, lenalidomide, and dexamethasone (KRd). Patients who experienced biochemical relapse/progression were given the option to receive DARZALEX FASPRO in combination with pomalidomide and dexamethasone (D-Pd).⁵ 
  • Mateos et al (2025)⁶  presented the results in patients who received D-Pd as early intervention. The ORR in these patients was 90%. The most common hematologic AE was neutropenia (any grade: 76%; grade 3/4: 69%).
• ASCENT is a phase 2 study evaluating the safety and efficacy of DARZALEX in combination with carfilzomib, lenalidomide, and dexamethasone (D-KRd) in patients with HR-SMM.^7,8
  • Kumar et al (2026)⁹ presented updated efficacy and safety data from the study at a median follow-up of 52.4 months. The best ORR was 98%, with 94% of patients achieving very good partial response or better (≥VGPR). The most common grade 3/4 AEs were neutropenia, hypertension, and pneumonia.
• B-PRISM is a phase 2 study evaluating the safety and efficacy of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) in patients with HR-SMM.¹⁰ 
  • Nadeem et al (2024)¹¹ presented results of the B-PRISM study. The ORR in patients who completed at least 2 cycles of therapy was 98%. The most common grade 3 toxicities were neutropenia (22%), increased alanine transaminase (ALT; 9%), diarrhea (7%), and lung infection (7%).
• Patel et al (2025)¹² presented the primary results of a phase 2, Simon 2-stage, investigator-initiated study evaluating the efficacy and safety of DARZALEX FASPRO in combination with carfilzomib and dexamethasone (D-Kd) in patients with HR-SMM. The ORR achieved was 100%. Two patients had undetectable minimal residual disease (MRD)-negativity with a VGPR. The grade 3 AEs reported were lymphopenia, hypertension, lung infection, and myocardial infarction. No grade 4 AEs were reported.

PRODUCT LABELING

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

CLINICAL studies

Phase 3 Study of DARZALEX FASPRO Monotherapy

AQUILA (SMM3001; NCT03301220) is a phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of DARZALEX FASPRO versus active monitoring in patients with HR-SMM.¹ 

Study Design/Methods

• Key eligibility criteria: ≥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 0-1, clonal bone marrow plasma cells (BMPCs) ≥10% and ≥1 of the following risk factors¹:
  • Serum myeloma protein (M-protein) ≥30 g/L
  • Immunoglobulin (Ig) A SMM
  • Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes
  • Serum involved:uninvolved free light chain (FLC) ratio ≥8 to <100
  • Clonal BMPCs >50% to <60%
• Primary endpoint: progression-free survival (PFS) by independent review committee (IRC) per IMWG SLiM-CRAB diagnostic criteria for MM.¹
• Key Secondary endpoints: ORR, CR rate, progressive disease (PD) 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.^1,2

Primary Results of the AQUILA Study

Dimopoulos et al (2024)^1,2 reported primary results of the AQUILA study at a median follow-up of 65.2 months (range, 0-76.6).

Results

Patient Characteristics

• Baseline characteristics were generally balanced between DARZALEX FASPRO and active monitoring groups.¹
  • 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.
• 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.^1,2
• 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 reasons²:
  • Death: 15 (7.7%) vs 26 (13.3%) patients, respectively.¹
  • Withdrawal by patient: 12 (6.2%) vs 23 (11.7%) patients, respectively.¹
  • Lost to follow-up: 1 (0.5%) vs 1 (0.5%) patients, respectively.²
  • Other reasons: 2 (1.0%) vs 1 (0.5%) patients, respectively.²

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.²
  • At a median follow-up of 65.2 months, the median PFS was not reached (NR) in the DARZALEX FASPRO group and was 41.5 months in the active monitoring group.²
  • The 5-year PFS rate was 63.1% vs 40.8% in the DARZALEX FASPRO vs active monitoring group, respectively.¹
• Patients identified as having a high risk per Mayo 2018 criteria experienced a greater PFS improvement with DARZALEX FASPRO.²
• A retrospective review of high risk per Mayo 2018 criteria showed that the median PFS was NR for the DARZALEX FASPRO group and was 22.1 months for the active monitoring group (HR, 0.36; 95% CI, 0.23-0.58).²
• 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).¹
  • 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.¹
• For a comparison of clinical outcomes between the DARZALEX FASPRO and active monitoring groups, see Table: Clinical Outcomes – ITT Population.^1,2,13

• The DARZALEX FASPRO group had an ORR of 63.4% vs 2.0% in the active monitoring arm (relative risk ratio, 31.00; 95% CI, 13.05-101.03; P<0.001).¹³ 
• DARZALEX FASPRO prolonged the time to first-line treatment for MM vs active monitoring (HR, 0.46; 95% CI, 0.33-0.62).²
  • 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.²
  • 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.¹
• DARZALEX FASPRO improved PFS on first-line treatment for MM vs active monitoring (HR, 0.58; 95% CI, 0.35-0.96).²
  • The most common first-line treatment for MM was bortezomib, lenalidomide, and dexamethasone (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 overall survival (OS) vs active monitoring (HR, 0.52; 95% CI, 0.27-0.98).²

Safety

• No new safety events were identified in the DARZALAEX FASPRO group. The safety overview is presented in Table: Summary of AEs - Safety Population.¹
  • The median duration of AE reporting was 35 vs 26 months in the DARZALEX FASPRO vs active monitoring group, respectively.²
  • The median duration of grade 3/4 infections was 9 days in the DARZALEX FASPRO group and 5 days in the active monitoring group; the majority were recovered or resolved.²
  • The frequency of second primary malignancies was similar between the DARZALEX FASPRO and active monitoring groups (9.3% and 10.2%, respectively).²

• Serious AEs occurred in 29.0% of patients in the DARZALEX FASPRO arm vs 19.4% of patients in the active monitoring arm.¹ 
  • 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.¹

Phase 2 Study of DARZALEX Monotherapy in Intermediate- or HR-SMM

CENTAURUS (SMM2001; NCT02316106) is a phase 2, randomized, open-label, multicenter study evaluating the safety and efficacy of 3 dose schedules of DARZALEX monotherapy in patients with previously untreated intermediate-risk SMM or HR-SMM.

Study Design/Methods

• Patients were randomized based on the number of risk factors (<2 vs ≥2) for progression to symptomatic MM.³
• Patients received 1 of 3 DARZALEX dosing schedules: extended intense (intense), extended intermediate (intermediate), and short.³
• Intense: Patients were administered DARZALEX 16 mg/kg intravenously (IV) weekly (QW) for cycle 1, every 2 weeks (Q2W) for cycles 2-3, every 4 weeks (Q4W) for cycles 4-7, and every 8 weeks (Q8W) for cycles 8-20.³
• Intermediate: Patients were administered DARZALEX 16 mg/kg IV QW for cycle 1 and Q8W for cycles 2-20.³
• Short: Patients were administered DARZALEX 16 mg/kg IV QW for cycle 1.³
• Pre-infusion medications included methylprednisolone 60-100 mg, diphenhydramine 25-50 mg, acetaminophen 650-1000 mg, and montelukast 10 mg (optional).³
• Key inclusion criteria: diagnosis of SMM for <5 years and an ECOG performance score of 0 or 1, BMPCs ≥10% to <60% and ≥1 of the following³:
  • 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 criteria: 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 magnetic resonance imaging (MRI), calcium elevation, renal insufficiency by creatinine clearance, anemia, or bone disease (CRAB) due to lytic bone lesions.³
• Coprimary endpoints: CR rate in each trial arm, and rate of PD/death per patient-year.⁴
• Secondary endpoints: ORR, PFS, OS, subsequent MM treatment, response to first subsequent MM treatment, biochemical progression, and safety.⁴

Final Analysis of the CENTAURUS Study

Landgren et al (2025)⁴ reported the final analysis efficacy and safety analysis of the CENTAURUS study at a median follow-up of 85.2 months (range, 0-94.3).

Results

Patient Characteristics

• A total of 123 patients were randomly assigned to treatment, with 41 patients assigned to each of the 3 treatment arms.^4,14 
  • The baseline characteristics were well balanced across the 3 arms as summarized in Table: Baseline Demographics and Disease Characteristics.⁴
  • Patient disposition in the 3 treatment arms is summarized in Table: Patient Disposition.¹⁴

• Among the 123 patients, 55 patients (44.7%; 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.⁴
  • In the long intense and intermediate treatment arms, 16/30 patients (53.3%) and 10/25 patients (40.0%), respectively, switched from DARZALEX to DARZALEX FASPRO in the extension phase.⁴
• 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.⁴
• 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.⁴

Efficacy

• The ORR was higher in the long intense and intermediate treatment arms compared with the short intense treatment arm as summarized in Table: Response Rates.⁴

• At the final analysis, patients across all 3 treatment arms had experienced PD and progression events as detailed in Table: Summary of Progression Events.¹⁴
  • 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).⁴

• The PFS and OS across the 3 treatment arms are summarized in Table: PFS and OS.⁴

• In the per-protocol phase including the extension phase, time to next treatment was NR in the long intense and intermediate treatment arms and was 76.3 months (90% CI, 40.4-80.3) in the short intense arm.⁴
• A total of 93 patients (75.6%) across all 3 treatment arms experienced biochemical progression and of these, 57 patients (61.3%) progressed to active MM.⁴
  • One patient had PD per the investigator’s diagnosis 1 month before biochemical progression and 35/93 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.^4,14

• 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.⁴
• Among the 35 patients who did not progress to active MM, 1 (2.9%) received further treatment, and all were alive at study completion.⁴

Safety

• No new safety concerns were reported with extended DARZALEX exposure.⁴
  • 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.⁴

• 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).⁴
  • 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.⁴
• Simultaneously, DARZALEX treatment increased the frequency and absolute number of T cells (CD45⁺CD3⁺) in each treatment arm.⁴

Phase 2 Study of DARZALEX FASPRO in Combination with Pd for HR SMM

GEM-CESAR is a phase 2, open-label, multicenter study evaluating biochemical progression following treatment with KRd. Patients who experienced biochemical relapse/progression were given the option to receive D-Pd.⁵

Study Design/Methods

• Patients with high-risk SMM were treated with 6 cycles of KRd induction, followed by high-dose melphalan, autologous stem cell transplant (ASCT), 2 cycles of KRd consolidation, and lenalidomide and dexamethasone (Rd) maintenance.⁶
• Patients who were identified to be in biochemical relapse/progression (biochemical progressive disease with no myeloma defining event, relapse from complete response, or relapse from MRD-negativity) were provided the option for early rescue intervention with D-Pd.⁶
• Dosing schedule⁶:
  • DARZALEX FASPRO: 1800 mg subcutaneously (SC) QW for cycles 1-2, Q2W for cycles 3-6, and Q4W for cycle 7 onward
  • Pomalidomide: 4 mg orally (PO) on days 1-21
  • Dexamethasone: 40 mg PO on days 1, 8, 15, 22 (20 mg if >75 years old)

Analysis of Patients Who Received D-Pd in the GEM-CESAR Study

Mateos et al (2025)⁶ presented the results in patients who received D-Pd as early intervention at a median follow-up of 45.4 months (range, 3.2-70.2) from inclusion in the early rescue intervention phase.

Results

Patient Characteristics

• Of the 90 patients in the intent-to-treat (ITT) population, 43 patients progressed (biochemical progression without myeloma defining event [28%], relapse from complete response [60%], relapse from MRD-negativity [12%]).⁶
  • Of the patients in biochemical relapse/progression, 29 were treated with D-Pd.
• Patients received a median of 28 cycles (range, 6-56) of D-Pd.⁶
• Baseline characteristics of the patients who experienced biochemical relapse/progression are summarized in Table: Baseline Characteristics.⁶

Efficacy

• Efficacy outcomes in patients who received D-Pd based on type of biochemical relapse/progression are summarized in Table: Response Rates by Type of Biochemical Relapse/Progression.⁶

• By 50 months, 95% of patients were progression-free, with 74% of patients biochemical progression-free.⁶
  • The median time to biochemical progression was 62 months.
• At a median follow-up of 45.4 months (range, 3.2-70.2) from inclusion in the early rescue intervention phase, the 50-month OS rate was 85%.⁶

Safety

• The most common hematologic AE in patients receiving D-Pd was neutropenia as summarized in Table: Safety Summary.⁶

• The most common reason for discontinuation was progression (n=10).⁶
• Three patients died (disease progression after discontinuing D-Pd because of biochemical progression [n=2] and ischemic stroke during D-Pd treatment [n=1]).⁶
• One patient developed cerebellar meningioma as a potential secondary primary malignancy.⁶

Phase 2 Study of DARZALEX in Combination with KRd in HR SMM

ASCENT (MMY2009; NCT03289299) is a phase 2, open-label, multicenter study evaluating the safety and efficacy of DARZALEX in combination with KRd in patients with high-risk-SMM.^7,8

Study Design/Methods

• Key inclusion criteria: adequate marrow and organ function, HR-SMM defined as the presence of either of the following (as defined by the IMWG criteria)^7,8:
  • Any 2 of the following: 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, BMPC percentage, and presence of high-risk fluorescence in situ hybridization (FISH)
• Key exclusion criteria: significant comorbidities, evidence of amyloidosis.^7,8
• This study included 3 treatment phases: induction, consolidation, and maintenance.^7,8
  • Induction phase (4-week cycles for 6 cycles):
    • DARZALEX: 16 mg/kg IV QW for cycles 1-2; Q2W for cycles 3-6
    • Carfilzomib: 36 mg/m² IV Q2W or 56 mg/m² IV QW
    • Lenalidomide: 25 mg PO on days 1-21 of each cycle
    • Dexamethasone: 40 mg QW
  • Consolidation phase (4-week cycles for 6 cycles):
    • DARZALEX: 16 mg/kg IV Q4W
    • Same as above for carfilzomib and lenalidomide
    • Dexamethasone: 20 mg QW
  • Maintenance phase (4-week cycles for 12 cycles):
    • Lenalidomide 10 mg PO daily on days 1-21 of each cycle
    • DARZALEX: 16 mg/kg IV Q8W
• Primary endpoint: stringent complete response (sCR) rate.^7,8
• Secondary endpoints: MRD-negativity (10^-5) after induction, consolidation, and maintenance phase; MRD-negativity (10^-5) at 1 year post treatment; OS; PFS; AEs.^7,8

Updated Efficacy and Safety Analysis of the ASCENT Study

Kumar et al (2026)⁹ presented updated efficacy and safety data from the study at a median follow-up of 52.4 months (95% CI, 49.2-60.5).

Results

Patient Characteristics

• A total of 87 patients were included in this study. A summary of baseline patient characteristics is summarized in Table: Baseline Patients Characteristics.⁹

• At the time of the analysis, all patients were no longer receiving active treatment; 70 patients (80%) completed all 24 cycles.⁹
• The median number of cycles administered was 24 (range, 1-24).⁹
• A total of 17 patients discontinued study treatment prior to completion (withdrawal [n=3], AE [n=4], physician decision [n=2], progression [n=4], death [n=3], and unknown [n=1]).⁹

Efficacy

• The best ORR was 98% (94% ≥VGPR) as summarized in Table: Response Outcomes.⁹

• MRD negativity (10^-5;≥CR) was achieved by 52 patients (60%).⁹
  • Of 28 patients who achieved VGPR, 22 (79%) were MRD-negative in the marrow via next-generation flow cytometry (NGF).
• MRD responses after induction, consolidation, maintenance, and 1-year post-treatment are summarized in Table: MRD Negativity Over Time.⁹

• The median PFS was not estimable (NE; 95% CI, NE-NE). At 3 years, the PFS rate was 89.9% (95% CI, 82.3-98.3).⁹
• Among patients with MRD-negativity, 7 progressed; an additional 3 patients became MRD positive, but did not meet criteria for PD.⁹
• The median OS was NE (95% CI, NE-NE).⁹
  • There were 5 patient deaths (cardiac arrest [n=2], COVID-19 [n=1], plasma cell leukemia/relapsed disease [n=1], unknown [n=1]).

Safety

• Any grade toxicities possibly related to treatment occurred in 81 patients (92%).⁹
• Grade ≥3 hematological toxicities occurred in 17 patients (20%) and non-hematological toxicities occurred in 52 patients (60%). See Table: Grade 3 and 4 Adverse Events.⁹

Phase 2 Study of DARZALEX FASPRO in Combination with VRd in HR-SMM

B-PRISM (NCT04775550) is a phase 2, open-label, single-arm, multicenter study evaluating the safety and efficacy of D-VRd in patients with HR-SMM.¹¹

Study Design/Methods

• In part 1 of the study, patients will receive the following¹¹:
  • 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.¹¹
• All eligible patients will undergo stem cell collection after 6 cycles of therapy.¹¹
• Inclusion criteria¹¹:
  • 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).¹¹
• Secondary endpoints: Sustained MRD-negativity rate (at 6, 12, 24, and 36 months); PFS; duration of response and OS.¹¹
• 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.¹¹

Primary Analysis of the B-PRISM Study

Nadeem et al (2024)¹¹ have reported efficacy analysis results and safety data for B-PRISM, which are summarized below.

Results

Baseline Characteristics

• A total of 45 patients have been enrolled in this study. Patient baseline characteristics are summarized in Table: B-PRISM: Baseline Patient Characteristics.¹¹

Efficacy

• Efficacy results were evaluated for patients who completed at least 2 cycles of therapy; these are summarized in Table: B-PRISM: Efficacy Results.¹¹

• Stem cells were successfully collected from all patients, with a mean stem cell yield of 4.89×10⁶ CD34+ cells/kg.¹¹
• Granulocyte-colony stimulating factor and plerixafor were used for mobilization.¹¹
• At a median follow-up of 25 months, the median OS was not reached.¹¹

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%).¹¹
• A summary of all-grade toxicities is presented in Table: B-PRISM: Toxicities.¹¹
• One patient was discontinued from therapy due to intolerance.¹¹

Exploratory Endpoints

• None of the patients experienced SLiM-CRAB progression.¹¹
• One patient experienced biochemical progression.¹¹

Phase 2 Study of DARZALEX FASPRO in Combination with Kd for HR-SMM

Patel et al (2025)¹² 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.¹²
• Patients received 8 cycles (28 days) of D-Kd, which included the following¹²:
  • 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 D-Kd received an additional 4 cycles.¹²
• All patients received monthly DARZALEX FASPRO maintenance for 24 cycles.¹²
• 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.¹²
• A pre-planned interim analysis assessed futility based on MRD-negative sCR rates of ≥55%.¹²
• Primary endpoint: MRD-negative sCR.¹²

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. Baseline characteristics and patient disposition are presented in Table: Baseline Characteristics.¹²

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).¹²
• 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.¹²
• One patient had a deepened response after a year of DARZALEX FASPRO maintenance and 2 patients were MRD-negative with a VGPR.¹²
• Of the 13 evaluable patients, 5 (38%; 95% CI, 18-65) patients had at least 1 MRD-negative bone marrow result.¹²
• Biochemical progression was observed in 1 patient.¹²
• No patient developed the SLiM CRAB criteria.¹²

Safety

• The grade 3 AEs reported were lymphopenia (n=1), hypertension (n=1), lung infection (n=1), and myocardial infarction (n=1).¹²
• No grade 4 AEs were observed.¹²

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 01 July 2026.