DARZALEX + DARZALEX FASPRO - Use in Plasma Cell Leukemia

SUMMARY

• DARZALEX/DARZALEX FASPRO are not approved by the regulatory agencies for the treatment of patients with plasma cell leukemia (PCL). Johnson & Johnson does not recommend the use of DARZALEX/DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
• Myeloma UK nine (MUK9) OPTIMUM is a phase 2 study evaluating DARZALEX in combination with cyclophosphamide, bortezomib, lenalidomide, and dexamethasone (D-CVRd) in patients with ultra high-risk multiple myeloma (UHiR MM) and PCL.^1,2
  • Kaiser et al (2023)³ reported the results of the MUK9 OPTIMUM trial at a median follow-up of 41.2 months. The progression-free survival (PFS) rate at 18 months was 81.7%. The most common grade 3/4 adverse events (AEs) across induction and consolidation were neutropenia, thrombocytopenia, and infection.  
  • Kaiser et al (2024)⁴ presented a 5-year PFS and overall survival (OS) analysis of the MUK9 OPTIMUM study. The median PFS and OS were not reached (NR). The PFS estimates for patients with UHiR MM (n=107) at 36, 48, and 60 months were 75.2%, 70.1%, and 61.4%, respectively. At 60 months, the OS estimate was 71.1%. In a subgroup analysis of PCL patients (n=9), the PFS estimates at 36, 48, and 60 months were 44.4%, 33.3%, and 16.7%, respectively.
• EUMELEIA is a phase 2 study evaluating PFS in patients with primary PCL (pPCL) receiving an induction regimen with alternating DARZALEX FASPRO in combination with bortezomib, doxorubicin, and dexamethasone (D-PAD) and DARZALEX FASPRO in combination with cyclophosphamide, bortezomib, and dexamethasone (D-CVD), followed by D-CVD consolidation and maintenance with DARZALEX FASPRO monotherapy.⁵
  • Katodritou et al (2025)⁶ presented the interim analysis results of the EUMELEIA study. Complete response (CR), very good partial response (VGPR), and partial response (PR) were achieved by 21.1%, 73.7%, and 5.3% of patients, respectively. The most common treatment-emergent adverse events (TEAEs) reported were neutropenia (40%), thrombocytopenia (40%), and diarrhea (15%).
• Katodritou et al (2023)⁷ reported results from a real-world retrospective study that evaluated the impact of bortezomib, lenalidomide, and dexamethasone (VRd)/DARZALEX-based quadruplet (DBQ) regimens vs bortezomib standard combinations (BSC)/chemotherapy (CT) in patients with pPCL. Of the 40 patients (37%) in the VRd/DBQ group, 23 received DBQ regimens. In the VRd/DBQ group, the overall response rate (ORR) was 94%, median PFS was 25 months, and median OS was NR.
• Shank et al (2023)⁸ reported results from a single-center retrospective study that evaluated hyperfractionated cyclophosphamide and dexamethasone (HyperCd) alone or in combination with carfilzomib and/or DARZALEX in patients with relapsed/refractory multiple myeloma (RRMM). Of the 97 patients analyzed, 12 had PCL. In patients with PCL who received DARZALEX-based therapies, 2 achieved PR and 2 achieved stable disease (SD).
• Parrondo et al (2021)⁹ reported results from a multicenter retrospective analysis of patients with PCL (pPCL and secondary [sPCL]) who were treated with DARZALEX-based regimens. Of the 68 patients identified with PCL, 28 received DARZALEX-based regimens. The ORR was 68%, PFS was 5 months (95% confidence interval [CI], 2-20), and OS was 8 months (95% CI, 5-21).
• Ge et al (2020)¹⁰ presented results of a retrospective cohort study of patients with pPCL or multiple myeloma (MM) with <20% circulating plasma cells (MM-CPC). Of the 54 patients identified (pPCL, n=38; MM-CPC, n=16), 40.7% of patients received DARZALEX. Median OS was 59.2 months in patients who were exposed to DARZALEX or carfilzomib vs 11.7 months in patients who were not exposed to either agent (P=0.02).
• Several case reports have been published describing patients with PCL who received DARZALEX as part of treatment.^11-22

CLINICAL DATA

Phase 2 Study of D-CVRd for the Treatment of UHiR MM and PCL

MUK9 OPTIMUM (NCT03188172) is a phase 2, multicenter study in the United Kingdom (UK) evaluating the combination of D-CVRd in patients with UHiR MM and PCL.^1,2

Study Design/Methods

The MUK9 OPTIMUM study is comprised of 2 parts:

• MUK9A (OPTIMUMscreen) genetically screened patients with suspected symptomatic MM to determine risk status. UHiR MM was identified by the presence of ≥2 high-risk cytogenetic abnormalities (HRCAs): t(4;14), t(14;16), t(14;20), del(1p), gain(1q), del(17p) or gene expression profiling (GEP; SKY92 signature). Patients identified with UHiR MM or PCL were invited to participate in MUK9B.¹
• MUK9B (OPTIMUMtreat) is a single arm trial in which patients will receive¹:
  • Induction (21-day cycles) with DARZALEX 16 mg/kg intravenous (IV) on days 1, 8, 15 (cycles 1 & 2), then on day 1 only (cycle 3+); cyclophosphamide 500 mg on days 1, 8; bortezomib 1.3 mg/m² on days 1, 4, 8, 11; lenalidomide 25 mg on days 1-14; dexamethasone 20-40 mg on days 1, 4, 8, 11.
  • Autologous stem cell transplant (ASCT) with prior melphalan 200 mg/m² and bortezomib 1.3 mg/m² on day -1, then bortezomib 1.3 mg/m² on days +5, +14.
  • Consolidation part 1 (28-day cycles) with DARZALEX 16 mg/kg on day 1; bortezomib 1.3 mg/m² on days 1, 8, 15, 22; lenalidomide 25 mg on days 1-21; dexamethasone 20-40 mg on days 1, 8, 15, 22.
  • Consolidation part 2 (28-day cycles) with DARZALEX 16 mg/kg on day 1; bortezomib 1.3 mg/m² on days 1, 8, 15; lenalidomide 10 mg on days 1-21.
  • Maintenance (28-day cycles) with DARZALEX 16 mg/kg on day 1; lenalidomide 10 mg on days 1-21.
• Key inclusion criteria: aged ≥18 years, Eastern Cooperative Oncology Group (ECOG) score ≤2.¹
  • MUK9B: confirmed high-risk status, fit for intensive CT and ASCT, previously untreated, measurable disease, alanine aminotransferase and/or aspartate aminotransferase ≤2.5× upper limit of normal (ULN), total bilirubin ≤2 × ULN, creatinine clearance (CrCl) ≥30 mL/min, platelet count ≥75×10⁹/L. (≥50×10⁹/L if myeloma involvement in the bone marrow is >50%), absolute neutrophil count (ANC) ≥1.0×10⁹/L, hemoglobin ≥8 g/dL.
• Key exclusion criteria: confirmed solitary bone/solitary extramedullary plasmacytoma; primary diagnosis of amyloidosis; monoclonal gammopathy of undetermined significance; smoldering MM or Waldenstrom’s disease; prior or concurrent invasive malignancies; any clinically significant cardiac disease; known chronic obstructive pulmonary disease (COPD); polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome; seropositive for human immunodeficiency virus (HIV), or known active hepatitis B, or hepatitis C.¹
• Primary objective: MUK9A, risk status turnaround time within 8 weeks; MUK9B, PFS.¹
• Key secondary objectives: safety, minimal residual disease (MRD)-negativity at 10^-5 sensitivity, OS.¹

Updated Analysis of the MUK9 OPTIMUM Study

Kaiser et al (2023)³ reported the results of the MUK9 OPTIMUM trial at a median follow-up of 41.2 months.

Results

Patient Characteristics

• Between September 2017 and July 2019, 412 patients with confirmed symptomatic MM or PCL were recruited across 39 UK hospitals.³
• Genetic risk profiles were successfully generated in 359 patients (87%), with partial results for an additional 24 patients (6%).³
• Median risk status turnaround time was 18 days (range, 0-37).³
• Ultra high-risk features were detected in 138 patients, and 107 of these patients (PCL, n=9) consented and were eligible for MUK9B OPTIMUM(treat).³
• Baseline characteristics are presented in Table: Select Baseline Characteristics.²

Efficacy

• At 18 months, 84/103 patients (81.7%) were alive and progression-free.³
• The 30-month estimated PFS rate was 77.0% (95% CI, 68.8-85.1).³
• The 30-month estimated OS rate was 83.5% (95% CI, 76.4-90.7).³
• At the median follow-up of 41.2 months, both PFS and OS were NR.³
• Response rates are summarized in Table: Maximum Response Rates in Patients with UHiR MM and PCL.³

• At the end of induction, 44 patients (41.1%) achieved MRD negativity (10^-5). By 100-120 days post-ASCT, 68 patients (63.6%) were MRD-negative (10^-5).³

Safety

• The most frequent grade 3/4 AEs during induction were neutropenia (21%), thrombocytopenia (12%), and infection (12%). See Table: Grade ≥2 AEs During Induction.²

• Of the 85 patients that completed consolidation part 1, the most common grade 3/4 AEs were thrombocytopenia (28.2%), neutropenia (21.2%), and infection (18.8%).²³
• Of the 80 patients what completed consolidation part 2, the most common grade 3/4 AEs were neutropenia (43.8%), thrombocytopenia (27.5%), and infection (15%).³

Phase 2 Study of Alternating D-PAD/D-CVD Induction, D-CVD Consolidation and DARZALEX FASPRO Maintenance for pPCL Treatment

EUMELEIA (NCT06636552) is a phase 2, prospective, open-label, single-arm, multicenter study evaluating the efficacy of the alternating D-PAD and D-CVD induction regimen followed by D-CVD consolidation and maintenance with DARZALEX FASPRO monotherapy in terms of PFS in the frontline setting of pPCL.⁵

Study Design/Methods

• EUMELEIA is a single-arm trial in which patients will receive the following⁵:
  • Induction: 6 cycles (21-day cycles) of alternating D-PAD and D-CVD.
    • For D-PAD (cycles 1, 3, and 5): DARZALEX FASPRO 1800 mg subcutaneous (SC) once weekly (QW) on days 1, 8, and 15 in cycles 1 and 3 and 1800 mg SC once every 3 weeks (Q3W) on day 1 in cycle 5.
    • For D-CVD (cycles 2, 4, 6,): DARZALEX FASPRO 1800 mg SC QW on days 1, 8, and 15 in cycle 2 and 1800 mg  SC Q3W on day 1 in cycles 4, and 6.
  • Consolidation: 2 cycles (21-day cycles) of D-CVD; DALZALEX FASPRO 1800 mg SC Q3W on day 1 of cycle 7 and 8.
  • Maintenance: 24 cycles (28-day cycles) of DARZALEX FASPRO monotherapy (cycles 9 to 32) with DARZALEX FASPRO 1800 mg SC once every 4 weeks (Q4W) on day 1 in patients who have achieved a PR or better (≥PR) at the end of the consolidation phase (cycle 8).
  • End-of-treatment visit: 30±7 days after discontinuation of all study treatment components.
  • Post treatment follow-up: initiated upon permanent discontinuation of study treatment.
• Key inclusion criteria: age 18 to 80 years; performance status ≤3; newly diagnosed pPCL according to International Myeloma Working Group (IMWG) diagnostic criteria of pPCL (≥5% and/or absolute count ≥0.5×10³/µL circulating plasma in peripheral blood (PB) smear or next generation flow cytometry); measurable disease; adequate bone marrow (BM)/renal/lever function.⁶
• Key exclusion criteria: severe cardiac/pulmonary dysfunction.⁶
• Primary endpoint: PFS.⁵

Interim Analysis of the EUMELIA Study

Katodritou et al (2025)⁶ presented the interim analysis results of the EUMELEIA study.

Results

Patient Characteristics

• A total of 20 patients across 6 hematological centers in Greece were enrolled in the study between November 2021 and December 2023.⁶
• The median time from diagnosis to treatment initiation was 11.5 days (range, 3-44).⁶
• Among the 20 patients enrolled, 19 completed the 6-cycle induction phase and were evaluated within 7 days after induction.⁶
• Patients baseline characteristics are presented in Table: Baseline Characteristics.⁶

Efficacy

• Among 19 evaluable patients, CR, VGPR, and PR were achieved by 4 patients (21.1%), 14 patients (73.7%), and 1 patient (5.3%), respectively.⁶
  • Responses after induction and the best overall responses throughout the induction phase are summarized in Tables: Responses to Study Treatment After Induction and Best Overall Responses Throughout the Induction Phase.

• Two of 5 assessed patients achieved MRD-negativity in the bone marrow, and all 7 patients achieved MRD-negativity in the peripheral blood.⁶
  • The MRD status is summarized in Table: MRD Status in BM and PB.

Safety

• Most common grade ≥3 AEs were cytopenias (n=7) and infections (n=4). TEAEs are summarized in Table: Safety Outcomes.
• One patient died due to respiratory tract infection (not related to the treatment) 30 days after baseline.⁶

Retrospective Analysis of Treatment of pPCL With VRd or DBQ Regimens

Katodritou et al (2023)⁷ reported results from a real-world retrospective study that evaluated the impact of VRd/DBQ regimens vs BSC/CT in patients with pPCL.

Study Design/Methods

• Medical records of patients with pPCL registered in the Greek Myeloma Study Group (GMSG) database between 2001 and 2021 were analyzed.⁷
• pPCL was defined as circulating plasma cells (cPCs) in the peripheral blood accounting for ≥5% of the differential white cell count, as proposed by the new IMWG diagnostic criteria for pPCL.⁷
• Outcomes assessed included response rates, OS, PFS, and safety.⁷

Results

• A total of 110 patients who fulfilled the criteria for pPCL were identified.⁷
• The median age was 65 years (range, 44-86).⁷
• The median number of lines of treatment was 1 (range, 1-5).⁷
• A total of 40 patients (37%) received VRd (n=17)/DBQ (n=23) regimens (VRd, n=17; DARZALEX with bortezomib, cyclophosphamide, and dexamethasone [D-VCd], n=14; DARZALEX with bortezomib, thalidomide, and dexamethasone [D-VTd], n=5; and DARZALEX with VRd [D-VRd], n=4), and 70 patients (64%) received BSC/CT regimens (BSC, n=58 and CT, n=12) as first-line treatment.⁷
  • In the VRd/DBQ vs BSC/CT group, ORR, CR, and VGPR were achieved in 94% vs 77%, 41% vs 17%, and 19% vs 26% of patients, respectively.
• A total of 51 patients (46%) received second-line treatment, of whom, 42 received novel agent combinations (lenalidomide-based regimens, n=17; proteasome inhibitor (PI)-based regimens, n=12; DARZALEX-based regimens, n=9; and pomalidomide-based regimens, n=4).⁷
  • After a median follow-up of 51 months, in the VRd/DBQ vs BSC/CT group, the median OS was NR vs 20 months (95% CI, 14-26; P<0.001); the 3-year OS rate was 70% vs 32%, and the median PFS was 25 months (95% CI, 13.5-36.5) vs 13 months (95% CI, 9-16.8; P=0.03; HR, 0.28).
• During the first-line treatment, in the VRd/DBQ vs BSC/CT group, grade 3/4 neutropenia, anemia, and grade 3/4 myelosuppression were reported in 12% vs 42% (P=0.01), 6% vs 44% (P=0.003), and 16% vs 42% (P=0.03) of patients, respectively. Overall, 4 patients had pneumonia due to cytomegalovirus (CMV) reactivation, of whom, 3 were treated with DBQ regimens.⁷

Retrospective Analysis of Treatment of PCL With HyperCd, Alone or With Carfilzomib and/or DARZALEX

Shank et al (2023)⁸ reported results from a single-center retrospective study that evaluated HyperCd, alone or in combination with carfilzomib and/or DARZALEX in patients with RRMM.

Study Design/Methods

• Adult patients with RRMM or PCL, who received at least 1 dose of HyperCd, alone or in combination with DARZALEX or with carfilzomib between May 1, 2016 and August 1, 2019 at the University of Texas MD Anderson Cancer Centre were included.⁸
• Primary objective: ORR (defined as the rate of patients achieving a best overall response of CR, VGPR, or PR).⁸
• Secondary objectives: PFS and OS, treatment characteristics (doses received, number of cycles, and time between cycles), rates of complications from the treatment, associated rates of hospitalization, and treatment-related mortality (TRM).⁸

Results

• The median follow-up was 32.2 months (95% CI, 24.1-NR) across all treatment groups.⁸
• Of the 97 patients included, 12 had PCL (HyperCd, n=2; HyperCdK, n=6; D-HyperCd, n=1; and D-HyperCdK, n=3).⁸
• In the DARZALEX-based regimens (D-HyperCd and D-HyperCdK), patients received a median of 2 DARZALEX doses per cycle (range, 1-4 in both groups).⁸
• Response outcomes in patients with PCL in the treatment groups were as follows⁸:
  • HyperCd group: 1 achieved PR and 1, SD.
  • HyperCdK group: 1 achieved VGPR; 2, PR; 1, SD; and 2 were not evaluable for response.
  • D-HyperCd group: 1 achieved PR.
  • D-HyperCdK group: 1 achieved PR and 2, SD.
• In the PCL vs overall population, median PFS was 2.6 months (95% CI, 1.05-NR) vs 5.0 months (95% CI, 3.68-6.8); P=0.009.⁸
• In the PCL vs overall population, median OS was 5.1 months (95% CI, 1.91-NR) vs 11.3 months (95% CI, 8.57-15.31); P=0.020.⁸
• Based on a univariate analysis, PCL was a predictor of worse median PFS (P=0.009).⁸
• Overall, 4 patients with PCL died within 60 days of treatment.⁸
• In the D-HyperCd vs D-HyperCdK group, grade 3/4 anemia, neutropenia, and thrombocytopenia were reported in 13 (68.4%) vs 18 (66.7%), 14 (73.7%) vs 19 (70.4%), and 12 (63.2%) vs 20 (74.1%) patients, respectively.⁸

Retrospective Analysis of the Treatment of PCL With DARZALEX-based Regimens

Parrondo et al (2021)⁹ reported the results from a multicenter retrospective analysis of patients with PCL who were treated with DARZALEX-based regimens.

Study Design/Methods

• Medical records of patients with pPCL and sPCL treated at the Mayo Clinic Cancer Center between January 2012 and June 2019 were analyzed.⁹
• PCL was defined as cPCs ≥5% or ≥0.5 x 10⁹/L, as proposed by the IMWG.⁹
• Objectives measured included response rate, PFS, and OS.⁹

Results

• Of the 68 patients with PCL who were identified, 28 received DARZALEX-based regimens.⁹
• Median age at PCL diagnosis was 67 years (range, 38-83).⁹
• Median follow-up from PCL diagnosis was 26 months (95% CI, 13-61) and 17 months (95% CI, 10-23) from initiation of DARZALEX.⁹
• DARZALEX-based induction was given to 4 patients with primary PCL while the remaining patients had relapsed/refractory disease.⁹
• Since the start of DARZALEX-based treatment, PFS was 5 months (95% CI, 2-20).⁹
  • PFS was longer in patients with pPCL vs sPCL (20 vs 2.5 months; hazard ratio [HR], 0.27; 95% CI, 0.09-0.76; P=0.013).
• After DARZALEX-based therapy, OS was 8 months (95% CI, 5-21).⁹
  • OS was longer in patients with pPCL vs sPCL (21 vs 5 months; HR 0.33; 95% CI, 0.12-0.91; P=0.032).
• ORR to DARZALEX-based regimens was 68% (n=19).⁹
  • Patients with pPCL and sPCL achieved ORR of 79% and 57%, respectively.
• ≥VGPR was achieved in 32% (n=9) of patients.⁹
  • ≥VGPR was observed in 50% of patients with pPCL and 14% with sPCL.
• At a landmark survival analysis of 3 months, patients who achieved ≥PR experienced longer PFS (6 vs 1 month, P=0.002) and OS (21 vs 1 month, P<0.0001) compared to patients who experienced less than a PR.⁹

Outcomes of PCL Patients Treated With Novel Agents Including DARZALEX

Ge et al (2020)¹⁰ presented a single-center, retrospective cohort study of patients with pPCL (cPCs ≥20% or 2.0 x 10⁹/L) or MM-CPC at a median follow-up of 28.1 months.

Study Design/Methods

• Patients with primary PCL or MM-CPC treated at the institution between January 1, 2000 and July 17, 2020 were identified.¹⁰
• Outcomes assessed included ORR, OS, and PFS.¹⁰

Results

• Fifty-four patients with pPCL (n=38) or MM-CPC (n=16) were identified.¹⁰
• Median age at diagnosis for the pPCL and MM-CPC groups was 59.2 years (range 43-94) and 59.8 years (range 29-79), respectively.¹⁰
• Fifty patients (92.6%) were exposed to bortezomib, 45 (83.3%) to lenalidomide, 33 (61.1%) to carfilzomib, 22 (40.7%) to DARZALEX, 13 (24.1%) to pomalidomide, and 4 (7.4%) to venetoclax.¹⁰
• ≥PR was achieved in 76.7%, 62.8%, and 37.9% of patients to first-, second-, and third-line therapy, respectively.¹⁰
• At a median follow-up of 28.1 months, median OS was 34.5 and 35.5 months (P=0.97) for the pPCL and MM-CPC groups, respectively. Median PFS was 13.9 and 10.9 months (P=0.52), respectively.¹⁰
• Median OS was 59.2 months in patients who were exposed to DARZALEX or carfilzomib (n=37) vs 11.7 months in patients who were not exposed to either agent (n=17, P=0.02).¹⁰

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File(and/or other resources, including internal/external databases) was conducted on 09 October 2025.