SUMMARY

• DARZALEX is not approved by the regulatory agencies for the treatment of patients with plasma cell leukemia (PCL). Janssen does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
• Myeloma UK nine (MUK9) OPTIMUM (NCT03188172)^1,2 is a phase 2 study evaluating the combination of DARZALEX, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone (D-CVRd) in patients with high-risk multiple myeloma (HiR MM) and PCL.
  • Kaiser et al (2021)³ presented results of patients with HiR MM and PCL treated with D-CVRd induction, augmented high-dose melphalan (HDMEL), and autologous stem cell transplant (ASCT) in the MUK9 OPTIMUM trial. Overall response rate (ORR) was 94% and 83% at the end of induction and 100-120 days post-ASCT, respectively. The most frequent grade 3/4 adverse events (AEs) during induction were neutropenia (21%), thrombocytopenia (12%), and infection (12%).
  • Jenner et al (2020)⁴ presented feasibility results of MUK9 OPTIMUM trial. Central bone marrow cluster of differentiation 138+ (CD138+) genetic and gene expression profiling (GEP) risk profiles were successfully generated in 93% of patients. Median risk status turnaround time was 18 (interquartile range [IQR], 13-22) days.
• EUMELEIA (NCT06636552)⁵ is an ongoing, prospective, multicenter, phase 2, open-label, single-arm clinical study evaluating the progression-free survival (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 in frontline setting of pPCL.
• Katodritou et al (2023)⁶ 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 (37%) patients who received VRd/DBQ regimens, 23 received DBQ regimens. In the VRd/DBQ group, ORR was 94%, median PFS was 25 months, and median overall survival (OS) was not reached (NR).
• Shank et al (2023)⁷ 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 (HyperCd, n=2; hyperfractionated cyclophosphamide, dexamethasone and carfilzomib [Hyper-CdK], n=6; DARZALEX with hyperfractionated cyclophosphamide and dexamethasone [D-HyperCd], n=1; and DARZALEX with hyperfractionated cyclophosphamide, dexamethasone and carfilzomib [D-HyperCdK], n=3). In patients with PCL who received DARZALEX-based therapies, 2 achieved partial response (PR; 1 each in the D-HyperCd and D-HyperCdK groups) and 2 achieved stable disease (SD; in the D-HyperCdK group).
• Parrondo et al (2021)⁸ 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% (n=19), PFS was 5 months (95% confidence interval [CI], 2-20), and OS was 8 months (95% CI, 5-21).
• Ge et al (2020)⁹ 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% (n=22) of patients received DARZALEX. 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).
• Several case reports have been published describing patients with PCL who received DARZALEX as part of treatment.^10-21

CLINICAL DATA

D-CVRd for the Treatment of HiR MM and PCL

MUK9 OPTIMUM (NCT03188172)^1,2 is an ongoing, multicenter, phase 2 study in the United Kingdom (UK) evaluating the combination of D-CVRd in patients with HiR MM and PCL. Kaiser et al (2021)³ presented results of patients with HiR MM and PCL treated with D-CVRd induction, HDMEL, and ASCT in the MUK9 OPTIMUM trial. Jenner et al (2020)⁴ presented feasibility results of MUK9 OPTIMUM trial.

Study Design/Methods

MUK9 OPTIMUM is comprised of 2 parts:

• MUK9A (OPTIMUMscreen) will genetically screen patients with suspected symptomatic MM to determine risk status. Patients who are not identified with HiR MM will receive standard of care treatment. Patients identified with HiR MM or PCL will be invited to participate in MUK9B.
• MUK9B (OPTIMUMtreat) is a single arm trial in which patients will receive:
  • 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.
  • 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.
  • 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; and major surgery within 2 weeks before registration; has not fully recovered from surgery; or planned surgery during planned study participation period.
• Primary objective: MUK9A, risk status turnaround time within 8 weeks; MUK9B, PFS.
• Key secondary objectives: safety, minimal residual disease (MRD)-negativity at 10^-5 sensitivity, OS, ORR, quality of life.
• Exploratory objectives: germline variability/mutations, genomic instability, clonal evolution.

Results

• Between September 2017 and July 2019, 472 patients with suspected MM or PCL were recruited across 39 UK hospitals.³
• Central bone marrow CD138+ genetic and GEP risk profiles were successfully generated in 93% of patients.⁴
  • The most common reason for technical failure of test was lone bone marrow aspirate quality.⁴
• Median risk status turnaround time was 18 (IQR, 13-22) days.⁴
• Ultra high-risk features were detected in 128 patients, and 107 of these patients (PCL, n=10) consented and were eligible for MUK9B OPTIMUM(treat).³
• Baseline characteristics of patients are presented in Table: Baseline Characteristics.

Efficacy

• Median follow-up was 22.2 months (95% CI, 20.6-23.9).³
• ORR was 94% and 83% at the end of induction and 100-120 days post-ASCT, respectively. See Table: Response Rates in Patients with HiR MM and PCL.³
• At day 100-120 post-ASCT, 8 patients with PCL were evaluable.³
  • Complete response (CR) was achieved in 25% (n=2) of patients, very good partial response (VGPR) in 25% (n=2), PR in 25% (n=2); 2 patients experienced progressive disease.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.³

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

EUMELEIA (NCT06636552)⁵ is an ongoing, prospective, multicenter, phase 2, open-label, single-arm clinical 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.

Study Design/Methods

• EUMELEIA is a single-arm trial in which patients will receive the following:
  • Induction: six 21-day cycles of alternating D-PAD and D-CVD (starting with D-PAD).
    • For D-PAD (cycles 1, 3, and 5): DARZALEX FASPRO 1800 mg (QW) subcutaneously (SC) on days 1, 8, and 15 in cycles 1 and 3 and 1800 mg (Q3W) SC on day 1 in cycle 5.
    • For D-CVD (cycles 2, 4, 6,): DARZALEX FASPRO 1800 mg (QW) SC on days 1, 8, and 15 in cycle 2 and 1800 mg (Q3W) SC on day 1 in cycles 4, and 6.
  • Consolidation: two 21-day cycles of D-CVD; DALZALEX FASPRO 1800 mg (Q3W) SC on day 1 of cycle 7 and 8.
  • Maintenance: twenty-four 28-day cycles of DARZALEX FASPRO monotherapy (cycles 9 to 32) with DARZALEX FASPRO 1800 mg (Q4W) SC 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.
  • ECOG performance status 0 to 3.
  • Newly diagnosed pPCL defined per International Myeloma Working Group (IMWG) criteria for PCL and MM: ≥5% peripheral blood progenitor cells (PBPCs) and/or absolute number ≥0.5×10³/µL, clonal bone marrow plasma cells (BMPCs) ≥10% or biopsy-proven bony or extramedullary plasmacytoma.
  • Serum calcium >0.25 mmol/L (>1 mg/dL) higher than upper normal limit (ULN) or >2.75 mmol/L (>11 mg/dL).
  • Creatinine clearance (CrCl) <40 mL/min or serum creatinine >177 µmol/L (>2 mg/dL).
  • Hemoglobin >20 g/L below the lower limit of normal (LLN) or hemoglobin <100 g/L.
  • One or more osteolytic lesion (of 5 mm or more in size) on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT.
  • Any one or more of the following biomarkers: clonal BMPCs, ≥60%, uninvolved serum free light chain (sFLC) ratio ≥100.
  • Measurable disease by protein electrophoresis.
  • Patient not currently or previously treated with any systemic therapy or stem cell transplant for any plasma cell dyscrasia.
  • Adequate bone marrow function (hemoglobin ≥7.0 g/dL, ANC ≥1.0×10⁹/L, and platelet count ≥50×10⁹/L).
  • Liver function (serum aspartate transaminase ≤2.5× ULN, serum alanine aminotransferase ≤2.5× ULN, and total bilirubin ≤1.5× ULN), and renal function (CrCl ≥20 mL/min).
• Key exclusion criteria:
  • sPCL.
  • Prior or concurrent invasive malignancy (other than PCL) within 5 years of the date of study treatment initiation, radiation therapy within 14 days before study treatment initiation, plasmapheresis within 28 days before study treatment initiation, meningeal or central nervous system involvement by PCL.
  • Peripheral neuropathy or neuropathic pain of grade ≥2.
  • Concurrent systemic amyloidosis, POEMS syndrome, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease, COPD, moderate or severe persistent asthma within the past 2 years.
  • Seropositivity for the human immunodeficiency virus, hepatitis B virus, and hepatitis C virus.
  • Clinically significant cardiac disease.
  • Pregnant or breast-feeding females.
  • Concurrent use of other anticancer agents/treatments.
  • Major surgery within 2 weeks before study treatment initiation or will not have fully recovered from surgery.
  • Contraindications to the use of any components of the study treatment (DARZALEX, bortezomib, dexamethasone, cyclophosphamide, and doxorubicin) per local prescribing information.
• Primary endpoint: PFS

Results

• Study results have not been published.

Retrospective Analysis of Treatment of pPCL With VRd or DBQ Regimens

Katodritou et al (2023)⁶ 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.
• 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.
• Outcomes assessed included response rates, OS, PFS, and safety.

Results

• A total of 110 patients who fulfilled the criteria for pPCL were identified.
• The median age was 65 (range, 44-86) years.
• The median number of lines of treatment was 1 (range, 1-5).
• A total of 40 (37%) patients received VRd (n=17)/DBQ (n=23) regimens (VRd, n=17; DARZALEX with bortezomib, cyclophosphamide, and dexamethasone [DVCd], n=14; DARZALEX with bortezomib, thalidomide, and dexamethasone [DVdT], n=5; and DARZALEX with VRd [DVRd], n=4), and 70 (64%) patients received BSC/CT regimens (BSC, n=58 and CT, n=12) as first-line treatment.
  • 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 (46%) patients 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).
  • 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 (CVM) reactivation, of whom, 3 were treated with DBQ regimens.

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

Shank et al (2023)⁷ 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 alone or with carfilzomib between May 1, 2016 and August 1, 2019 at the University of Texas MD Anderson Cancer Centre were included.
• Primary objective: ORR (defined as the rate of patients achieving a best overall response of CR, VGPR, or PR)
• 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)

Results

• The median follow-up duration was 32.2 months (95% CI, 24.1-NR) across all treatment groups.
• Of the 97 patients included, 12 had PCL (HyperCd, n=2; HyperCdK, n=6; D-HyperCd, n=1; and D-HyperCdK, n=3).
• In the DARZALEX-based regimens ie, D-HyperCd and D-HyperCdK, patients received a median of 2 DARZALEX doses per cycle (range, 1-4 in both groups).
• Response outcomes in patients with PCL in the treatment groups were as follows:
  • 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.
• 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.
• Based on a univariate analysis, PCL was a predictor of worse median PFS (P=0.009).
• Overall, 4 patients with PCL died within 60 days of treatment.
• 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.

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

Parrondo et al (2021)⁸ 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.
• PCL was defined as cPCs ≥5% or ≥0.5 x 10⁹/L, as proposed by the IMWG.
• Objectives measured included response rate, PFS, and OS.

Results

• Of the 68 patients with PCL who were identified, 28 received DARZALEX-based regimens.
• Median age at PCL diagnosis was 67 (range, 38-83) years.
• Median follow-up from PCL diagnosis was 26 months (95% CI, 13-61) and 17 months (95% CI, 10-23) from initiation of DARZALEX.
• DARZALEX-based induction was given to 4 patients with primary PCL while the remaining patients had relapsed/refractory disease.
• Since the start of DARZALEX-based treatment, PFS was 5 months (95% CI, 2-20).
  • 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).
  • 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).
  • Patients with pPCL and sPCL achieved ORR of 79% and 57%, respectively.
• ≥VGPR was achieved in 32% (n=9) of patients.
  • ≥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.

Outcomes of PCL Patients Treated With Novel Agents Including DARZALEX

Ge et al (2020)⁹ 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.
• Outcomes assessed included ORR, OS, and PFS.

Results

• Fifty-four patients with pPCL (n=38) or MM-CPC (n=16) were identified.
• Median age at diagnosis for the pPCL and MM-CPC groups was 59.2 (range 43-94) and 59.8 (range 29-79) years, respectively.
• Fifty (92.6%) patients 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.
• ≥PR was achieved in 76.7%, 62.8%, and 37.9% of patients to first-, second-, and third-line therapy, respectively.
• 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.
• 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).

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 19 August 2025.