SUMMARY

• DARZALEX for intravenous (IV) use and DARZALEX FASPRO for subcutaneous (SC) use are not approved by the regulatory agencies for use in combination with ixazomib for the treatment of multiple myeloma (MM). Janssen does not recommend the use of DARZALEX or DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
• C16047 (NCT03439293)¹ was an open-label, multicenter, phase 2 study evaluating the safety and efficacy of DARZALEX in combination with ixazomib and DARZALEX, ixazomib, and dexamethasone (D-Id) in patients with relapsed and/or refractory multiple myeloma (RRMM).
  • Delimpasi et al (2024)² reported the final analysis of the of C16047 study. In all response-evaluable patients, the very good partial response (VGPR) or better rate was 30.5% and the overall response rate (ORR) was 64.4%. Overall, the median progression-free survival (PFS) was 16.8 months (95% confidence interval [CI], 10.1-23.7). The most common any-grade treatment-emergent adverse event (TEAE) was diarrhea (42.6%). The most common grade ≥3 TEAEs were thrombocytopenia and pneumonia (11.5% each).
• DARIA (NCT03746652)³ was a prospective, open-label, multicenter, phase 2 study evaluating the effectiveness of D-Id as a second-line therapy in patients with RRMM who have received prior treatment with lenalidomide-based regimens.
  • Terpos et al (2024)⁴ reported the efficacy and safety results of the DARIA study. The ORR was 64%. The median PFS was 8.1 months (95% CI, 5.2-15.8), and the median overall survival (OS) was 39.2 months (95% CI, 17.439.3). The most frequent grade 3/4 adverse event (AE) was thrombocytopenia (18.0%).
• IDARA (IFM 2018-02) (NCT03757221)⁵ is an ongoing, open-label, multicenter, phase 2 study evaluating the efficacy and safety of DARZALEX in combination with ixazomib (DI) without dexamethasone in elderly patients with RRMM.
  • Macro et al (2022)⁶ presented the results of IFM 2018-02 study evaluating the efficacy and safety of DI in frail patients with RRMM. The ≥VGPR rate was 34% in all evaluable patients. The most common grade ≥3 AEs were thrombocytopenia (n=10), diarrhea (n=2), infusion-related reactions (IRRs) to DARZALEX (n=2), and nausea/vomiting (n=1).
  • Touzeau et al (2023)⁷ presented the results of the phase 2 IFM 2018-02 study at a data cutoff date of January 19, 2023. The ≥VGPR rate was 32% in all evaluable patients. The grade ≥3 AEs reported were thrombocytopenia (n=10), other cytopenia (n=8), infection (n=5), hypertension (n=3), gastrointestinal (GI) disorder (n=5), and IRRs (n=2).
• HOVON-143^8-11 was a prospective, multicenter, phase 2 study evaluating the efficacy, tolerability, and safety of D-Id in unfit or frail patients with newly diagnosed multiple myeloma (NDMM).
  • Groen et al (2023)⁹ reported the results from transplant-ineligible intermediate-fit patients in the induction and maintenance phases of the HOVON-143 study. After the induction phase, the ORR was 71%, with 37% of patients achieving ≥VGPR. The median PFS was 18.2 months (95% CI, 10.5-28.1) and the median OS was not reached (NR; 95% CI, 47.2-NR). Grade ≥3 hematologic AEs were reported in 12% of patients; the most common being neutropenia (6%). Grade ≥3 nonhematologic AEs were reported in 51% of patients; the most common being gastrointestinal (14%; mainly diarrhea) and central nervous system (CNS)-related (14%) AEs.
  • Stege et al (2021)¹⁰ reported results from transplant-ineligible frail patients in the induction phase of the HOVON-143 study. The ORR was 78% and grade ≥3 hematologic and nonhematologic AEs were reported in 31% and 74% of patients, respectively.
  • Groen et al (2022)¹¹ presented the long-term results from frail patients in the maintenance phase of the HOVON-143 study. The overall median PFS was 13.8 months. Grade ≥3 hematologic AEs reported during the maintenance phase were anemia (3%) and thrombocytopenia (9%).
• 180638 (NCT03590652)¹² is an ongoing, multicenter, phase 2 study evaluating the ORR of patients with MM to DARZALEX in combination with ixazomib, pomalidomide, and dexamethasone (D-IPd).
  • Kumar et al (2023)¹³ reported the interim analysis (as of October 2023) of the 180638 study in patients with early RRMM. The ORR was 82%. The most frequent grade ≥3 TEAE was neutropenia (63%).
• DeRIVE (NCT03942224)¹⁴ is an ongoing phase 2 study evaluating the efficacy and safety of a combination induction therapy with D-Id, with or without bortezomib in treating patients with NDMM.
  • Nooka et al (2023)¹⁵ presented the safety and efficacy of the DeRIVE study. The safety and efficacy results were similar in both treatment arms.

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 Data

Phase 2 Study of D-Id in Patients With RRMM

C16047 (NCT03439293)¹ was an open-label, multicenter, phase 2 study evaluating the safety and efficacy of DARZALEX in combination with ixazomib and D-Id in patients with RRMM. Delimpasi et al (2024)² reported the final analysis of this study.  

Study Design/Methods

• Prospective, single-arm, open-label, multicenter, phase 2 study.
• Patients received 28-day cycles of the following until disease progression or unacceptable toxicity:
  • DARZALEX: 16 mg/kg IV once weekly (QW) during cycles 1-2, once every two weeks (Q2W) during cycles 3-6, and once every 4 weeks (Q4W) thereafter
  • Ixazomib: 4 mg orally (PO) on days 1, 8, and 15 of each cycle
  • Dexamethasone: 20 mg IV (required prior to first DARZALEX dose only)/PO on days 1, 2, 8, 9, 15, 16, 22, and 23.
  • Antipyretics, antihistamines, and montelukast were administered before DARZALEX to reduce the risk of infusion-related reactions.
  • DARZALEX dose reductions were not permitted.
• Primary endpoint: ≥VGPR
• Key secondary endpoints: ORR, PFS, time to progression (TTP), OS, time to response (TTR), duration of response (DOR), safety, and collection of ixazomib plasma concentration-time data.
• Exploratory objectives included: minimal residual disease (MRD) detection in patients with complete response (CR), health-related quality of life (HRQoL), and clinical efficacy in subgroups of high-risk and expanded high-risk cytogenetic abnormalities.

Results

Patient Characteristics

• Details of the 61 patients from 19 study centers in 6 countries enrolled from June 8, 2018 to July 18, 2019 are presented in Table: Patient Demographics and Baseline Characteristics.
• At the data cut-off of January 1, 2022, 15 (24.6%) patients were ongoing treatment, while study treatment was discontinued in 46 patients due to progressive disease (PD, n=36), AE (n=7), and physician decision/patient withdrawal (n=3).

Efficacy

• At final analysis, 59 patients were included in the all-response evaluable patient population with response rates detailed in Table: Confirmed Best Reponses in All Response-Evaluable Patients.  
  • Median time to best response of partial response (PR) or greater was 1.0 months (95% CI, 1.0-1.9)
  • Median DOR was 24.0 months (95% CI, 15.9-NR)
  • Among 18 patients who achieved ≥VGPR,
    • Median time to best response was 4.2 months (95% CI, 1.9-5.5)
    • Median DOR was not estimable (95% CI, 11.8-NR)
• Prespecified subgroups response rates are detailed in Table: Confirmed Best Reponses in Patient Subgroups.  

• PFS details are summarized in Table: PFS in Overall, High-Risk Cytogenetics, Expanded High-Risk Cytogenetics, and Lenalidomide-Refractory Patients.
• At a median follow-up of 30.9 months (95% CI, 27.9-33.8), the median TTP in all patients was 21.1 months (95% CI, 10.2-27.9) with 35 events.
• At a median follow-up of 32.5 months (95% CI, 30.6-33.6), the median OS was not reached with 18 deaths.
  • The 1-year OS rate was 91.4% (95% CI, 80.6-96.3).

• MRD was evaluated in 8 patients who achieved a confirmed CR and maintained it at 6 and 12 cycles after initial CR.
  • Overall, 4 patients achieved MRD-negativity at any timepoint during treatment.
• Patient reported HRQoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30) and Quality of Life Questionnaire Myeloma Module (QLQ-MY20) instruments.
  • HRQoL was generally maintained during treatment with D-Id.

Safety

• At data cut-off, all enrolled patients were included in the safety population, with patients receiving a median of 16 cycles of D-Id (range: 1-45).
• The median relative dose intensities (RDIs) were 98.9%, 97.4%, and 92.9% for ixazomib, DARZALEX, and dexamethasone, respectively.¹⁶ 
• Safety data is summarized in Tables: Safety Data Summary and Most Common Any-Grade^a and Grade ≥3 TEAEs^b.

Phase 2 Study of D-Id as Second-Line Therapy in Patients With RRMM

DARIA (NCT03746652)³ was a prospective, open-label, multicenter, phase 2 study evaluating the effectiveness of D-Id as a second-line therapy in patients with RRMM who have received prior treatment with lenalidomide-based regimens. Terpos et al (2021)¹⁷ presented the primary results of this study. Terpos et al (2024)⁴ presented the final efficacy and safety results of this study. The final outcomes have been summarized below.

Study Design/Methods

• Prospective, open-label, multicenter, phase 2 study.
• Key inclusion criteria: RRMM, measurable disease after 1 prior line of therapy with a lenalidomide-based regimen, Karnofsky performance status score ≥70, no previous anti-cluster of differentiation (CD)38 or ixazomib treatment, no treatment with CYP3A inducers within 14 days before cycle 1 day 1 (C1D1), no antimyeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment prior to C1D1, no allogeneic stem cell transplant or autologous stem cell transplant (ASCT) within 12 weeks before C1D1.
• Patients received 28-day cycles of the following induction treatment:
  • DARZALEX: 16 mg/kg IV from initiation to November 2020 and DARZALEX FASPRO 1800 mg SC thereafter QW during cycles 1-2, Q2W during cycles 3-6, and Q4W thereafter
  • Ixazomib: 4 mg PO on days 1, 8, and 15 of each cycle
  • Dexamethasone: 40 mg PO QW
• After induction, patients received 28-day cycles of the following maintenance treatment until PD or unacceptable toxicity:
  • DARZALEX: 16 mg/kg IV from initiation to November 2020 and DARZALEX FASPRO 1800 mg SC thereafter Q4W
  • Ixazomib: 4 mg PO on days 1, 8, and 15 of each cycle
• Primary endpoint: ORR
• Key secondary endpoints: Toxicity profile of D-Id, PFS, OS, DOR, TTP, time to next treatment (TtNT), changes in serum bone metabolism biomarkers

Results

Patient Characteristics

• Overall, 50 patients were included. The baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics.
• The median follow-up was 23.4 months (range, 1.1-47.6).
• The median number of treatment cycles was 9 (range, 1-38).

Efficacy

• At the end of the study, the ORR was 64% (n=32)
  • One patient (2%) achieved CR, 16 (32%) achieved VGPR, and 15 (30%) achieved partial response (PR).
• The median PFS was 8.1 months (95% CI, 5.2-15.8), and the median OS was 39.2 months (95% CI, 17.4-39.3).
• The median DOR was 16.52 months (95% CI, 9.18-NR) and the median time to first response (≥PR) was 1.0 month (range, 0.9-17.6).
• The median TTP was 10.4 months (95% CI, 5.8-17.9) and the median TtNT was 14.5 months (95% CI, 9.1-39.3).
• Reasons for treatment discontinuation included PD (n=29, 58%), death (n=3, 6%), end of follow-up (n=13, 26%), AEs (n=2, 4%), and physician’s decision due to inadequate depth of response (n=3, 6%).
• Among the evaluated serum bone metabolism biomarkers, the changes from baseline in the levels of tartrate-resistant acid phosphatase isoform 5b (TRACP-5b) at 6, 9, 12, 15, 18, 21, and 24 months and bone-specific alkaline phosphatase (bALP) at 12, 15, 18, 21, and 24 months and the level of osteocalcin (OC) at 3, 6, 9, 12, 15, 18, 21, and 24 months were statistically significant (P<0.05).

Safety

• At least 1 grade ≥3/4 AE was reported in 21 patients (42%).
  • The most frequent grade 3/4 AE was thrombocytopenia (18.0% [n=9]).
• At least 1 serious adverse event (SAE) was reported in 14 patients (28.0%).
  • The most frequent SAEs were lower respiratory tract infection (6.0% [n=3]) and acute kidney injury (4.0% [n=2]).
  • Four fatal infection-related SAEs were reported.
  • Five patients experienced ≥1 IRR; all were grade 2 and completely resolved, but 1 patient experienced grade 4 infusion-related dyspnea and bronchospasm that led to discontinuation.

Phase 2 Study of D-I in Frail Patients With RRMM

Macro et al (2022)⁶ presented the results of the single-arm, phase 2 IFM 2018-02 study evaluating the efficacy and safety of D-I in frail patients with RRMM.

Study Design/Methods

• Key inclusion criteria: naïve to D-I, age >65 years, RRMM after 1 or 2 prior lines of therapy, frailty score ≥2 as per International Myeloma Working Group (IMWG) criteria, Eastern Cooperative Oncology Group performance status (ECOG PS) score ≤2, and adequate bone marrow and organ function.
• Patients received 28-day cycles of the following treatment until PD:
  • DARZALEX: 16 mg/kg IV on days 1, 8, 15, and 22 during cycles 1-2; on days 1 and 15 during cycles 3-6; and on day 1 during cycles 7+
  • Ixazomib: 4 mg PO on days 1, 8, and 15 of each cycle
  • Methylprednisolone: 100 mg IV on days 1 and 8 during cycle 1, and 60 mg thereafter; before administration of DARZALEX
• Primary endpoint: VGPR rate
• Secondary endpoints: safety, ORR, PFS, OS, TTP, and TTR

Results

Patient Characteristics

• Overall, 55 patients were included. The baseline patient and disease characteristics are presented in the Table: Key Baseline Patient and Disease Characteristics.
• The median duration of follow-up was 15.2 months (range, 11.2-22.3) and the median duration of treatment was 13 months (range, 8-35).

Efficacy

• The response outcomes are summarized in the Table: Response Outcomes.
• The estimated 1-year OS and PFS rate was 87% and 70%, respectively.

Safety

• Safety outcomes are summarized in the Table: Safety Outcomes.
• Treatment was discontinued in 33 (60%) patients (PD, n=21; AE, n=3; withdrawal, n=2; death, n=6).

Touzeau et al (2023)⁷ presented the results of the single-arm, phase 2 IFM 2018-02 study evaluating the efficacy and safety of D-I in elderly frail patients with RRMM at a data cutoff date of January 19, 2023.

Study Design/Methods

• Key inclusion criteria: naïve to D-I, age >65 years, RRMM after 1 or 2 prior lines of therapy, frailty score ≥2 as per IMWG criteria, and ECOG PS score ≤2.
• Patients received 28-day cycles of the following treatment until PD:
  • DARZALEX: 16 mg/kg IV on days 1, 8, 15, and 22 during cycles 1-2; on days 1 and 15 during cycles 3-6; and on day 1 during cycles 7+
  • Ixazomib: 4 mg PO on days 1, 8, and 15 of each cycle
• Primary endpoint: ≥VGPR rate at 1 year
• Secondary endpoints: safety, ORR, PFS, and OS

Results

Patient Characteristics

• Overall, 55 patients were included. The baseline patient and disease characteristics are presented in Table: Key Baseline Patient and Disease Characteristics.
• The median duration of treatment was 22 months (range, 16-40).
• The median follow-up for OS was 22.5 months (range, 18.0-29.1) and PFS was 23 months (range, 19.6-29.1).

Efficacy

• The response outcomes are summarized in Table: Response Outcomes.
• The estimated OS at 27.9 months was 75%.
• The median PFS was 18.5 months (range, 11.0 to 29.9).
• Fourteen patients (25%) are ongoing treatment at a median follow-up of 23 months.

Safety

• Safety outcomes are summarized in Table: Safety Outcomes.
• Treatment was discontinued in 41 (75%) patients at a median treatment duration of 10 months (range, 0-31) (PD, n=24; AE, n=9; withdrawal, n=3; death, n=5).

Phase 2 Study of D-Id in Transplant-Ineligible Frail or Unfit Patients With NDMM

HOVON-143 (EudraCT number: 2016-002600-90)^8-11 was a prospective, multicenter, phase 2 study evaluating the efficacy, tolerability, and safety of D-Id in unfit or frail patients with NDMM. Groen et al (2023)⁹ reported the results from transplant-ineligible intermediate-fit patients in the induction and maintenance phases of the HOVON-143 study.

Study Design/Methods

• Patients who were intermediate-fit based on IMWG frailty index were included and received 9 cycles of the following induction treatment (28 days/cycle):
  • DARZALEX: 16 mg/kg on days 1, 8, 15, and 22 during cycles 1-2; on days 1 and 15 during cycles 3-6; and on day 1 during cycles 7-9
  • Ixazomib: 4 mg on days 1, 8, and 15
  • Dexamethasone: 20 mg during cycle 1-2 and 10 mg thereafter, on the days on which DARZALEX was administered
• Patients received 8-week cycles of the following maintenance treatment up to a maximum of 2 years:
  • Ixazomib: 4 mg on days 1, 8, 15, 29, 36, and 43
  • DARZALEX: 16 mg/kg on day 1
  • Dexamethasone: 10 mg on day 1
• Primary endpoint: ORR
• Key secondary endpoints: PFS, PFS on subsequent line of treatment (PFS2), OS, tolerability, and safety.
• Post hoc assessment of event-free survival (EFS; defined as time until treatment discontinuation, PD, death, grade 4 hematologic AE, or grade 3/4 nonhematologic AE).
• HRQoL was assessed at baseline, after 3 and 9 induction cycles, and after 3, 6, and 12 months of maintenance treatment.
• The global health status (GHS) was measured at baseline, after 3 and 9 induction cycles, and after 3, 6, and 12 maintenance cycles.

Results

Patient Characteristics

• The baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics.
• The median relative dose intensity was 0.99 (interquartile range; IQR, 0.94-1.00) for DARZALEX, 0.96 (IQR, 0.87-1.00) for ixazomib, and 1.00 (IQR, 0.97-1.00) for dexamethasone. The dose modifications during induction and maintenance treatment are summarized in Table: Dose Modifications During Induction and Maintenance.

Efficacy - Induction Phase

• The ORR was 71% (95% CI, 63-73), with 37% of patients achieving ≥VGPR.
• The median time to first response was 2 months (range, 1-5), and the median DOR was 20.8 months (95% CI, 12.0-36.7).
• At a median follow-up of 41.0 months (IQR, 36-46 months), the median PFS was 18.2 months (95% CI, 10.528.1), and the median PFS2 was NR (95% CI, 37.9-NR months); 72.3% (47/65) patients had progressed or died.
• The median OS was NR (95% CI, 47.2-NR), and the 36-month OS was 83% (95% CI, 71%-90%).
• Relapse-related mortality occurred in 7 patients (11%), and nonrelapse-related mortality in 10 (15%).
• The median EFS was 5.1 months (95% CI, 2.8-7.2). Rates of incidence of individual events were:
  • Grade 3/4 nonhematologic AE: 62%
  • PD: 22%
  • Treatment discontinuation: 5%
  • Grade 4 hematologic AE: 3%
  • Death: 2%

Efficacy - Maintenance Phase

• The ORR during induction and maintenance treatment was 72%.
• The median duration of follow-up in patients who reached maintenance treatment (n=35) was 41.3 months (range, 34.6-53.8).
• The following improvement of response was reported in 12 (34%) patients in total during the maintenance phase.
  • Minimal response to PR: n=1
  • PR to VGPR: n=4
  • VGPR to stringent complete response (sCR): n=7

Safety - Induction Phase

• Overall, 46% of patients did not proceed to the maintenance phase due to PD (63%), toxicity (13%), incompliance (10%), sudden death (3%), or other reasons (10%).
• Grade ≥3 hematologic AEs were reported in 12% of patients; the most common being neutropenia (6%).
• Grade ≥3 nonhematologic AEs were reported in 51% of patients; the most common being gastrointestinal (14%; mainly diarrhea) and CNS-related (14%) AEs.
• All-grade polyneuropathy (PNP) was reported in 42% of patients (grade 1, 18%; grade 2, 15%; grade 3, 8%).
• Grade 3 infections occurred in 8% of patients.

Safety - Maintenance Phase

• Among the 20 patients who discontinued the maintenance treatment, the reasons for treatment discontinuation were PD (65%), patient’s choice (10%), toxicity (10%), death (5%), or other reasons (10%).
• The most common grade ≥3 hematologic AE was neutropenia (3%).
• Nonhematologic grade ≥3 AEs were reported in 46% of patients; the most common being gastrointestinal AEs (12%) and infections (9%).
• Grade 2 PNP was reported in 11% of patients. No new onset grade ≥3 PNP was reported.

Health-Related Quality of Life

• A significant improvement (P=0.002) in GHS was reported by patients on study treatment, which was clinically relevant from induction cycle 9 onwards.
• At all timepoints, the number of patients experiencing a clinically relevant improvement in their GHS was numerically higher than those who reported a deterioration. See Table: Improvement or Worsening of GHS Across Timepoints.

Stege et al (2021)¹⁰ reported results from transplant-ineligible frail patients in the induction phase of the HOVON-143 study.

Study Design/Methods

• Prospective, multicenter, single-arm, phase 2 study
• Inclusion criteria: previously untreated symptomatic MM, frail according to IMWG frailty index, sufficient bone marrow capacity (absolute neutrophil count ≥1.0×10⁹/L)
• Exclusion criteria: severe organ dysfunction with active malignancy requiring treatment, neuropathy grade 1 with pain, neuropathy grade ≥2, active or uncontrolled infection
• Patients received nine 28-day cycles of the following induction treatment:
  • DARZALEX: 16 mg/kg IV on days 1, 8, and 15 during cycles 1-2; on days 1 and 15 during cycles 3-6; and on day 1 during cycles 7-9
  • Ixazomib: 4 mg on days 1, 8, and 15
  • Dexamethasone: 20 mg during cycle 1-2 and 10 mg thereafter, on the days on which DARZALEX was administered.
• Patients received 8-week cycles of the following maintenance treatment until PD or up to a maximum of 2 years:
  • Ixazomib: on days 1, 8, 15, 29, 36, and 43
  • DARZALEX: on day 1
• Patients were classified into frailty subgroups based on the following parameters:
  • Age only (>80 years)
  • Other frailty parameters only (activities of daily living [ADL], instrumental activities of daily living [iADL], and/or Charlson Comorbidity Index) and age ≤80 years
  • Both age (>80 years) and other frailty parameters
• Antibiotic and antiviral prophylaxis was recommended in the protocol.
• Primary endpoint: ORR (PR or better) during induction treatment
• Key secondary endpoints: treatment discontinuation due to toxicity, relative dose intensity, MRD-negative CR, PFS, HRQoL, and safety
• GHS or quality of life was evaluated using the EORTC-QLC-C30 at baseline and after induction cycles 3 and 9 for patients still receiving study treatment.

Results

Patient Characteristics

• The median duration of follow-up was 22.9 months (range, 12.7-31.0).
• Overall, 65 patients were included.
  • Induction treatment was initiated by 64 patients and completed by 41 patients.
  • Maintenance treatment was initiated by 32 (49%) patients. The median follow-up duration for the maintenance phase was 13.6 months (range, 7.4-21.2).
• Key baseline patient and disease characteristics are summarized in the Table: Key Baseline Patient and Disease Characteristics.

Efficacy

• Efficacy outcomes are summarized in the Table: Efficacy Outcomes.
• At data cutoff, 43 (66%) patients had progressed or died (deaths, n=25 [38%]).

Patient Reported Outcomes

• HRQoL questionnaire was completed by all patients at baseline, 96.6% patients after 3 induction cycles, and by 92.7% patients after 9 induction cycles.
• The GHS score was 54.1 (standard deviation [SD], 26.2) at baseline, 65.8 (IQR, 50.083.3) after cycle 3, and 71.5 (IQR, 58.3-83.3) after cycle 9.
• The improvement in GHS became statistically significant (P<0.001) after cycle 3.¹⁰

Safety

• AEs reported during the induction phase are summarized in the Table: AEs During the Induction Phase.
• SAEs were reported in 53 (81.5%) patients, most commonly due to prolongation of hospitalization. No difference in incidence of SAEs was observed between frailty subgroups.
  • Thirteen SAEs resulted in death; none were considered treatment-related.
• In the induction phase, treatment with D-Id was discontinued in 33 (51%) patients (PD, n=12 [19%]; intercurrent death, n=6 [9%]; toxicity, n=6 [9%]; noncompliance, n=4 [6%]; other reasons, n=5 [8%]).
  • Four (6%) patients discontinued treatment due to an infection.
  • Twelve (18%) patients discontinued ixazomib only (peripheral neuropathy, n=10).
• In the maintenance phase, after a median follow-up of 13.6 months (range, 7.4-21.2), treatment was discontinued in 15 (47%) patients (PD, n=12; other reasons, n=3).
• Thirteen patients died while on study treatment, of whom 3 patients died due to PD (relapse mortality, n/N=3/65 [5%]) and 10 patients died due to other reasons (nonrelapse mortality, n/N=10/65 [15%]; of which infections, n/N=4/10; organ dysfunction, n/N=3/10; sudden death, n/N=2/10; and bleeding due to thrombocytopenia, n/N=1/10).
  • Five (8%) patients died within 60 days of treatment initiation (frail based on both age and other parameters, n=3; frail based on age only, n=1; and frail based on other parameters only, n=1). Four of these deaths were due to toxicity.
  • In patients who died early (≤60 days) vs those who D-Id not, the age was >80 years in 80% vs 40% of patients, the R-ISS stage was III in 60% vs 24% of patients, and elevated lactate dehydrogenase (LDH) was present in 40% vs 16% of patients.

Groen et al (2022)¹¹ presented the long-term results from frail patients in the maintenance phase of the HOVON-143 study.

Results

Patient Characteristics

• Overall, 65 frail patients were included.
• The median duration of follow-up was 39 months.

Efficacy

• The efficacy outcomes are summarized in the Table: Efficacy Outcomes.
• A total of 32 (49%) patients were transitioned to the maintenance phase.
  • Compared with the induction phase, an improvement in response was observed in 6 (19%) patients during the maintenance phase (stable disease to minimal response, n=1; PR to VGPR, n=3; VGPR to CR, n=1; VGPR to stringent CR [sCR], n=1).
  • The rate of ≥VGPR improved from 41% to 50% during the maintenance phase.
  • Treatment was discontinued during the maintenance phase in 21 (66%) patients due to PD (n=14 [67%]), infection and intracranial hemorrhage (n=2 [10%]), non-compliance (n=1 [5%]), intercurrent death (n=1 [5%]), and other reasons (n=3 [14%]).

Safety

• Grade ≥3 hematologic AEs reported during the maintenance phase were neutropenia (0%), anemia (3%), and thrombocytopenia (9%).
• Grade ≥3 nonhematologic AEs were reported in 18 (56%) patients.
• The most common AEs were infections (9%), nervous system disorders (9%), and gastrointestinal complaints (6%).
• Grade 3 neuropathy was reported in 1 (3%) patient.
• Second primary malignancies were reported in 2 (6%) patients.

Kumar et al (2023)¹³ presented the interim results of a prospective, open-label, multicenter, phase 2 trial evaluating the safety and efficacy of D-IPd in patients with early RRMM at data cut-off date, October 2023.

Study Design/Methods

• Inclusion criteria: RRMM, ≥1 and ≤3 prior lines of therapy, ECOG 0-2, no prior progression on pomalidomide, no prior exposure to ixazomib or DARZALEX.
• Six patients received the following treatment during the safety run-in:
  • DARZALEX: 16 mg/kg IV
  • Pomalidomide: 4 mg PO on day 1 to 21/28
  • Ixazomib: 4 mg PO weekly
  • Dexamethasone: 20-40 mg PO weekly
• Forty patients received the following treatment at stage 1/2:
  • DARZALEX FASPRO: 1800 mg SC
  • Pomalidomide: 3 mg PO on day 1 to 21/28
  • Ixazomib: 3 mg PO weekly
  • Dexamethasone: 20-40 mg PO weekly
• Primary endpoint: ORR to D-IPd and 80% power to detect 20% improvement
• Key secondary endpoints: clinical benefit rate, DOR, PFS, OS, and rates of MRD negativity

Results

Patient Characteristics

• For key baseline patient and disease characteristics see Table: Key Baseline Patient and Disease Characteristics.

Efficacy

• The response outcomes are summarized in Table: Response Outcomes.
• The median time to response was 0.93 months.
• The median OS was 38.9 months (95% CI, ≥28.5) for all patients and 30.5 months (95% CI, ≥28.5) for the high-risk group.
• The median PFS was 22.4 months (95% CI, ≥9.49) for all patients and 22.4 months (95% CI, ≥7.64) for the high-risk group.
• The following correlative immunophenotypic changes were reported in patients treated with D-IPd:
  • Increased proliferating/acting cytotoxic T cells
  • Decrease in natural killer (NK) cells, with a general shift towards proliferating/activated NK and NK-T cells
  • Increase in monocytes
  • Decrease in plasmacytoid dendritic cells with a shift towards classical dendritic cells  

Safety

• Safety outcomes are summarized in Table: Safety Outcomes.

Nooka et al (2023)¹⁵ presented the results of the DeRIVE study, a randomized, interventional, open-label, phase 2 study, that evaluated the combination induction therapy of D-Id vs DARZALEX, bortezomib, and dexamethasone (D-Vd) followed by D-Id in treating patients with NDMM.

Study Design/Methods

• Inclusion criteria: MM, ECOG 0-1, no prior exposure to ixazomib or anti-CD38 therapy.¹⁴
• Patients randomized to arm A received the following treatment regimen (D-Id×8 cycles):
  • DARZALEX: 16 mg/kg IV on days 1, 8, 15, and 22 every 28 days for 2 cycles; then on days 1 and 15 every 28 days for 6 cycles and every 28 days during maintenance (or DARZALEX FASPRO 1800 mg SC at the same schedule)
  • Ixazomib: 4 mg PO on days 1, 8, and 15 every 28 days
  • Dexamethasone: 40 mg PO on days 1, 8, 15, and 22 every 28 days
• Patients randomized to arm B received the following treatment regimen (D-Vd×3 cycles followed by D-Id×5 cycles):
  • DARZALEX: 16 mg/kg IV on days 1, 8, 15, and 22 every 28 days for 2 cycles; then on days 1 and 15 every 28 days for 6 cycles and every 28 days during maintenance (or DARZALEX FASPRO 1800 mg SC at the same schedule)
  • Bortezomib: 1.3 mg/m² SC on days 1, 4, 8, and 11 every 21 days
  • Dexamethasone: 40 mg PO on days 1, 8, 15, and 22 every 28 days
• During the maintenance phase, patients received D-Id for a total of 32 cycles.
• Transplant eligible patients could receive transplant after cycle 8.
• Primary endpoint: ≥VGPR rate post-induction cycle 8
• Key secondary endpoints: ORR, PFS, and OS

Results

Patient Characteristics

• The median age was 63.5 years for 48 evaluable patients, and 48% of patients were Black. For key baseline patient and disease characteristics, see Table: Key Baseline Patient and Disease Characteristics.

Efficacy

• For response outcomes, see Figure: Response Outcomes.

Safety

• Grade 3/4 AE occurred in 6 (24%) patients in arm A and 7 (30%) patients in arm B (P=0.27).
• No grade 3/4 peripheral neuropathy (PN) was reported in either arms. Grade 1/2 PN was higher in arm B.
• Two secondary primary malignancies were reported in arm B (prostate and esophageal adenocarcinoma).

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 30 June 2025.