SUMMARY

• Janssen cannot recommend any practices, procedures or practice guidelines that deviate from the product labeling or are not approved by the regulatory agencies.
• Clinical judgement should be used with regards to assess specific treatment regimens for patients, progression, and the individual patient’s response to their current regimen.
• Currently there are no systemically collected data available regarding retreatment or rechallenge with DARZALEX for intravenous (IV) use or DARZALEX FASPRO for subcutaneous (SC) use or after previous relapse or refractoriness with DARZALEX or after a treatment-free interval.
• Tan et al (2024)¹ presented (at the American Society of Clinical Oncology [ASCO] Annual Meeting) the results from a retrospective study that evaluated clinical outcomes of DARZALEX-based retreatment in patients with relapsed/refractory multiple myeloma (RRMM).
• Abdallah et al (2023)² conducted a single-center, retrospective, chart review to evaluate the efficacy and safety of retreatment with DARZALEX-based therapy in patients with RRMM who were refractory to DARZALEX, and compared the response data after retreatment with the response data after the first DARZALEX-based line of therapy.
• Ciardiello et al (2022)³ presented (at the ASCO Annual Meeting) the results of a single-center, retrospective, chart review comparing the efficacy of second-line treatment with DARZALEX-based regimens in patients who had previously received induction treatment with DARZALEX-based vs DARZALEX-free regimens.
• Szabo et al (2022)^4,5 conducted a retrospective real-world study that evaluated the life expectancy and clinical outcomes in patients who discontinued their first DARZALEXcontaining index regimen (IR).
• Atrash et al (2021)⁶ conducted a multicenter, retrospective, chart-review to evaluate the clinical outcomes of patients with multiple myeloma (MM) who received DARZALEX-based regimens across different lines of therapy. Results specific to patients who were retreated with DARZALEX have been summarized below.
• Nooka et al (2019)⁷ conducted a retrospective analysis of long-term follow-up results of a cohort of patients with RRMM that were grouped as DARZALEX-naïve and a cohort of patients that were reinitiated with DARZALEX who were DARZALEX- and/or pomalidomide-refractory.
• Kim et al (2019)⁸ presented (at the International Myeloma Workshop [IMW]) the results of a retrospective chart review evaluating the efficacy and safety of reinitiation of DARZALEX after an interruption in previous DARZALEX-based treatment.
• For information on ongoing clinical trials for our products, please visit www.clinicaltrials.gov.

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

Retrospective Study in Patients With RRMM Retreated With DARZALEX-Based Regimens

Tan et al (2024)¹ presented the results from a retrospective study that evaluated clinical outcomes of DARZALEX-based retreatment in patients with RRMM.

Study Design/Methods

• Patients with RRMM who had received DARZALEX-based retreatment at Memorial Sloan Kettering Cancer Center from January 1, 2015, to December 31, 2023, were included.
• The last follow-up date for analysis was May 8, 2024.
• Inclusion criteria: Patients with RRMM who had received ≥1 cycle of initial DARZALEX-based treatment and DARZALEX-based retreatment.
• Exclusion criteria: Patients who had received initial DARZALEX-based treatment in the newly diagnosed multiple myeloma (NDMM) setting.
• Responses were assessed according to the International Myeloma Working Group (IMWG) Response Criteria.
• Progression-free survival (PFS) and overall survival (OS) were evaluated via the Kaplan-Meier Method.
• DARZALEX-based regimens used for treatment and retreatment have been summarized in Table: DARZALEX-Based Regimens Used for Treatment and Retreatment.

Results

Patient Characteristics

• A total of 157 patients with RRMM received DARZALEX-based retreatment, with a majority of patients receiving combination therapy for DARZALEX-based treatment and retreatment.
  • Of these, 32% of patients received DARZALEX monotherapy in treatment and 4% of patients in retreatment.
• Of the 119 patients who were DARZALEX-refractory, 100 were DARZALEX-refractory at the start of DARZALEX-based retreatment.
• The baseline patient characteristics in the DARZALEX retreatment cohort are summarized in Table: Key Baseline Patient Characteristics.

Efficacy

• At a median follow-up duration of 53.9 months (95% confidence interval [CI],
  48.3-60.1), the median PFS and OS in the DARZALEX retreatment cohort were 10.8 months (95% CI, 8.48-16.5) and 47.4 months (95% CI, 41.5-not reached [NR]), respectively.
• Efficacy in the treatment vs retreatment cohort is summarized in Table: Efficacy in the DARZALEX Treated vs Retreated Cohort.

Retrospective Chart Review in Patients with RRMM Retreated with DARZALEX

Abdallah et al (2023)² conducted a single-center, retrospective, chart review to analyze the efficacy and safety of retreatment with DARZALEX in patients with RRMM who were refractory to DARZALEX, and compared the response data after retreatment with the response data after the first DARZALEX-based line of therapy.

Study Design/Methods

• Key inclusion criteria: Patients with RRMM who were initially naïve to DARZALEX or any other anti-cluster of differentiation 38 (CD38) therapy and relapsed after receiving their first line of DARZALEX-based treatment.
• DARZALEX-refractory patients were retreated with a DARZALEX based regimen.
• Results are summarized as a comparison of the outcomes reported after the first line of DARZALEX treatment (designated as DARZALEX-naïve cohort) vs the current line of DARZALEX retreatment (designated as DARZALEX retreatment cohort).

Results

Patient Characteristics

• Overall, 43 patients were included (single-agent DARZALEX treatment, n=12; DARZALEX-based combination treatment, n=31). The baseline patient and disease characteristics of patients in the DARZALEX retreatment cohort are summarized in Table: Key Baseline Patient and Disease Characteristics.
• The median duration of follow-up after DARZALEX retreatment was 19.5 months
  (IQR, 10.3-25.93).
• Patients had received a median of 2 lines of therapy (range, 1-8) before their first DARZALEX-based regimen and a median of 4 lines of therapy (range, 2-14) before the current DARZALEX-based retreatment.
• The DARZALEX-based regimens received by both the cohorts are summarized in Table: Regimens Received During DARZALEX Treatment.
• The treatment characteristics of the DARZALEX retreatment cohort are summarized in Table: Treatment Characteristics of Patients Retreated with DARZALEX-Based Regimen.

Efficacy

• Efficacy outcomes in both the cohorts are summarized in Table: Efficacy Outcomes.
• In the DARZALEX-naïve cohort:
  • The median time to first response was 27 days (range, 15-56).
  • The median duration of response was 12.4 months (95% CI, 5.8-24.8).
  • The median time to relapse or progressive disease (PD) was 6.77 months (95% CI, 4.57-12.97).
  • The ORR was 65% (n=13) in patients with Revised International Staging System (R-ISS) stage III and 65% (n=13) in patients with R-ISS stage I or II.
• In the DARZALEX retreatment cohort:
  • The median time to first response was 28 days (range, 14-77).
  • Among patients who responded to retreatment, a response to the previous DARZALEX-based therapy was observed in 13 (62%) patients, including 5 (23%) patients previously achieving ≥VGPR and 8 (38%) patients previously achieving PR.
  • Eight (38%) patients who responded to retreatment (≥VGPR, 5% [n=1]; PR, 33% [n=7]) had not responded to the previous DARZALEX-based therapy.
  • Among patients who responded to retreatment, the most common regimen was DARZALEX in combination with pomalidomide and dexamethasone (DPd; 52% [n=11]), followed by DKd (43% [n=9]) and DARZALEX in combination with bortezomib and dexamethasone (DVd; 5% [n=1]).
  • The ORR was 55% (n=11) in patients with R-ISS stage III and 45% (n=9) in patients with R-ISS stage I or II.
  • The median PFS was 7.97 months (95% CI, 5.23-NR).
    • The median PFS was NR among patients with ≥PR and 5.2 months among patients with no response (hazard ratio [HR], 0.17; 95% CI, 0.05-0.58; P=0.0017).
  • The median OS was 32.6 months (95% CI, 19.5-NR).
    • The median OS was NR among patients with ≥PR and 32.6 months in patients with no response (HR, 0.63; 95% CI, 0.18-2.28; P=0.48).

Safety

• Treatment-emergent adverse events (TEAEs) reported in retreated patients are summarized in Table: Most Common TEAEs in DARZALEX Retreated Patients.
• No treatment-related deaths were reported.
• Treatment discontinuations occurred due to congestive heart failure, neutropenia, and thrombocytopenia.

Retrospective Chart Review of DARZALEX as a Second Line of Therapy in Patients with RRMM

Ciardiello et al (2022)³ conducted a single-center, retrospective, chart review to compare DARZALEX-based retreatment as a second line of therapy for patients who had previously received induction treatment with DARZALEX-based vs DARZALEX-free regimens.

Study Design/Methods

• Primary endpoint: ORR (≥PR as per IMWG criteria)

Results

Patient Characteristics

• Overall, 33 patients were included. The baseline patient and disease characteristics are summarized in Table: Key Baseline Patient and Disease Characteristics. The treatment characteristics are summarized in Table: DARZALEX-Based Regimens as a Second Line of Therapy.
  • Cohort 1 included patients (n=6) who received DARZALEX-based induction therapy without meeting DARZALEX-refractory criteria (DARZALEX in combination with carfilzomib, lenalidomide, and dexamethasone [D-KRd], n=5; DARZALEX in combination with lenalidomide and dexamethasone [DRd], n=1).
  • Cohort 2 included patients (n=27) who had induction with KRd.
• The median duration of follow-up was 13.8 and 14.5 months for cohorts 1 and 2, respectively.
• The median duration between the last dose of DARZALEX in the first line of therapy and the first dose of DARZALEX in the second line of therapy was 17.5 months (IQR, 12.119.8).

Efficacy

• The median PFS was NR in cohort 1 and 16.2 months in cohort 2.
• Efficacy outcomes are summarized in Table: Efficacy Outcomes.

Retrospective Real-World Study of Patients who Discontinued their DARZALEX-Containing IR

Szabo et al (2022)⁴ conducted a retrospective real-world study that evaluated the life expectancy and clinical outcomes in patients who discontinued their DARZALEX-containing IR.

Study Design/Methods

• Patients were classified into 4 cohorts based on the IR:
  • DVd
  • DRd
  • DARZALEX monotherapy (D-mono)
  • DARZALEX in combination with other regimens (D-other)
• At the date of discontinuation of the IR (T₀), patients were classified into 4 cohorts based on drug exposure:
  • Double class exposed (exposed to DARZALEX + 1 other class of drug)
  • Triple class exposed (exposed to DARZALEX + 2 other classes of drugs)
  • Quadruple class exposed (exposed to DARZALEX + 3 other classes of drugs)
  • Alkylator-bortezomib-carfilzomib-DARZALEX-lenalidomide-pomalidomide exposed

Results

Patient Characteristics

• Overall, 474 patients who discontinued their DARZALEX-containing IR were included in the study. Key baseline characteristics of the included patients are summarized in Table: Key Baseline Patient Characteristics.
• Median follow-up duration after T₀ was 9.2 months (IQR, 1.817.6).

• The most common regimens used at the first line of therapy after T₀ (P1) are summarized in Table: Most Common Regimens Used at P1.

• The most common reasons for IR discontinuation were progressive disease (PD; 42%), toxicity (11%), and insufficient response (8%).

Efficacy

• Median OS in the entire cohort was 12.2 months (95% CI, 9.914.7). Retreatment with DARZALEX was associated with longer OS (HR, 0.59; 95% CI, 0.41-0.87; P=0.006).
• Survival data are summarized in Table: Median OS According to Patient Cohorts.

• ORR in patients who received retreatment with DARZALEX and in those who did not was 48% and 41%, respectively. Response to retreatment following discontinuation of IR is summarized in Table: Response After the First Retreatment.

• PD on DARZALEX-containing IR was reported in 46% patients retreated with DARZALEX vs 80% patients treated without DARZALEX.
• The most frequently used regimen in patients retreated with DARZALEX were DPd (n=57 [30%]), DRd (n=44 [23%]), and DVd (n=22 [12%]).
• The most frequently used regimen in patients retreated without DARZALEX were carfilzomib-dexamethasone (n=36 [20%]), pomalidomide-dexamethasone (n=22 [12%]), and carfilzomib-pomalidomide-dexamethasone (n=16 [7%]).
• Of the patients who received a subsequent line of therapy after T₀, 192 (51%) were retreated with a DARZALEX-containing regimen in P1.
• Median time to next treatment was 4.6 months both in patients with and without DARZALEX retreatment.

Retrospective Real-World Study in Patients Retreated with DARZALEX

Atrash et al (2021)⁶ conducted a multicenter, retrospective, real-world study to evaluate the clinical outcomes of patients with MM who received DARZALEX-based regimens across different lines of therapy. Results specific to patients who were retreated with DARZALEX have been summarized below.

Study Design/Methods

• Key inclusion criteria: patients with a confirmed diagnosis of MM who were ≥18 years old during the initiation of DARZALEX
• Key exclusion criteria: patients who received DARZALEX through clinical trial
• A cohort of patients who were retreated with DARZALEX (resumed a DARZALEX-based regimen after an interruption of ≥90 days) at least once were evaluated in this study. Patients who had a stem cell transplant during the period of DARZALEX interruption were excluded from this cohort.
• Key outcomes: ORR (≥PR), ≥VGPR, PFS, OS, and time to next treatment (TTNT)

Results

Patient Characteristics

• Overall, 299 patients were included, of whom 19 patients were retreated with DARZALEX. The baseline patient and disease characteristics are summarized in Table: Key Baseline Patient and Disease Characteristics.
• The mean duration of follow-up for the total population was 18.4 months (standard deviation, 12.5).
• In the total population, the mean number of lines of therapy received prior to DARZALEX was 2.4 (standard deviation, 1.6) and the mean number of regimens received prior to DARZALEX was 3.2 (standard deviation, 2.0).
• In the retreatment cohort, all patients (except 1) initiated DARZALEX at the third line of therapy or later.
• The most common regimen used for the initial treatment segment was DARZALEX monotherapy (with or without dexamethasone, n=6 [31.6%]), and the most common regimen used for the subsequent treatment segment was DPd (n=5 [26.3%]).
• The mean duration of the initial segment was 195 days and the mean duration of the second segment was 103 days.
• The mean duration of DARZALEX interruption was 258 days (range, 93-644).
• During the interruption of DARZALEX, 14 [73.7%] patients received a non-DARZALEX-based regimen (carfilzomib, n=7 [50%]; pomalidomide, n=7 [50%]; cyclophosphamide, n=6 [43%]; etoposide n=5 [36%]; other agents, n=12 [85%]).
• Of the six patients who received the same regimen before and after the interruption, 4 patients did not receive any treatment during the interval.
  • The duration of interruption for these 4 patients ranged from 112-195 days.
  • Of the remaining 2 patients, 1 patient was treated with VRd and the other patient received 8 regimens (carfilzomib based, 7; investigational antibody-drug conjugate, 1), during the interval.

Efficacy

• The efficacy outcomes in the retreatment cohort are summarized in Table: Efficacy Outcomes.

Retrospective Study on DPd with or without Prior DARZALEX Exposure

Nooka et al (2019)⁷ conducted a retrospective safety and efficacy analysis of DPd. The analysis also presented long-term follow-up results of patients that were either refractory to DARZALEX or pomalidomide or both; or without prior exposure to DARZALEX and pomalidomide.

Study Design/Methods

• The analysis reviewed data from 34 patients with relapsed myeloma or RRMM and were treated with DPd.
• This retrospective analysis had 3 cohorts:
  • Cohort 1: patients without prior exposure to DARZALEX and pomalidomide.
  • Cohort 2: patients refractory to DARZALEX and/or pomalidomide.
  • Cohort 3: patients refractory to both DARZALEX and pomalidomide.
• Patients were administered 28-day cycles of DARZALEX 16mg/kg in the DPd arm as follows:
  • Cycles 1 & 2: once weekly for 8 weeks.
  • Cycles 3-6: every 2 weeks for 16 weeks.
  • Cycles 7+: every 4 weeks.
• Patients in cohorts 2 and 3 who had received prior DARZALEX treatment and were considered to be refractory to DARZALEX, resumed their previous weekly dose at retreatment.  
• Majority of patients in cohort 3 had DARZALEX washout periods of less than 1 month.
  • Patients that responded to DARZALEX retreatment in this cohort had a washout period ranging from 0 to 6 months.

Results

• The analysis included a total of 34 patients who received DPd. The baseline characteristics and refractory status of patients is presented in Table: Key Baseline Characteristics and Refractory Status of Patients.

Baseline Characteristics

Efficacy

• The median duration of follow-up was 41 months.
• The response rates from each cohort are summarized in Table: Response Rates.

Safety

• Neutropenia, the most common grade ≥3 treatment-emergent adverse event among all cohorts, was observed in 41% of patients.

Retrospective Chart Review on Reinitiation of DARZALEX after Interruption

Kim et al (2019)⁸ presented the results of a retrospective chart review evaluating the efficacy and safety of reinitiation of DARZALEX after an interruption in previous DARZALEX-based treatment.

Study Design/Methods

• Inclusion criteria: patients who received DARZALEX as a prior line of therapy and were reinitiated on DARZALEX after an interruption of >8 weeks.

Results

Patient Characteristics

• Overall, 19 patients were included who were reinitiated on DARZALEX after a treatment break.
  • Among the included patients, treatment was interrupted due to PD in 8 (42%) patients and due to delay in the same therapy in 11 (58%) patients. Patients who had treatment-interruption due to PD had received other therapies before restarting DARZALEX.
• Upon reinitiation, 3 patients received DARZALEX as a first dose (1000 mL infused over 7 hours) and 16 patients received as a non-first dose (500 mL infused at a rapid rate over 90 minutes [n=6] and a second dose over 4 hours [n=10]).
• The duration of treatment interruption ranged from 54-931 days and the number of DARZALEX doses received prior to reinitiation ranged from 2-25.
• Among 8 patients who got reinitiated on a different regimen of DARZALEX upon progression, the number of subsequent lines of therapies after the initial DARZALEX regimen ranged from 1-7. The duration of therapy upon reinitiation ranged from 1-14 doses.

Safety

• No patients reported IRRs upon reinitiation.

Efficacy

• Due to the patient population being heavily pretreated, the response rates after retreatment were variable and generally lower than the initial response.

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 07 June 2024.