SUMMARY  

• Janssen does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
• CASSIOPEIA is a phase 3 study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, thalidomide and dexamethasone (D-VTd) in transplant eligible patients with previously untreated multiple myeloma (MM).^1,2
  • Individual dose modification of DARZALEX was not permitted, but dose delay was recommended as the primary method for managing DARZALEX-related toxicities.³

PRODUCT LABELING

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

CLINICAL DATA

CASSIOPEIA is an ongoing, open-label, 2-arm, multicenter, randomized, phase 3 study evaluating the safety and efficacy of D-VTd in patients with previously untreated MM who are eligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT).^1,2 Moreau et al (2019)¹ reported the results from Part 1 of this study. Moreau et al (2021)² reported the results from Part 2 of the CASSIOPEIA study.

Study Design/Methods

• Part 1: Patients were randomized to 1 of 2 treatment groups (each cycle is 28 days):
  • Arm A: Up to 4 cycles of VTd induction therapy followed by ASCT, followed by 2 cycles of VTd consolidation.
    • Bortezomib: 1.3 mg/m² subcutaneously (SC) twice a week in week 1 (days 1 and 4) and week 2 (days 8 and 11) of each cycle.
    • Thalidomide: 100 mg orally (PO) daily in all cycles.
    • Dexamethasone: 40 mg PO or intravenous (IV) on days 1, 2, 8, 9, 15, 16, 22, and 23 of induction cycles 1 and 2 and days 1 and 2 of induction cycles 3 and 4 and 20 mg on days 8, 9, 15, and 16 of induction cycles 3 and 4 and days 1, 2, 8, 9, 15, and 16 of both consolidation cycles.
  • Arm B: Up to 4 cycles of D-VTd induction therapy, followed by ASCT, followed by 2 cycles of D-VTd consolidation.
    • DARZALEX: 16 mg/kg IV of actual body weight once weekly in induction cycles 1 and 2 and once every 2 weeks during induction cycles 3 and 4 and consolidation.
    • VTd as above.
• Part 2: Responders were re-randomized to 1 of 2 treatment groups:
  • Arm A: Observation.
  • Arm B: DARZALEX 16 mg/kg maintenance therapy every 8 weeks for 2 years.
• Inclusion criteria: age 18-65 years old, previously untreated confirmed MM, eligible for high dose chemotherapy and ASCT, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-2.

Dose Modifications or Dose Delays (General Principles)

Cycle Delay

• On the first day of each new treatment cycle and before each DARZALEX dose, the patient was evaluated by the treating physician for possible toxicities that may have occurred after the previous dose(s). Toxicities were assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 4). Dose modifications or delays were made based on the toxicity experienced during the previous cycle of therapy or newly encountered on Day 1 of a cycle. For any neurological deficits that developed, it was strongly recommended that these would be evaluated by the same physician who performed the neurological assessment at baseline. The parameters must be met on the first day of a new cycle (i.e., the following represent baseline inclusion criteria levels) as presented in the Table: Re-Treatment Criteria Before the Start of Each Cycle.³

• If the above parameters were not met during the induction/consolidation phase, the start of the next cycle was held for a minimum of 1 week and a maximum of 28 days until recovery to the specified levels. During the cycle delay, DARZALEX, bortezomib, thalidomide, and dexamethasone must be held.³
• If there was a delay in the start of a new cycle (DARZALEX, bortezomib, thalidomide, and dexamethasone should not be given during this period) for more than 28 days due to insufficient recovery from toxicity, patients will discontinue taking D-VTd permanently.³
• If the above parameters were not met during the maintenance phase, the start of the next cycle was held for a minimum of 3 weeks and a maximum of 28 days until recovery to the specified levels.³

Dose Modification Guidelines

• Toxicities should have been attributed, whenever possible, specifically to DARZALEX, bortezomib, thalidomide, and dexamethasone so that dose modifications could be made rationally. Reduction of a single agent and not others was appropriate if toxicity was considered to be related primarily to one of the agents. If multiple toxicities were attributed to an individual drug, dose adjustment should have been made according to the guidelines for the most severe toxicity. For dose reduction steps and dose modification guidelines, see Tables: Dose Modification for Bortezomib, Dose Reduction for Thalidomide, and Dose Reductions for Dexamethasone.³
• Once dose reduction for a medication was implemented, unless otherwise stated specifically, dose re-escalation should not have occurred, unless in the judgment of the investigator there was clinical benefit and a reasonable and acceptable risk profile. For dose reduction steps and dose modification guidelines, see Tables: Dose Modification for Bortezomib, Dose Reduction for Thalidomide, and Dose Reductions for Dexamethasone.³

DARZALEX Dose Modification

• Individual dose modification of DARZALEX was not permitted, but dose delay was recommended as the primary method for managing DARZALEX-related toxicities.³

DARZALEX-Related Toxicity Management

• If any of the following criteria were met and the event could not be ascribed to bortezomib or thalidomide, the DARZALEX infusion was held to allow for recovery from toxicity. The criteria for a dose delay were³:
  • Grade 4 hematologic toxicity
  • Grade 3 thrombocytopenia with bleeding
  • Febrile neutropenia
  • ≥Grade 3 non-hematologic toxicities with the following exceptions:
    • Grade 3 nausea that responds to antiemetic treatment within 7 days
    • Grade 3 vomiting that responds to antiemetic treatment within 7 days
    • Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
    • Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last administration of DARZALEX
    • Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last administration of DARZALEX
• If DARZALEX administration did not commence within the prespecified window of the scheduled administration date, then the dose was considered a missed dose. Administration was resumed at the next planned dosing date. See table: DARZALEX-Related Toxicity Management.³
• A missed dose was not to be made up. If a dose was delayed, then the dates of all subsequent doses must be adjusted. Any adverse event deemed to be related to DARZALEX that required a dose hold of more than 28 days resulted in permanent discontinuation of DARZALEX.³

Daratumumab Interruption or Missed Doses

• A DARZALEX dose that was held for more than the permitted time from the per-protocol administration date for any reason other than toxicities suspected to be related to DARZALEX would be brought to the attention of the sponsor’s study team at the earliest possible time. Patients whose dose was delayed for more than 28 days would be withdrawn from study treatment, unless, upon consultation with the sponsor and the review of safety and efficacy, continuation is agreed upon.³

Dose Reductions (Bortezomib, Thalidomide, and Dexamethasone)

• Bortezomib was modified or discontinued as presented in Table: Dose Modification for Bortezomib.³

• Thalidomide was reduced or discontinued as presented in the Table: Dose Reduction for Thalidomide.³

• Dexamethasone was reduced or discontinued as presented in Table: Dose Reductions for Dexamethasone.³

• If reduction of dexamethasone dose occurred prior to Week 2 of Cycle 3, dose of dexamethasone from Week 2 of Cycle 3 onwards should also be reduced by 50% (i.e. dexamethasone 10 mg instead of dexamethasone 20 mg). Dose Modification Guidelines for bortezomib, thalidomide and dexamethasone as per the Figure: Dose Modification Guidelines for Bortezomib, Thalidomide, and Dexamethasone.³

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 12 July 2024.