Evaluation of Daratumumab in Combination with Bortezomib, Cyclophosphamide, and Dexamethasone for Transplant-Ineligible Multiple Myeloma Patients

Trial ID: 2024-517761-17-00
Protocol: UNI-KOELN-3946
Sponsor: University Of Cologne

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Diseases & Conditions

Plasma cell myeloma

Objectives

The primary objective of this clinical trial is to investigate the **safety** and **efficacy** of adding **daratumumab** to a standard induction regimen consisting of bortezomib, cyclophosphamide, and dexamethasone (VCd) for the treatment of **Multiple Myeloma** in transplant-ineligible patients. This is clinically relevant as it aims to enhance treatment outcomes by integrating daratumumab, a monoclonal antibody, into the existing therapeutic protocol, potentially improving patient response and survival rates.

Secondary objectives include:

Assessing the efficacy of induction and maintenance therapy using daratumumab in combination with bortezomib and dexamethasone by evaluating minimal residual disease (MRD) negativity before and during maintenance therapy.
Evaluating the response and progression-free survival of a daratumumab-containing regimen at first progression/relapse 12 months after the start of second-line therapy.
Assessing the progression-free survival (PFS) of first-line therapy.
Evaluating the time to next treatment (TTNT) of first-line therapy DVCd.
Examining overall survival (OS) at the 36-month timepoint after the start of second-line treatment.
Investigating the overall response rate to first- and second-line treatment using the International Myeloma Working Group (IMWG) response criteria.

Participants

The clinical trial focuses on evaluating the safety and efficacy of adding **daratumumab** to a standard induction regimen for patients diagnosed with **Multiple Myeloma**. The study population includes both male and female participants aged 18 years and above. Participants are required to have an untreated diagnosis of multiple myeloma according to the International Myeloma Working Group diagnostic criteria and must not be eligible or willing to undergo autologous transplantation. The trial does not involve a vulnerable population. Participants are expected to maintain a general health status with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Lifestyle considerations include the use of effective contraception methods for both male and female participants of childbearing potential, with specific requirements for women regarding pregnancy testing and breastfeeding. The sponsor has not provided information on the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and **efficacy** of adding **daratumumab** to a standard induction regimen of bortezomib, cyclophosphamide, and dexamethasone (VCd) in patients with **multiple myeloma** who are ineligible for transplantation. This is a phase IV, randomized, double-blind, controlled trial. The trial is expected to run until December 31, 2030, with recruitment having commenced on June 2, 2021. Participants will be involved in the study for a maximum treatment period of 60 months, receiving **daratumumab** via subcutaneous injection.

The study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening visit, will confirm eligibility based on criteria such as age, diagnosis, and treatment history. Participants must provide signed informed consent and meet specific health criteria, including an ECOG performance status of ≤2. Women of childbearing potential must have a negative pregnancy test and adhere to contraception guidelines. Follow-up visits will occur regularly to assess primary and secondary endpoints, including response rates and progression-free survival. The end-of-study visit will evaluate the overall response and safety outcomes.

Participants may be withdrawn from the study if they experience adverse effects, fail to comply with the protocol, or choose to withdraw consent. The primary endpoint is the response rate (≥VGPR) after eight cycles of DVCd. Secondary endpoints include minimal residual disease negativity, progression-free survival, and overall survival. The trial aims to provide valuable insights into the therapeutic potential of **daratumumab** in this patient population.

Treatment

The clinical trial involves the administration of **DARZALEX**, a solution for injection containing the active substance **daratumumab**. This experimental medication is provided in a pharmaceutical form suitable for **subcutaneous injection**. Each dose contains 1800 mg of daratumumab, with a maximum daily dose of 1800 mg and a cumulative maximum dose of 108,000 mg over the treatment period. The treatment is administered according to a predefined schedule, with a maximum treatment period of 60 days. The administration of DARZALEX is conducted under controlled conditions to ensure participant compliance and safety.

In addition to the experimental treatment, participants in the study receive a standard induction regimen consisting of **bortezomib**, **cyclophosphamide**, and **dexamethasone** (VCd). This regimen serves as the standard-of-care therapy and is administered according to established clinical guidelines. The combination of daratumumab with the VCd regimen aims to evaluate the safety and efficacy of the treatment in patients with transplant-ineligible myeloma. Compliance with the dosing schedule and administration of both the experimental and standard treatments is closely monitored throughout the trial to ensure adherence to the protocol and to assess the therapeutic outcomes accurately.

Efficacy

Efficacy in this clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the response rate, specifically the proportion of patients achieving a response of at least very good partial response (≥VGPR) after 8 cycles of the treatment regimen consisting of daratumumab, bortezomib, cyclophosphamide, and dexamethasone (DVCd). Secondary endpoints include several measures: minimal residual disease (MRD) negativity at any time before and during maintenance therapy with daratumumab, bortezomib, and dexamethasone (DVd), assessed by next-generation sequencing (NGS) at a level of 10^-5; progression-free survival (PFS) at 12 months from the start of second-line therapy; overall progression-free survival from trial inclusion; time to next treatment (TTNT); overall survival (OS); and overall response rates for both first-line and second-line treatments. Additionally, MRD negativity will also be assessed at other thresholds or by flow cytometry.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed Written Informed Consent
Untreated patients with multiple myeloma diagnosis according to the International myeloma working group (IMWG) diagnostic criteria
ECOG ≤2
Not eligible or willing for autologous transplantation
Age 18 years or above
Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception and must agree to use adequate method to avoid pregnancy for 6 months after the last dose of IMP.
Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25IU/L or equivalent units of β-HCG) within one to two weeks prior to the start of Daratumumab
Women will be not be considered to be of childbearing potential if they are post-menopausal and/or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). To be considered post-menopausal the appropriate age-specific requirements have to be met.
Women must not be breastfeeding.
Male trial participants who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year and must be willing to adhere to any approved contraception method for a period of 6 months post treatment completion.

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Exclusion Criteria

Subject has received any multiple myeloma therapy previously, except dexamethasone to a maximum cumulative dose of 160mg, emergency radiotherapy or surgery for symptom control
Participation in other interventional clinical trials
Subject has known meningeal involvement of multiple myeloma.
Subjects with plasma cell leukemia or AL amyloidosis
Non-hematologic malignancy within the past 2 years with the exception defined in the protocol
Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% of predicted normal.
Known moderate or severe persistent asthma, within the past 2 years, uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the trial.
Subject is known to be seropositive for human immunodeficiency virus (HIV)
Active hepatitis B (defined by a positive test for HBV DNA) or hepatitis C (defined by a positive test for HCV-RNA-quantification). (Patients with a positive test for HBs antigen or antibodies, but negative HBC DNA may be included but must be monitored for HBV activation throughout the study.)
Subject has any concurrent medical condition or disease (e.g. active systemic infection) that is likely to interfere with trial procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this trial.
Concomitant chemotherapy or myeloma-specific therapy other than trial treatment (incl. standard intensification) is not permitted. The sponsor must be notified in advance (or as soon as possible thereafter) of any instances on which prohibited medications are administered.
Patients has known current symptomatic congestive heart failure (New York Heart Association Class III-IV, see APPENDIX III B) unstable angina pectoris, or uncontrolled cardiac arrythmia
Absolute neutrophil count ≤0.5 × 109/L
Platelet count <30 × 109/L
Aspartate aminotransferase (AST) or alanine aminotransferase level (ALT) ≥4.5 times the upper limit of normal (ULN)
Alkaline phosphatase level ≥4.5 × ULN
Total bilirubin level ≥2.5 × ULN, (except for Gilbert Syndrome: direct bilirubin 1.5 × ULN)
Pregnant women and nursing mothers, or women planning to become pregnant while enrolled in this trial or within 3 months after the last dose of daratumumab
Failure to use highly-effective contraceptive methods.
Persons with any kind of dependency on the principal investigator or employed by the sponsor or principal investigator
Legally incapacitated persons
Subject is known or suspected of not being able to comply with the trial protocol (e.g. because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g. compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
Persons held in an institution by legal or official order