This phase II trial compares the effect of the combination of daratumumab-hyaluronidase (daratumumab) and teclistamab to the usual treatment of daratumumab, pomalidomide, dexamethasone or daratumumab, carfilzomib and dexamethasone in treating patients with multiple myeloma that has not responded to previous treatment (refractory) or that has come back after a period of improvement (relapsed). Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Teclistamab is a bispecific antibody that can bind to two different antigens at the same time. Teclistamab binds to B-cell maturation antigen, a protein found on some B-cells and myeloma cells, and CD3 on T-cells (a type of white blood cell) and may interfere with the ability of cancer cells to grow and spread. Pomalidomide is in a class of medications called immunomodulatory agents. It works by helping the immune system kill cancer cells and by helping the bone marrow to produce normal blood cells. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Carfilzomib, a type of proteasome inhibitor, blocks the action of enzymes called proteasomes, which may help keep cancer cells from growing and may kill them. Giving daratumumab and teclistamab may be more effective than the usual treatment of daratumumab, pomalidomide, dexamethasone or daratumumab, carfilzomib and dexamethasone in reducing myeloma cells to undetectable levels in patients with relapsed or refractory multiple myeloma.
PRIMARY OBJECTIVE: I. To determine whether patients with high-risk multiple myeloma (MM) that is refractory or in first relapse randomized to daratumumab and recombinant human hyaluronidase (daratumumab-hyaluronidase) in combination with teclistamab (DT) have superior efficacy measured by minimal residual disease (MRD)-negative status after 6 cycles of therapy compared to investigator's choice of daratumumab-hyaluronidase, pomalidomide and dexamethasone (DPd) or daratumumab-hyaluronidase, carfilzomib and dexamethasone (DKd). SECONDARY CLINICAL OBJECTIVES: I. To compare toxicity rates up to 6 cycles and overall on treatment between arms. II. To compare progression-free and overall survival between arms. III. To evaluate best response per International Myeloma Working Group (IMWG) criteria after 6 cycles and overall on treatment. IV. To evaluate safety and tolerability. EXPLORATORY CLINICAL OBJECTIVES: I. To evaluate treatment exposure and adherence. II. To evaluate time to progression and event free survival. III. To evaluate association of MRD-negative status after 6 cycles with best response per IMWG criteria and time to event outcomes. EXPLORATORY THROMBOEMBOLISM RISK OBJECTIVES: I. To estimate cumulative incidence of venous and arterial thromboembolic events. II. To calculate IMPEDE and SAVED risk scores at baseline and at time of venous thromboembolic event. III. To validate IMPEDE and SAVED risk stratification models. IV. To describe thromboprophylaxis strategies on treatment and assess the association with venous and arterial thromboembolic events. V. To estimate incidence of clinically significant (major) bleeding events and assess association with thromboprophylaxis strategy. VI. To assess the association of venous and arterial thromboembolic events and overall survival. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients are assigned to 1 of 2 treatments per investigator's choice. Treatment I (DPD): Patients receive daratumumab-hyaluronidase subcutaneously (SC) over 3-5 minutes on days 1, 8, 15, and 22 of cycles 1 and 2, on days 1 and 15 of cycles 3-6, then on day 1 of subsequent cycles. Patients also receive pomalidomide orally (PO) on days 1-21 of each cycle, dexamethasone PO or intravenously (IV) on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Treatment II (DKD): Patients are assigned to 1 of 2 options for carfilzomib. OPTION 1: Patients receive daratumumab-hyaluronidase SC over 3-5 minutes on days 1, 8, 15, and 22 of cycles 1 and 2, on days 1 and 15 of cycles 3-6, then on day 1 of subsequent cycles, carfilzomib IV on days 1, 2, 8, 9, 15, and 16 of each cycle, and dexamethasone PO or IV on days 1, 2, 8, 9, 15, and 16 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. OPTION 2: Patients receive daratumumab-hyaluronidase SC over 3-5 minutes on days 1, 8, 15, and 22 of cycles 1 and 2, on days 1 and 15 of cycles 3-6 and on day 1 of subsequent cycles, carfilzomib IV on days 1, 8, and 15 of each cycle, and dexamethasone PO or IV on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive daratumumab-hyaluronidase SC over 3-5 minutes on days 1, 8, 15, and 22 of cycles 1 and 2, on days 1 and 15 of cycles 3-6 and on day 1 of subsequent cycles. Patients also receive teclistamab SC on day 2, 4, 8, 15 and 22 of cycle 1, on days 1, 8, 15, and 22 of cycle 2, on days 1 and 15 of cycles 3-6 and then on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo urine and blood sample collection, bone marrow biopsy, and fludeoxyglucose F-18 (FDG) positron emission tomography (PET)/computed tomography (CT) throughout the study. After completion of study treatment, patients are followed up every 3 months for up to year 2, every 6 months up to year 5 then yearly for up to 10 years from randomization.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
80
Undergo urine and blood sample collection
Undergo bone marrow biopsy
Given IV
Undergo FDG PET/CT
Given SC
Given PO or IV
Undergo FDG PET/CT
Given PO
Given SC
ECOG-ACRIN Cancer Research Group
Philadelphia, Pennsylvania, United States
RECRUITINGMinimal residual disease (MRD) negativity
Will be determined by the Adaptive Biotechnologies clonoSEQ assay result. Analysis will be performed using Cochran-Mantel-Haenszel (CMH) test, stratified on prior anti-CD38 antibody therapy and investigator's choice of therapy if assigned to Arm A. MRD-negative status requires both MRD negativity and achievement of complete response. Will be summarized using descriptive statistics by treatment arm with two-sided exact binomial 80% confidence intervals (CI), Clopper-Pearson. The corresponding CMH odds ratio (OR) estimate with an 80% CI, and p-value will be reported. Logistic regression will be used to assess the treatment effect within subgroups including but not limited to age 70 status, prior anti-CD38 antibody therapy and high-risk by fluorescence in situ hybridization status.
Time frame: After 6 cycles of treatment (cycle length = 28 days), assessed at 6 months
Incidence of adverse events (AEs)
Will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) and classified by Medical Dictionary for Regulatory Activities (MedDRA) system organ class. Maximum grade toxicity by AE type will be tabulated. Summaries (count and percentages) will be reported by AE type by arm.
Time frame: Up to 6 cycles (cycle length = 28 days) and overall assessed up to 10 years
Incidence of grade 3 or higher hematologic and/or non-hematologic AEs
Will be graded according to the NCI CTCAE and classified by MedDRA system organ class. Maximum grade toxicity by AE type will be tabulated. Summaries (count and percentages) will be reported by AE type by arm. Rates of maximum grade 3 or higher (including grade 5) non-hematologic, hematologic and overall toxicity will be calculated along with 90% CIs. AEs will be further analyzed by arm in subsets of serious AEs per protocol, lethal AEs and treatment-emergent AEs status.
Time frame: Up to 6 cycles (cycle length = 28 days) and overall assessed up to 10 years
Progression-free survival (PFS)
PFS will be estimated in the treated population using the Kaplan-Meier method and compared between arms using the stratified log-rank test. Stratified cox proportional hazards (PH) regression will be used to produce the treatment hazard ratio (HR) along with the 90% CI, provided PH assumption is valid. Sensitivity analyses excluding untreated patients will be conducted.
Time frame: From randomization until the earlier of progression or death due to any cause, assessed up to 10 years
Overall survival (OS)
OS will be estimated in the treated population using the Kaplan-Meier method and compared between arms using the stratified log-rank test. Stratified cox PH regression will be used to produce the treatment HR along with the 90% CI, provided PH assumption is valid. Sensitivity analyses excluding untreated patients will be conducted.
Time frame: From randomization to death due to any cause, assessed up to 10 years
Response rates
Will be reported by treatment arm. Rates of stringent complete response (CR) or better, very good partial response (VGPR) or better and partial response (PR) or better will be computed along with 90% CIs in all treated patients. Stratified CMH test will be used to test the difference in VGPR or better rates between arms. Sensitivity analyses excluding untreated patients will be conducted.
Time frame: After 6 cycles of treatment (cycle length = 28 days) and overall, assessed up to 10 years
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