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Iberdomide-Combinations for the Treatment of Positive Minimal Residual Disease (>10-5) after Autologous Hematopoietic Cell Transplantation as Upfront Therapy in Patients with Multiple Myeloma, The COMMANDER Trial
Trial Status: active
This phase I/II trial studies the safety, side effects, best dose, and effectiveness of iberdomide in combination with daratumumab and hyaluronidase-fihj, dexamethasone, and carfilzomib after autologous hematopoietic cell transplantation (AHCT) to eliminate minimal residual disease (MRD) in patients with multiple myeloma (MM). MRD is MM cells at very low level only detectable using a specially developed test utilizing a bone marrow sample. The presence of MRD after AHCT indicates higher risk of the myeloma returning or worsening. It has not yet been determined if more anti-myeloma treatment that makes the MRD non-detectable improves the patient’s survival or duration of myeloma control. Immunotherapy with iberdomide, may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Daratumumab is in a class of medications called monoclonal antibodies. It works by helping the body to slow or stop the growth of cancer cells. Hyaluronidase-fihj is an endoglycosidase. It helps to keep daratumumab in the body longer so that the medication will have a greater effect. 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 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving iberdomide in combination with daratumumab and hyaluronidase-fihj, dexamethasone, and carfilzomib after AHCT may reduce the number of circulating cancer cells detected in the blood in patients with MM.
Inclusion Criteria
Age > 18 years with no upper age limit
Confirmation of newly diagnosed multiple myeloma (MM) with 1-2 prior regimens utilized in induction that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI) combined or in different regimens
Eastern Cooperative Oncology Group (ECOG) performance status 0–2
Prior AHCT 100-180 days prior to initiation of protocol-directed therapy
MRD >= 10^-5 by clonoSEQ registered trademark next-generation sequencing (NGS) platform, determined 60-120 days after AHCT as part of the usual care
No prior disease progression (either before or since AHCT)
Overall response (i.e post-AHCT compared to historical baseline prior to initiation of any therapy for MM) >= partial response (PR)
Measurable disease at the time of the initial diagnosis (i.e. prior to starting any therapy for MM) meeting at least one of the following criteria:
* Serum monoclonal (M) protein >= 1.0 g/dl
* >= 200 mg of M protein/24 hours (h) in the urine
* Difference between involved and uninvolved free light chain >= 10 mg/dL and abnormal kappa to lambda ratio
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
Bilirubin =< 1.5 ULN
Platelets >= 75,000 /mm^3 (without transfusion of platelets in the prior 7 days)
Absolute neutrophil count >= 1,000/mm^3
Creatinine clearance (CrCl) >= 40 mL/minute within 28 days prior to start of therapy either measured or calculated using standard Cockcroft and Gault formula
Females of childbearing potential (FCBP) must have two negative pregnancy tests as verified by the investigator and agree to ongoing pregnancy testing and to practice contraception during treatment. Male subjects must agree to practice contraception and refrain from donating sperm during treatment
In line with the higher incidence of MM in Blacks, and to address the historical underrepresentation of ethnical minorities in MM trials, at least 25% of the enrolled patients will be of ethnical minorities
Written informed consent in accordance with federal, local, and institutional guidelines
Exclusion Criteria
Diagnosis of amyloidosis, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS), Waldenstrom’s macroglobulinemia, plasma cell leukemia or smoldering multiple myeloma (i.e. never evolved to active myeloma)
Major surgery or radiotherapy within 28 days of starting protocol-directed treatment
Acute active infection requiring treatment within 14 days of starting protocol-directed treatment
Current or prior involvement of central nervous system by multiple myeloma
MM refractory to prior CD38 monoclonal antibody therapy and/or to carfilzomib (prior exposure allowed). Refractoriness here is defined as not achieving at least a PR in a regimen containing the agent or disease progression < 60 days from last dose of the agent
Pregnant or lactating females
Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
Unstable angina or myocardial infarction within 4 months prior to starting protocol-directed treatment, New York Heart Association (NYHA) class II, III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemaker
A prolongation of QT interval on screening electrocardiogram (ECG) as defined by corrected QT interval (QTc) > 480 ms using Fridericia’s QT correction formula
Cerebrovascular disease manifested as prior stroke at any time or transient ischemic attack (TIA) in the 12 months prior to initiation of therapy
Uncontrolled hypertension (per investigator assessment, despite optimal medical management)
Diagnosis of interstitial lung disease
Nonhematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or localized thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
Significant neuropathy (grades 3–4, or grade 2 with pain) within 28 days prior to starting protocol-directed treatment
For regimen B - Known history of allergy to Captisol (registered trademark) (a cyclodextrin derivative used to solubilize carfilzomib)
Contra indication or intolerance to required supportive care medications (Aspirin and Acyclovir)
Concomitant use of strong inhibitors or inducers of CYP3A4, P-gp, or BCRP, or BCRP substrate with a narrow therapeutic index, for at least 14 days or 5 half-lives (whichever is shorter)
Any other clinically significant medical disease or condition that, in the investigator’s opinion, may interfere with protocol adherence or a subject’s ability to give informed consent. Diagnosis of amyloidosis, POEMS, Waldenstrom’s macroglobulinemia
Additional locations may be listed on ClinicalTrials.gov for NCT05434689.
I. To determine the safety and recommended phase 2 dose (RP2D) of the following iberdominde combinations when employed as consolidation therapy post autologous hematopoietic cell transplantation (AHCT) in MRD(+) patients (>= 10^-5) (Part I):
Ia. Regimen A: Iberdomide, daratumumab and dexamethasone (Part I);
Ib. Regimen B: Iberdomide, daratumumab, carfilzomib and dexamethasone (if regimen A is considered safe) (Part I).
II. To determine the efficacy of regimens A and B in post AHCT consolidation as assessed by conversion of MRD (to < 10^-5) (Part II).
SECONDARY OBJECTIVES:
I. To determine the sustainability of MRD (-) status achieved with regimen A or B.
II. To estimate the achievement of MRD <10^-6 with regimens A and B.
III. To determine the safety and tolerability of regimens A and B when utilized as post-AHCT consolidation.
IV. To estimate the risk of death or disease progression of patients treated with regimen A or B as post-AHCT consolidation.
OUTLINE: This is phase I, dose-escalation study of iberdominde followed by a phase II study.
PART 1 CONSOLIDATION THERAPY: Patients are assigned to 1 of 2 arms.
ARM I: Patients receive iberdomide orally (PO) on days 1-21 and dexamethasone PO or intravenously (IV) on days 1,8,15 and 22 of each cycle. Patients also receive daratumumab and hyaluronidase-fihj subcutaneously (SC) on days 1, 8, 15, 22 of cycles 1 and 2 or on days 1 and 15 of cycles 3-6. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) during screening and bone marrow aspiration during Part 1 of the study. Patients also undergo blood and urine sample collection throughout Part 1 of the study. Patients completing 6 cycles without disease progression and unacceptable toxicity and receiving clinical benefit have the option to proceed to Part 2 Continuation Therapy.
ARM II: Patients receive iberdomide PO on days 1-21, dexamethasone PO or IV on days 1,8,15 and 22, and carfilzomib IV over 30 minutes on days 1, 8, and 15 of each cycle. Patients also receive daratumumab and hyaluronidase-fihj SC on days 1, 8, 15, 22 of cycles 1 and 2 or on days 1 and 15 of cycles 3-6. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO during screening and bone marrow aspiration Part 1 of the study. Patients also undergo blood and urine sample collection throughout Part 1 of the study. Patients completing 6 cycles without disease progression and unacceptable toxicity and receiving clinical benefit have the option to proceed to Part 2 Continuation Therapy.
PART 2 CONTINUATION THERAPY: Patients receive iberdomide PO on days 1-21 of each cycle. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and undergo blood and urine sample collection throughout Part 2 of the study.
Patients are followed for up to 2 years from completion of Consolidation Therapy.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationUniversity of Alabama at Birmingham Cancer Center
