Iberdomide

Based on the mechanism of action and findings from animal studies, iberdomide can cause birth defects or embryo-fetal death in humans when administered to a pregnant female and is contraindicated during pregnancy.

Iberdomide has a shared mechanism of action with thalidomide. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented, and mortality at or shortly after birth has been reported in about 40% of infants.

There are no available data on the use of iberdomide in pregnant women to evaluate for drug associated risk. Oral administration of iberdomide in pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes including embryo-fetal mortality, alterations to growth, and structural abnormalities. Iberdomide crossed the placenta after administration to pregnant rats and rabbits. Advise patients of the potential risk to a fetus.

If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to iberdomide to the REMS Call Center at 1-888-423-5436.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There is no information regarding the presence of iberdomide or its metabolites in human milk, the effects of iberdomide on the breastfed child, or the effects of iberdomide on milk production. Iberdomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from iberdomide, advise women not to breastfeed during treatment with iberdomide. Refer to daratumumab and hyaluronidase-fihj or dexamethasone prescribing information for additional information.

Carcinogenesis

Carcinogenicity studies have not been conducted for iberdomide.

Mutagenesis

Iberdomide was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay but was clastogenic in the in vitro assay using human peripheral blood lymphocytes. Subsequently, iberdomide was negative in the in vivo micronucleus assay and DNA damage in liver (Comet assay) in rats and, therefore, iberdomide is not genotoxic.

Impairment of Fertility

In the 9-month monkey study, animals were treated with oral doses of up to 0.4 mg/kg/day. Testicular hypospermatogenesis and intraluminal cell debris in the epididymis occurred at the high dose of 0.40 mg/kg/day (approximately 3-fold greater than the human exposure at the recommended dose based on AUC at steady state).

In a fertility and early embryonic development toxicity study in rabbits, males and females were treated with oral doses of up to 50 mg/kg and 15 mg/kg, respectively, and were mated with untreated rabbits. Treatment in males began 65 days prior to mating, continued during mating and for up to 81 days post-mating. In females, treatment began 14 days prior to mating, continued during mating and until GD 7. Males treated with ≥5 mg/kg/day (approximately 32-fold greater than the human exposure at the recommended dose based on AUC steady state) had epithelial cell degeneration in seminiferous tubules, cellular debris in epididymal lumen, and abnormal sperm morphology. These effects were reversible after stopping dosing. Due to mortality in males at doses ≥5 mg/kg/day, mating and effects on fertility were not evaluated. Female rabbits had reduced fertility and increased pre- and post-implantation loss at ≥5 mg/kg/day (approximately 50-fold greater than the human exposure at the recommended dose based on AUC at steady state).

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of iberdomide in combination with daratumumab and hyaluronidase-fihj and dexamethasone was evaluated in EXCALIBER-RRMM, a two-stage, phase 3, randomized, multicenter open-label study in patients with relapsed or refractory multiple myeloma (RRMM) after 1 or 2 prior lines of therapy. Patients were randomized to receive iberdomide (at 1 of 3 dose levels) in combination with daratumumab and hyaluronidase-fihj and dexamethasone or daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (DVd) in stage 1, and iberdomide 1 mg in combination with daratumumab and hyaluronidase-fihj and dexamethasone (IberDd) or DVd in stage 2. The MRD Primary Analysis Group included the first 420 patients randomized to iberdomide 1 mg in combination with Dd (N=207) or DVd (N=213) in stage 1 and stage 2. Safety was assessed in patients in the MRD Primary Analysis Group who received at least one dose of the study drug (IberDd: N=204; DVd: N=204). Among patients who received iberdomide, 86% were exposed for 6 months or longer and 73% were exposed for greater than one year.

Serious adverse reactions occurred in 58.3% of patients who received iberdomide. Serious adverse reactions in ≥2% of patients included pneumonia (26%), upper respiratory tract infection (6.4%), second primary malignancy (5.9%), neutropenia (4.9%), febrile neutropenia (3.9%), COVID-19 (4.4%), and sepsis (2.9%). Fatal adverse reactions occurred in 10 patients (4.9%) who received iberdomide. Sepsis (1.5%) was the only fatal drug reaction that occurred in more than 1 patient. The following fatal adverse reactions occurred in one patient each: listeria encephalitis, influenza, lung adenocarcinoma, cardiac arrest, large intestine perforation, metabolic acidosis, and respiratory failure.

Permanent discontinuation of iberdomide due to an adverse reaction occurred in 7.8% of patients. The most frequent adverse reaction which resulted in permanent iberdomide discontinuation was neutropenia (1%).

Dosage interruption of iberdomide due to an adverse reaction occurred in 84% of patients. Adverse reactions which required dosage interruption in >10% of patients included neutropenia, upper respiratory tract infection, pneumonia and COVID-19.

Dosage reductions of iberdomide due to an adverse reaction occurred in 29% of patients. Adverse reactions which required dose reductions in >2% of patients included neutropenia, fatigue, pneumonia, and sensory neuropathy.

The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, musculoskeletal pain, pneumonia, diarrhea, motor dysfunction, rash, sleep disorder, hypogammaglobulinemia, COVID-19, and constipation.

The most common Grade 3 to 4 laboratory abnormalities (≥30%) were decreased neutrophils, decreased white blood cells, and decreased lymphocytes.

Tables 1 and 2 summarize adverse reactions and laboratory abnormalities, respectively, in the EXCALIBER-RRMM study.

Table 1. Adverse Reactions (≥10%) in Patients Who Received Iberdomide in Combination with Daratumumab and Hyaluronidase-fihj and Dexamethasone in EXCALIBER-RRMM:

Adverse reactions were graded according to NCI CTCAE Version 5.0.
^* Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, sinusitis, and other related terms.
^† Includes fatal adverse reaction: IberDd (n=1).
^‡ Pneumonia includes atypical pneumonia, bacterial pneumonia, lower respiratory tract infection, lung consolidation, viral pneumonia and other related terms.
^§ Includes other related terms.
^¶ Motor dysfunction includes ataxia, balance disorder, gait disturbance, muscle contracture, muscle spasms, muscular weakness, myopathy, paralysis, peripheral motor neuropathy and other related terms.
^# Sensory neuropathy includes anosmia, hypoesthesia, mononeuropathy, neuralgia, paresthesia, peripheral neuropathy, peripheral sensory neuropathy, polyneuropathy, radiculopathy and other related terms.
^Þ Sleep disorder includes insomnia, restless legs syndrome, sleep disorder and other related terms.
^ß Hypogammaglobulinemia includes hypogammaglobulinemia, hypoglobulinemia, and other related terms.
^à Hemorrhage includes epistaxis, gastrointestinal hemorrhage, hematuria, injection site hemorrhage, rectal hemorrhage, subarachnoid hemorrhage, subdural hematoma and other related terms.

Clinically relevant adverse reactions in <10% of patients who received iberdomide (in combination with daratumumab and hyaluronidase-fihj and dexamethasone) included:

• Venous thromboembolic event (includes retinal vein occlusion, pulmonary embolism, deep vein thrombosis, embolism venous, post thrombotic syndrome, superficial vein thrombosis, and thrombophlebitis).
• Arterial thromboembolic event (includes myocardial infarction, stress cardiomyopathy, ischemic stroke, lacunar infarction, peripheral arterial occlusive disease).
• Second primary malignancy
• Febrile neutropenia
• Sepsis
• Hepatotoxicity

Table 2. Select Laboratory Abnormalities (≥30%) That Worsened from Baseline* in Patients Who Received Iberdomide in EXCALIBER-RRMM:

^* The denominator used to calculate the rate varied from 201 to 204 for both IberDd and DVd arms based on the number of patients with a baseline value and at least one post-treatment value.