This is a phase II study to evaluate the efficacy of once weekly carfilzomib, lenalidomide,
dexamethasone, and isatuximab (KRDI) in patients with newly diagnosed, transplant-eligible
multiple myeloma. The research study procedures include screening for eligibility and study
treatment including evaluations and follow up visits. The study treatment portion of this
study is comprised of an induction phase and a maintenance phase.
- Induction Phase :
- All participants will receive the same study drugs (carfilzomib, isatuximab,
lenalidomide, and dexamethasone) for up to 8 cycles. Each cycle is 28 days in
length.
- All participants will perform stem cell collection after 4 cycles of therapy. Based
on the recommendation participants may or may not proceed to an autologous stem
cell transplant (SCT) as part of induction therapy.
- Maintenance Phase: During maintenance, participants will receive the study treatment for
up to two years after induction until progressive disease or unacceptable toxicity
It is expected that about 50 people will take part in this research study.
This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational drug combination to learn whether the drug
combination works in treating a specific disease.
"Investigational" means that the drug combination is being studied.
The U.S. Food and Drug Administration (FDA) has approved carfilzomib or isatuximab as a
treatment for relapsed/refractory multiple myeloma.
The FDA has also approved lenalidomide and dexamethasone as a treatment option for
transplant-eligible multiple myeloma.
However, the FDA has not approved the combination of isatuximab, carfilzomib, lenalidomide,
and dexamethasone as an approved regimen. The combination is considered to be investigational
for the treatment of individuals with newly diagnosed multiple myeloma.
Inclusion Criteria:
- Subject must be at least 18 years of age.
- Subject must have documented multiple myeloma satisfying the CRAB criteria and
measurable disease defined as:
- Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy-proven
Plasmacytoma.
- Measurable disease as defined by any of the following:
- IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥.5 g/dL or urine
M-protein level ≥200 mg/24 hours; or
- IgA, IgM, or IgD multiple myeloma: serum M-protein level ≥0.25 g/dL or urine
M-protein level ≥200 mg/24 hours; or
- Light chain multiple myeloma: Serum immunoglobulin free light chain ≥10 mg/dL and
abnormal serum immunoglobulin kappa lambda free light chain ratio.
- Sixty percent or greater clonal plasma cells on bone marrow examination.
- Serum involved / uninvolved free light chain ratio of 100 or greater, provided
the absolute level of the involved free light chain is at least 100 mg/L (a
patient's "involved" free light chain - either kappa or lambda - is the one that
is above the normal reference range; the uninvolved light chain is the one that
typically is in, or below, the normal range).
- More than one focal lesion on magnetic resonance image (MRI) that is at least 5
mm or greater in size.
- Newly diagnosed and considered candidate for high-dose chemotherapy with stem cell
transplant.
- Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status
score of 0, 1, or 2.
- Subject must have pretreatment clinical laboratory values meeting the following
criteria during the Screening Phase:
- hemoglobin ≥ 7.5 g/dL (≥ mmol/L; prior RBC transfusion or recombinant human
erythropoietin use is permitted);
- absolute neutrophil count ≥1.0 x 109/L (granulocyte colony stimulating factor
[GCSF] use is permitted);
- platelet count ≥70 x 109/L for subjects in whom <50% of bone marrow nucleated
cells are plasma cells; otherwise platelet count >50 × 109/L (transfusions are
not permitted to achieve this minimum platelet count)
- aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN);
- alanine aminotransferase (ALT) ≤2.5 x ULN;
- total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia,
such as Gilbert syndrome (direct bilirubin ≤2.0 x ULN)
- creatinine clearance ≥30 mL/min
- corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L); or free ionized calcium <6.5
mg/dL (<1.6 mmol/L).
- Women of childbearing potential must commit to either abstain continuously from
heterosexual sexual intercourse or to use 2 methods of reliable birth control
simultaneously. This includes one highly effective form of contraception (tubal
ligation, intrauterine device [IUD], hormonal [birth control pills, injections,
hormonal patches, vaginal rings or implants] or partner's vasectomy) and one
additional effective contraceptive method (male latex or synthetic condom, diaphragm,
or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable
contraception is indicated even where there has been a history of infertility, unless
due to hysterectomy or bilateral oophorectomy.
- A man who is sexually active with a woman of childbearing potential must agree to use
a latex or synthetic condom, even if they had a successful vasectomy. All men must
also not donate sperm during the study, for 4 weeks after the last dose of
lenalidomide, for 90 days after the last dose of carfilzomib, and for 4 months after
the last dose of isatuximab.
- A woman of childbearing potential must have 2 negative serum or urine pregnancy tests
at Screening, first within 10 to 14 days prior to dosing and the second within 24
hours prior to dosing.
- Each subject (or their legally acceptable representative) must sign an informed
consent form (ICF) indicating that he or she understands the purpose of and procedures
required for the study and are willing to participate in the study. Subject must be
willing and able to adhere to the prohibitions and restrictions specified in this
protocol, as referenced in the ICF.
Exclusion Criteria:
- Any potential subject who meets any of the following criteria will be excluded from
participating in the study.
- Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined
significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined
significance is defined by presence of serum M-protein <3 g/dL; absence of lytic bone
lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein; and
(if determined) proportion of plasma cells in the bone marrow of 10% or less.
Smoldering multiple myeloma is defined as asymptomatic MM with absence of related
organ or tissue impairment end organ damage.
- Subject has a diagnosis of Waldenström's disease, or other conditions in which IgM
M-protein is present in the absence of a clonal plasma cell infiltration with lytic
bone lesions
- Subject has prior or current systemic therapy or SCT for MM, with the exception of an
emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4
days) of corticosteroids before treatment.
- Subject has a history of malignancy (other than MM) within 5 years before the date of
enrollment (exceptions are squamous and basal cell carcinomas of the skin and
carcinoma in situ of the cervix, or malignancy that in the opinion of the
investigator, with concurrence with the sponsor's medical monitor, is considered cured
with minimal risk of recurrence within 5 years).
- Subject has had radiation therapy within 14 days of enrollment.
- Subject has had plasmapheresis within 28 days of enrollment.
- Subject is exhibiting clinical signs of meningeal involvement of MM.
- Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced
expiratory volume [FEV] in 1 second <60% of predicted normal), persistent asthma, or a
history of asthma within the last 2 years (intermittent asthma is allowed). Subjects
with known or suspected COPD or asthma must have a FEV1 test during screening.
- Subject is known to be seropositive for history of human immunodeficiency virus (HIV)
or known to have active hepatitis B or hepatitis C.
- Subject has any concurrent medical or psychiatric condition or disease (eg, active
systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary
disease) that is likely to interfere with the study procedures or results, or that in
the opinion of the investigator, would constitute a hazard for participating in this
study.
- Subject has clinically significant cardiac disease, including:
- myocardial infarction within 1 year before enrollment, or an unstable or
uncontrolled disease/condition related to or affecting cardiac function (eg,
unstable angina, congestive heart failure, New York Heart Association Class
III-IV;
- uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology
Criteria for Adverse Events [NCI CTCAE] Version 4 Grade ≥2) or clinically
significant ECG abnormalities;
- screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's
formula (QTcF) >470 msec.
- uncontrolled hypertension
- Subject has known allergies, hypersensitivity, or intolerance to corticosteroids,
monoclonal antibodies or human proteins, or their excipients (refer to respective
package inserts or IB) or known sensitivity to mammalian-derived products.
- Subject has plasma cell leukemia (according to World Health Organization [WHO]
criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of
more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,
monoclonal protein, and skin changes).
- Subject is known or suspected of not being able to comply with the study protocol (eg,
because of alcoholism, drug dependency, or psychological disorder). Subject has any
condition for which, in the opinion of the investigator, participation would not be in
the best interest of the subject (eg, compromise the well-being) or that could
prevent, limit, or confound the protocol specified assessments.
- Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant
while enrolled in this study within 30 days after the last dose of lenalidomide or
carfilzomib, or within 4 months after the last dose of isatuximab. Or, subject is a
man who plans to father a child while enrolled in this study, within 4 weeks after the
last dose of lenalidomide, within 90 days of the last dose of carfilzomib, or within 4
months after the last dose of isatuximab.
- Subject has had major surgery within 2 weeks before enrollment or has not fully
recovered from surgery, or has surgery planned during the time the subject is expected
to participate in the study. Kyphoplasty or vertebroplasty is not considered major
surgery.
- Subject has received an investigational drug (including investigational vaccines) or
used an invasive investigational medical device within 4 weeks before enrollment or is
currently enrolled in an interventional investigational study.
- Subject has contraindications to required prophylaxis for deep vein thrombosis and
pulmonary embolism.
- Incidence of gastrointestinal disease that may significantly alter the absorption of
oral drugs.
- Peripheral neuropathy ≥ Grade 2 on clinical examination during the screening period.
- Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong
inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole,
ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin,
rifapentine, rifabutin, carbamazepine, phenytoin, phenobartital), or use of Ginkgo
biloba, St. John's wort within 14 days before the first dose of study treatment.
