A Phase II Study of Lenalidomide, Ixazomib, Dexamethasone, and Daratumumab in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma
A Phase II Study of Lenalidomide, Ixazomib, Dexamethasone, and Daratumumab in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma
A randomized Phase II clinical trial will be conducted to assess the impact on progression free survival (PFS) with the addition of ixazomib and daratumumab to lenalidomide as a maintenance treatment following induction with lenalidomide, ixazomib, dexamethasone, and daratumumab.
Patients will be randomized to either:
Arm A: 12 cycles of lenalidomide, ixazomib, daratumumab, and dexamethasone followed by lenalidomide until disease progression or unacceptable toxicity or a maximum of 2 years of maintenance therapy.
Arm B: 12 cycles of lenalidomide, ixazomib, daratumumab and dexamethasone, followed by lenalidomide, ixazomib, and daratumumab until disease progression or unacceptable toxicity or a maximum of 2 years maintenance therapy.
Induction Phase: 28-day treatment cycle. Treatment continues until disease progression or for a maximum of 12 cycles as follows:
Cycles 1-2:
Cycles 3-6:
Cycles 7-12:
Maintenance Phase: 28-day treatment cycle. Treatment continues until progression or a maximum of 2 years of maintenance treatment:
Arm A
• Lenalidomide - 10 mg PO QD on Days 1-21
Arm B
In the maintenance phase, dexamethasone, 20 mg PO orally or IV will be administered to patients as a pre-infusion medication prior to daratumumab dosing. When dexamethasone is reduced to 20 mg/week and is given as pre-infusion medication, patients may receive low-dose methylprednisolone (≤20 mg) orally (or equivalent in accordance with local standards) for the prevention of delayed IRRs as clinically indicated.
If the investigator wishes to continue the maintenance regimen at the end of the 2 years maintenance treatment, patients may continue current maintenance as per standard of care.
Inclusion Criteria:
Patient must be at least 18 years of age.
Subject must have documented multiple myeloma:
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma
Following CRAB features and/or myeloma-defining events (MDEs):
Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
OR any one or more of the following biomarkers of malignancy (MDEs):
Measurable disease as defined by any of the following:
Newly diagnosed and not considered candidate for high-dose chemotherapy with stem cell transplant due to:
Patient must have an ECOG performance status score of 0, 1, or 2.
Patient must have adequate pretreatment clinical laboratory values meeting the following criteria ≤14 days of registration date:
Women of childbearing potential (WOCBP) 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 initial 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 WOCBP 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, and for 4 months after the last dose of daratumumab. A WOCBP must have 2 negative serum or urine pregnancy tests first within 10 to 14 days prior to the registration date.
All study patients must be registered into the mandatory Revlimid REMS program and be willing and able to comply with the requirements of the REMS program.
Females of reproductive potential must agree to adhere to the scheduled pregnancy testing as required in the Revlimid REMS program.
At the time of registration, confirmation of adequate contraceptive method(s) should be documented in the medical record.
Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
Patient has primary AL amyloidosis.
Prior history 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.
Prior or current systemic therapy or stem cell transplantation (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 initial dosing. 1 cycle or less of urgent systemic treatment may be allowed after discussion with the Study Chair.
Patients undergoing treatment for a malignancy within 5 years prior to study enrollment with the exception of non-invasive malignancies that in the opinion of the site investigator are considered cured or have minimal risk of recurrence within 5 years. Patient must not have active concomitant, invasive malignancy. Note: patients on chronic hormonal therapy for localized breast or prostate cancer with no evidence for the primary malignancies or prostate cancer undergoing active surveillance can be included.
Radiation therapy ≤14 days prior to C1D1.
Plasmapheresis ≤28 days prior to C1D1.
Exhibiting clinical signs of meningeal involvement of MM ≤28 days prior to screening.
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 ≤ 2 years prior to screening (intermittent asthma is allowed).
Note: Patients with known or suspected COPD or asthma must have a FEV1 test within 28 days prior to screening.
Patient has history or evidence of unstable/uncontrolled medical or psychiatric disorder, condition or disease (e.g., 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 site investigator, would pose a risk to subject safety or interfere with study evaluation, procedures or completion.
Clinically significant cardiac disease, including:
Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies, or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure) or known sensitivity to mammalian-derived products.
History of plasma cell leukemia (by WHO criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of more than 2×10^9/L) or POEMS syndrome (ie, polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
Patient is:
A woman who is pregnant, or breast-feeding, or planning to become pregnant during the study period or a man who plans to father a child during the study period. See Section 12.8 for further details.
Major surgery ≤14 days prior to screening or has not fully recovered from surgery, or has surgery planned during the time the patient is expected to participate in the study.
Note: Kyphoplasty or vertebroplasty is not considered major surgery.
Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device ≤28 days prior to initial dosing or is currently enrolled in an interventional investigational study.
Contraindications to required protocol prophylaxis for deep vein thrombosis and pulmonary embolism.
Peripheral neuropathy Grade 2 or severe ≤28 days prior to screening.
Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort ≤14 days prior to screening.