Summary

This phase II trial studies how well daratumumab, ixazomib, and dexamethasone with or without bortezomib work in treating patients with newly diagnosed multiple myeloma. Daratumumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Ixazomib and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Anti-inflammatory drugs, such as dexamethasone lower the body’s immune response and are used with other drugs in the treatment of some types of cancer. It is not yet known whether giving daratumumab, ixazomib, and dexamethasone with or without bortezomib may work better in treating patients with multiple myeloma.

Objectives

PRIMARY OBJECTIVE:
I. To determine the >= very good partial response (VGPR) rate after 8 cycles in subjects treated with daratumumab and hyaluronidase-fihj (daratumumab), ixazomib and dexamethasone (DId) versus (vs) daratumumab, bortezomib and dexamethasone (DVd) followed by DId among newly diagnosed myeloma patients (NDMM).

SECONDARY OBJECTIVES:
I. To estimate the proportion of subjects with successful stem cell mobilization after receiving 3 cycles of treatment in both arms (DId x 8 vs DVd x 3 then DId x 5).
II. To establish safety among patients receiving the combination of DId and DVd then DId.
III. To obtain anti-tumor activity (best response rates: overall response rate [ORR], VGPR, complete response [CR], stringent complete response [sCR] and minimal residual of disease [MRD] negativity) in patients treated with these combinations.
IV. Progression free survival (PFS), progression free survival 2 (PFS2), duration of response (DOR), time to progression (TTP), determine the time to next therapy (TTNT).
V. Overall survival (OS).
VI. Engraftment parameters among the autologous stem cell transplant (ASCT) group.
VII. Determine whether tumor response and PFS may change in subgroups with different prognosis according to current prognostic factors.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I:
INDUCTION: Patients receive dexamethasone intravenously (IV) and orally (PO) on days 1, 8, 15, and 22, daratumumab and hyaluronidase-fihj subcutaneously (SC) on days 1, 8, 15, and 22 of cycles 1-2 and on days 1 and 15 of cycles 3-8, and ixazomib PO on days 1, 8, and 15. Treatment repeats every 28 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Eligible patients then undergo stem cell transplant per standard of care. Patients who have at least stable disease after induction and patients who have undergone transplant continue to Maintenance.

MAINTENANCE: Patients receive dexamethasone IV and PO on days 1, 8, 15, and 22, daratumumab and hyaluronidase-fihj SC on day 1, and ixazomib PO on days 1, 8, and 15. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

ARM II:
INDUCTION CYCLES 1-3: Patients receive dexamethasone IV and PO on days 1, 8, and 15, daratumumab and hyaluronidase-fihj SC on days 1, 8, and 15, and bortezomib SC on days 1, 4, 8, and 11. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

INDUCTION CYCLES 4-8: Patients receive dexamethasone IV and PO on days 1, 8, 15, and 22, daratumumab and hyaluronidase-fihj SC on days 1 and 15, and ixazomib PO on days 1, 8, and 15. Treatment repeats every 28 days for 5 cycles in the absence of disease progression or unacceptable toxicity. Eligible patients then undergo stem cell transplant per standard of care. Patients who have at least stable disease after induction and patients who have undergone transplant continue to Maintenance.

MAINTENANCE: Patients receive dexamethasone IV on day 1, daratumumab and hyaluronidase-fihj SC on day 1, and ixazomib PO on days 1, 8, and 15. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Eligibility

1. Patients must meet the following criteria on screening examination to be eligible to participate in the study. All laboratory assessments should be performed within 21 days of initiation of protocol therapy unless otherwise specified. Subject is, in the investigator’s opinion, willing and able to comply with the protocol requirements
2. Subject has given voluntary signed written informed consent before performance of any study-related procedure that is not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to their future medical care
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
4. Have documented multiple myeloma as defined by the International Myeloma Working Group (IMWG) 2014 criteria including: Clonal bone marrow plasma cells >= 10% (If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement). In addition, the patient must meet one of the criteria in d1 or d2: * Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically (one or more of the following): ** Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal (ULN) or > 2.75 mmol/L (> 11 mg/dL) ** Renal insufficiency: Creatinine clearance (CrCl) < 40 mL/min (measured or estimated by validated equations) or serum creatinine > 177 umol/L (> 2 mg/dL) ** Anemia: hemoglobin value of > 20 g/L below the lower limit of normal, or a hemoglobin value < 100 g/L ** Bone lesions: 1 or more osteolytic lesions on skeletal radiography, computed tomography (CT), or magnetic resonance imaging (MRI) *** Clonality should be established by showing kappa/lambda-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used * Any one or more of the following: ** Clonal bone marrow plasma cell percentage >= 60% *** Clonality should be established by showing kappa/lambda-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used ** Involved:uninvolved serum free light chain (FLC) ratio > 100 *** These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The involved FLC must be >= 100 mg/L ** > 1 focal lesions on MRI studies; Each focal lesion must be 5 mm or more in size
5. Measurable disease as defined by any of the following: * Serum M-protein level >= 1.0 g/dL or urine M-protein level >= 200 mg/24 hours. Note: All attempts should be made to determine eligibility of the subject based on the central laboratory results of screening blood and urine M-protein measurements. In exceptional circumstances, the local laboratory results for blood and urine M-protein measurements may be used to determine eligibility, but only if the results are clearly (e.g., 25% or more) above the thresholds for measurability; or * IgA, IgD, IgE, or IgM multiple myeloma: serum M-protein level >= 0.5 g/dL or urine M-protein level >= 200 mg/24 hours; or * Light chain multiple myeloma without measurable disease in the urine: serum Ig FLC >= 10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio
6. Prior treatment to stabilize the patient with steroids up to 160 mg IV equivalents of dexamethasone is allowed
7. Prior treatment to stabilize the patient with bortezomib up to 2 doses of 1.3 mg/m^2 each dosing equivalent is allowed
8. Subject agrees to refrain from blood donations during therapy on study and for 8 weeks after therapy is completed
9. Female patients who: * Are postmenopausal for at least 1 year before the screening visit, OR * Are surgically sterile, OR * If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) * Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior to and again within 24 hours of starting study drugs
10. Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following: * Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)

Treatment Sites in Georgia