Testing the Addition of Ixazomib/Placebo to Lenalidomide in Patients With Evidence of Residual Multiple Myeloma, OPTIMUM Trial

Phase 3

Completed

Conditions: Multiple Myeloma

Interventions: Procedure: Biospecimen Collection
Procedure: Bone Marrow Aspirate
Procedure: Bone Marrow Biopsy
Procedure: Computed Tomography
Drug: Ixazomib Citrate
Drug: Lenalidomide
Other: Placebo Administration
Other: Quality-of-Life Assessment
Procedure: Positron Emission Tomography
Other: Questionnaire Administration

Registration Number: NCT03941860

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase III trial studies how well lenalidomide in combination with ixazomib works compared to lenalidomide alone in treating patients with evidence of residual multiple myeloma after stem cell transplantation. Lenalidomide may help shrink or slow the growth of multiple myeloma. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving lenalidomide and ixazomib together may work better than giving lenalidomide alone in treating patients with evidence of residual multiple myeloma after a stem cell transplantation.

Detailed Description: PRIMARY OBJECTIVE:

I. To evaluate whether escalating maintenance therapy with the addition of ixazomib citrate (ixazomib) to lenalidomide improves overall survival (OS) among patients who are minimal residual disease (MRD) positive after approximately 1 year of lenalidomide maintenance following an early stem cell transplant (=\< 12 months from diagnosis).

SECONDARY OBJECTIVES:

I. To establish whether progression-free survival (PFS) is superior with the addition of ixazomib to lenalidomide maintenance.

II. To evaluate best response on treatment and compare response rates between arms.

III. To evaluate the safety profile of ixazomib added to lenalidomide and compare toxicity rates between arms.

EXPLORATORY OBJECTIVES:

I. To measure treatment exposure and adherence. II. To estimate treatment duration, duration of response and time to progression.

PATIENT-REPORTED OUTCOMES (PRO) OBJECTIVES:

I. To quantify the extent to which the addition of ixazomib to lenalidomide maintenance contributes to neuropathy and associated physical and functional impairments. (Primary) II. To assess the impact of the addition of ixazomib to lenalidomide maintenance on disease control and associated physical and functional well-being. (Primary) III. To evaluate time to worsening and recovery rate related to neuropathy. (Secondary) IV. To evaluate time to improvement and response rate related to disease control. (Secondary) V. To evaluate attributes of select patient reported treatment-emergent symptomatic adverse events (Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events \[PRO-CTCAE\]) longitudinally and compare responses with provider-reported adverse events. (Exploratory) VI. To measure the likelihood of medication adherence and examine the relationship with treatment exposure. (Exploratory) VII. To assess correlation among patient reported outcome measures and association with clinical outcomes. (Exploratory) VIII. To tabulate PRO compliance and completion rates. (Exploratory)

IMAGING OBJECTIVES:

I. To evaluate the association between baseline fludeoxyglucose F-18 (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) and patient outcomes.

II. To compare overall survival (OS) with the addition of ixazomib to lenalidomide among baseline 18F-FDG PET/CT-positive and 18F-FDG PET/CT -negative subgroups.

III. To compare the change in quantitative 18F-FDG PET/CT parameters over time with the addition of ixazomib to lenalidomide.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and positron emission tomography (PET) and computed tomography (CT) scan at screening and on study as well as undergo collection of blood samples throughout the trial.

ARM B: Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up every 3 months if \< 2 years from study entry, every 6 months if 2-5 years from study entry, then every 12 months for up to 10 years from study entry.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1

Inclusion Criteria

STEP 0: PRE-REGISTRATION
Patient must be >= 18 years of age
Patient must be previously diagnosed with multiple myeloma (MM) and be on lenalidomide maintenance with >= 5mg daily for at least 6 months and no more than 18 months after an early autologous stem cell transplantation (SCT =< 12 months of diagnosis). Patient must not be off lenalidomide maintenance therapy for more than 30 days prior to start of treatment on Step 1 of this protocol
Patient must be able to undergo a diagnostic bone marrow aspirate following pre-registration to Step 0
- NOTE: A bone marrow aspirate specimen must be submitted to Mayo Clinic Hematology Laboratory for central assessment of minimal residual disease (MRD) status to confirm patient's eligibility for Step 1 randomization. Mayo Clinic will forward results to the submitting institution within three (3) business days of receipt of the bone marrow specimen
Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
Patient must have been able to maintain at least 5mg daily dose of lenalidomide without growth factor support
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
STEP 1 RANDOMIZATION
Patient must meet Step 0 eligibility criteria at the time of Step 1 randomization
Patients must have evidence of residual disease by central MRD testing or by presence of monoclonal protein in serum or urine
Patient must have serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum free light chain (FLC) performed =< 28 days prior to randomization
- NOTE: UPEP (on a 24-hour collection) is required, no substitute method is acceptable. Urine must be followed monthly if the baseline urine M-spike is >= 200 mg/24 hour (hr). Please note that if both serum and urine M-components are present, both must be followed in order to evaluate response
Hemoglobin >= 8 g/dL (obtained =< 14 days prior to randomization)
Untransfused platelet count >= 75,000 cells/mm^3 (obtained =< 14 days prior to randomization)
Absolute neutrophil count (ANC) >= 1000 cells/mm^3 (obtained =< 14 days prior to randomization)
Calculated creatinine clearance >= 30 mL/min (obtained =< 14 days prior to randomization)
Total bilirubin =< 1.5 times the upper limit of normal (ULN) (obtained =< 14 days prior to randomization)
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 times the upper limit of normal (ULN) (obtained =< 14 days prior to randomization)
Patient must agree to register into the mandatory Revlimid Risk Evaluation and Mitigation Strategies (REMS) registered trademark program and be willing and able to comply with the requirements of Revlimid REMS registered trademark
Patients of childbearing potential must either abstain from sexual intercourse for the duration of their participation in the study or agree to use TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME for 1) at least 28 days before starting study treatment; 2) while participating in the study; 3) during dose interruptions; and 4) for at least 90 days after the last dose of protocol treatment. Patients must also agree to not breastfeed during this same time period. Men must agree to either abstain from sexual intercourse for the duration of their participation in the study or use a latex condom during sexual contact with a partner of childbearing potential while participating in the study and for 90 days after the last dose of protocol treatment even if they have had a successful vasectomy. Patients must also agree to abstain from donating sperm while on study treatment and for 28 days after the last dose of protocol treatment even if they have had a successful vasectomy. All patients must agree to abstain from donating blood during study participation and for at least 28 days after the last dose of protocol treatment

Exclusion Criteria

Patient must not have primary refractory or progressive disease on a proteasome inhibitor-based regimen during induction therapy prior to stem cell transplant
Patient must not be on other concurrent chemotherapy, or any ancillary therapy considered investigational
- NOTE: Bisphosphonates are considered to be supportive care rather than therapy and are allowed while on protocol treatment
Patient must not have uncontrolled psychiatric illness or social situations that would limit compliance with study requirements
Patient must not have another malignancy requiring treatment or have received treatment within two years before pre-registration or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
Patients must not have known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib or lenalidomide including difficulty swallowing
Patient must not have known hepatitis B surface antigen-positive status or known or suspected active hepatitis C infection, but testing specifically for the trial is not required
Patient must not be off lenalidomide maintenance therapy for more than 30 days prior to start of treatment on Step 1 of this protocol
Patients must not have grade 2 or higher peripheral neuropathy or grade 1 peripheral neuropathy with pain per Common Terminology Criteria for Adverse Events (CTCAE)
Patients must not have uncontrolled intercurrent illness
Patients must not have grade 2 or higher diarrhea per CTCAE in the absence of antidiarrheals
Patients must not have been on systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A inducers (such as rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort
Patient must not be pregnant due to potential harm to the fetus from ixazomib and lenalidomide. All patients of childbearing potential must have a blood test or urine study with a sensitivity of at least 25 mIU/mL within 10-14 days prior to the first dose of lenalidomide and again within 24 hours prior to the first dose of lenalidomide. Patients of childbearing potential must also agree to ongoing pregnancy testing while on treatment. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A (lenalidomide, ixazomib citrate)	Bone Marrow Biopsy	Patients receive lenalidomide PO QD on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm A (lenalidomide, ixazomib citrate)	Quality-of-Life Assessment	Patients receive lenalidomide PO QD on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm A (lenalidomide, ixazomib citrate)	Biospecimen Collection	Patients receive lenalidomide PO QD on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm B (lenalidomide, placebo)	Computed Tomography	Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm A (lenalidomide, ixazomib citrate)	Computed Tomography	Patients receive lenalidomide PO QD on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm A (lenalidomide, ixazomib citrate)	Ixazomib Citrate	Patients receive lenalidomide PO QD on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm A (lenalidomide, ixazomib citrate)	Questionnaire Administration	Patients receive lenalidomide PO QD on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm B (lenalidomide, placebo)	Questionnaire Administration	Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm A (lenalidomide, ixazomib citrate)	Bone Marrow Aspirate	Patients receive lenalidomide PO QD on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm A (lenalidomide, ixazomib citrate)	Lenalidomide	Patients receive lenalidomide PO QD on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm B (lenalidomide, placebo)	Biospecimen Collection	Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm B (lenalidomide, placebo)	Bone Marrow Aspirate	Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm B (lenalidomide, placebo)	Positron Emission Tomography	Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm B (lenalidomide, placebo)	Placebo Administration	Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm B (lenalidomide, placebo)	Bone Marrow Biopsy	Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm B (lenalidomide, placebo)	Quality-of-Life Assessment	Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
Arm B (lenalidomide, placebo)	Lenalidomide	Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Assessed every 3 months if patient is <2 years from randomization, every 6 months if patient is 2-5 years from randomization, annually if patient is 5 years or more from randomization.	Overall survival is defined as time from randomization to death or date last known alive.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	Assessed every 3 months if patient is <2 years from randomization, every 6 months if patient is 2-5 years from randomization, annually if patient is 5 years or more from randomization.	Progression-free survival defined as the time from randomization until the earlier of progression or death due to any cause, or censored at date of last disease evaluation. Progression is defined as one of the following criteria is met. * Increase of ≥ 25% from lowest value reported in serum M-component (the absolute increase must be ≥ 0.5 g/dL) and/or urine M-component (the absolute increase must be ≥ 200 mg/ 24 hours). * Only in patients without measurable serum and urine M protein levels: the difference between involved and uninvolved FLC levels. The absolute increase must be \> 10 mg/dL. * If the only measurable disease is bone marrow, bone marrow plasma cell percentage: the absolute % must be ≥ 10%. * Development of new bone lesions or soft tissue plasmacytomas or ≥ 50% increase from nadir in the size (SPD) of existing bone lesions or soft tissue plasmacytoma or ≥ 50% increase in the longest diameter of a previous lesion \> 1cm in short axis.
Best Response on Treatment	Assessed every 3 months if patient is <2 years from randomization, every 6 months if patient is 2-5 years from randomization, annually if patient is 5 years or more from randomization.	Response is evaluated based on standard International Myeloma Working Group (IMWG) criteria and tabulated by category. Response (stringent complete response \[sCR\], complete response \[CR\], very good partial response \[VGPR\]) is defined as below. sCR: All CR criteria and the following have to be met. Normal serum FLC ratio at two consecutive times and absence of clonal cells in bone marrow by immunohistochemistry or 2- to 4- color flow cytometry. Presence/absence of clonal cells is based upon the κ/λ ratio. An abnormal κ/λ ratio by immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is κ/λ ratio of 4:1 or 1:2. CR: Complete disappearance of an Mprotein and no evidence of myeloma in the bone marrow. VGPR: Serum M-protein detectable by immunofixation but not quantifiable on electrophoresis and urine M-protein \< 100 mg/24 hours

Trial Locations

Locations (222): AdventHealth Porter
🇺🇸
Denver, Colorado, United States
Cancer Center at Saint Joseph's
🇺🇸
Phoenix, Arizona, United States
CHI Saint Vincent Cancer Center Hot Springs
🇺🇸
Hot Springs, Arkansas, United States
Mission Hope Medical Oncology - Arroyo Grande
🇺🇸
Arroyo Grande, California, United States
Pacific Central Coast Health Center-San Luis Obispo
🇺🇸
San Luis Obispo, California, United States
Mission Hope Medical Oncology - Santa Maria
🇺🇸
Santa Maria, California, United States
Penrose-Saint Francis Healthcare
🇺🇸
Colorado Springs, Colorado, United States
Rocky Mountain Cancer Centers-Penrose
🇺🇸
Colorado Springs, Colorado, United States
Mercy Medical Center
🇺🇸
Durango, Colorado, United States
Southwest Oncology PC
🇺🇸
Durango, Colorado, United States
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AdventHealth Porter
🇺🇸Denver, Colorado, United States