A Study of Venetoclax Plus Lenalidomide and Dexamethasone for the Treatment of Newly Diagnosed t(11;14)-Positive Multiple Myeloma in Subjects Who Are Ineligible for High-Dose Therapy

Study Overview
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Brief Summary
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This study will evaluate the safety and preliminary efficacy of venetoclax when combined with lenalidomide and dexamethasone for participants with newly diagnosed, active t(11;14) positive multiple myeloma (MM). This study will consist of 2 parts: Part 1 Dose Escalation and Part 2 Dose Expansion.

Official Title
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A Phase 2, Multicenter, Single Arm, Open Label Study of Venetoclax Plus Lenalidomide and Dexamethasone for the Treatment of Newly Diagnosed t(11;14)-Positive Multiple Myeloma in Subjects Who Are Ineligible for High-Dose Therapy

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: venetoclax
* Drug: lenalidomide
* Drug: dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have documented, confirmed active multiple myeloma (MM) with greater than or equal to 10% clonal bone marrow plasma cells or biopsy-proven bone or extramedullary plasmacytoma and any one or more of the following myeloma-defining events: Evidence of end organ damage attributed to the underlying plasma cell proliferative disorder and satisfying at least one of the protocol specified laboratory criteria for calcium elevation, renal failure, anemia, or lytic bone lesions; OR One or more of the biomarkers of malignancy as described in the protocol. Must have MM positive for the t(11;14) translocation, as determined by methods described in the protocol. Must have measurable disease defined by at least one of the following criteria: Serum M-protein ≥ 1.0 g/dL (immunoglobulin [Ig]G myeloma) or greater than or equal to 0.5 g/dL (IgA, IgM, IgD, or IgE myeloma); Urine M-protein greater than or equal to 200 mg/24 hours; Serum free light chain (FLC) greater than or equal to 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal. Newly diagnosed and not considered a candidate for high-dose therapy and hematopoietic stem cell transplantation (HSCT) Must have Eastern Cooperative Oncology Group performance status less than or equal to 2. Exclusion Criteria: Has a co-existing condition as specified in the protocol. Has history of other active malignancies, including myelodysplastic syndromes (MDS) within the past 3 years with specific exceptions detailed in the protocol. Has been treated with or received any of the following: Prior or current systemic therapy or hematopoietic stem cell transplantation (HSCT) for MM (a short course of treatment with corticosteroids equivalent to dexamethasone 40 mg/day for a maximum of 4 days is allowed before treatment); use of systemic strong or moderate inhibitor or inducer of cytochrome P450(CYP)3A within 7 days before the first dose of study drug. Radiation therapy within 2 weeks of dosing Plasmapheresis within 4 weeks of dosing Immunization with live vaccine within 8 weeks of dosing Has a contraindication or inability to comply with antithrombotic prophylaxis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venetoclax + Lenalidomide + Dexamethasone<br>Venetoclax up to 800 mg orally every day (QD) QD on Days 1 - 28 plus lenalidomide up to 25 mg orally QD on Days 1 - 21 (28 day cycle) plus dexamethasone up to 40 mg orally once weekly (QW). | Drug: venetoclax<br>* tablet; oral<br>* Other names: ABT-199;Drug: lenalidomide<br>* capsule; oral<br>* Other names: Revlimid;Drug: dexamethasone<br>* tablet; oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participates Who Achieve CR | Complete response (CR) is defined as negative immunofixation of serum and urine, and disappearance of any soft tissue plasmacytomas, and < 5% plasma cells in bone marrow. | From baseline up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants Who Achieve MRD Negativity | Minimal residual disease (MRD) negative after treatment is described as less than one myeloma cell per 100,000 bone marrow cells. | From baseline up to approximately 24 months | 
| Percent of Participants Who Achieve VGPR or Better | Very Good Partial Response (VGPR) per international myeloma working group (IMWG) criteria is defined as serum or urine myeloma protein (m-protein) detectable by immunofixation but not on electrophoresis, or greater than or equal to 90% reduction in serum m-protein and urine m-protein less than 100 mg/24 hours. | From baseline up to approximately 24 months | 
| Overall Response Rate (ORR) | ORR is described as the percentage of participants who experience partial response (PR) or better; PR per IMWG is described as follows: ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M protein by ≥ 90% or to < 200 mg/24 h If the serum and urine M-protein are not measurable, a decrease ≥ 50% in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M-protein criteria If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, ≥ 50% reduction in bone marrow plasma cells is required in place of M-protein, provided baseline percentage was ≥ 30% In addition, if present at baseline, ≥ 50% reduction in size of soft tissue plasmacytomas is also required | From baseline up to approximately 24 months | 
| Time to Response (TTR) | Time to response is defined as the time from randomization to the first response (CR, stringent complete response [sCR], VGPR, PR). | From baseline up to approximately 24 months | 
| Duration of response (DOR) | DOR is defined as the time from first observation of PR to the time of disease progression, with deaths from causes other than progression censored. | Approximately 7 years | 
| Progression-free Survival (PFS) | PFS is defined as time from start of the treatment to disease progression or death (regardless of cause of death), whichever comes first. | Approximately 7 years | 
| Minimal Residual Disease (MRD) Negativity Rate at 12 Months | Percent of participants meeting the MRD Negative criteria at 12 months after initial dose; MRD Negative defined as less than one myeloma cell per 100,000 bone marrow cells. | Approximately 12 months after initial dose of study drug | 
| Time to Disease Progression (TTP) | TTP is defined as the time from start of treatment to disease progression, with deaths from causes other than progression censored. | Approximately 7 years | 
| Time to Next Treatment (TTNT) | The time to next treatment is defined as the time between the date of the first study drug intake and the date of the first next treatment intake after study drug discontinuation. | Approximately 7 years | 
| Overall Survival (OS) Rate | OS was defined as the time from the date the participant was randomized to the date of death. | Approximately 7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Cancer, t(11;14)-Positive Multiple Myeloma, Venetoclax, Lenalidomide