Study Assessing Activity of Intravenous (IV) ABBV-383 Monotherapy Versus Standard Available Therapies in Adult Participants With Relapsed or Refractory Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
Multiple myeloma (MM) is a cancer of the blood's plasma cells. The cancer is typically found in the bones and bone marrow (the spongy tissue inside of the bones) and can cause bone pain, fractures, infections, weaker bones, and kidney failure. Treatments are available, but MM can come back (relapsed) or may not get better (refractory) with treatment. This is a study to determine change in disease symptoms of ABBV-383 compared to standard available therapies in adult participants with relapsed/refractory (R/R) MM. ABBV-383 is an investigational drug being developed for the treatment of R/R MM. This study is broken into 2 Arms; Arm A and Arm B. . In Arm A, participants will receive ABBV-383 as a monotherapy. In Arm B, participants will receive the standard available therapy (SAT) identified by the Investigator during screening, in accordance with the local (or applicable) approved label, package insert, summary of product characteristics, and/or the institutional guidelines, as applicable. Around 380 adult participants with relapsed/refractory multiple myeloma will be enrolled at approximately 140 sites across the world. In Arm A participants will receive ABBV-383 as an infusion into the vein in 28 day cycles, during the 3.5 year study duration. In Arm B, participants will receive the SAT identified by the Investigator during screening, in accordance with the local (or applicable) approved label, package insert, summary of product characteristics, and/or the institutional guidelines, as applicable, during the 3.5 year study duration. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and questionnaires.

Official Title
-----------------
A Phase 3, Multicenter, Randomized, Open Label Study of ABBV-383 Compared With Standard Available Therapies in Subjects With Relapsed or Refractory Multiple Myeloma (3L+ RRMM Monotherapy Study)

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: ABBV-383
* Drug: Carfilzomib
* Drug: Pomalidomide
* Drug: Elotuzumab
* Drug: Selinexor
* Drug: Bortezomib
* Drug: Dexamethasone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance of <= 2. Confirmed diagnosis of relapsed/refractory (R/R) multiple myeloma (MM) with documented evidence of progression during or after the participant's last treatment based on the Investigator's determination of the international myeloma working group (IMWG) (2016) response criteria. Must have measurable disease with at least 1 of the following assessed within 28 days of enrollment: Serum M-protein >= 0.5 g/dL (>= 5 g/L). Urine M-protein >= 200 mg/24 hours. In participants without measurable serum or urine M protein, serum free light chain (FLC) >= 100 mg/L (10 mg/dL) (involved light chain). Must have received at least 2 or more lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory imide (IMiD), and an anti-CD38 monoclonal antibody (mAb). Must be naïve to treatment with B-cell maturation antigen (BCMA)-targeted therapy. Must be eligible to receive the Investigator's choice standard available therapy (SAT) based on approved prescribing information, previous MM treatment history, and institutional guidelines. Exclusion Criteria: Clinically significant (per Investigator's judgment) drug or alcohol abuse within the last 6 months. Clinically significant conditions such as but not limited to the following: renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, pulmonary, or hepatic disease within the last 6 months that would adversely affect the participant's participation in the study. Central nervous system involvement of MM.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABBV-383<br>Participants will receive ABBV-383 as a monotherapy. | Drug: ABBV-383<br>* Intravenous (IV) Infusion<br>|
| Experimental: Standard Available Therapy (SAT)<br>Participants will receive SAT, in accordance with the local (or applicable) approved label, package insert, summary of product characteristics, and/or the institutional guidelines, as applicable. SAT choices are carfilzomib + dexamethasone (Kd), elotuzumab + pomalidomide + dexamethasone (EloPd), selinexor + bortezomib + dexamethasone (SVd). | Drug: Carfilzomib<br>* IV Infusion<br>Drug: Pomalidomide<br>* Oral Capsule<br>Drug: Elotuzumab<br>* IV Infusion<br>Drug: Selinexor<br>* Oral Tablet<br>Drug: Bortezomib<br>* Subcutaneous or IV Injection<br>Drug: Dexamethasone<br>* Oral Tablet or IV Infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the duration from the date of randomization to the date of confirmed disease progression (PD) determined by independent review committee (IRC) per international myeloma working group (IMWG) (2016) response criteria, or death, whichever occurs first. | Up to Approximately 5 Years | 
| Change in Rate of Very Good Partial Response (VGPR) or Better (>= VGPR) | The rate of >= VGPR is defined as the proportion of participants who achieve a VGPR or better determined by IMWG (2016) response criteria, per IRC assessment, prior to the initiation of new myeloma therapy. | Up to Approximately 5 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the percentage of participants who achieve confirmed partial response (PR) + VGPR + complete response (CR) + stringent complete response (sCR) or per IRC assessment. | Up to Approximately 5 Years | 
| Overall Survival (OS) | OS is defined as the duration from the date of randomization to the date of the participant's death. | Up to Approximately 5 Years | 
| Change in Rate of CR or Better (>=CR) | >=CR is defined as the percentage of participants who achieve confirmed CR + sCR or per IRC assessment. | Up to Approximately 5 Years | 
| Change in Rate of Minimum Residual Disease (MRD) negativity with >= CR | MRD negativity with >= CR, defined as achievement of CR or better by IMWG (2016) response criteria (per IRC assessment) and MRD negative status as assessed by next-generation sequencing (NGS) Adaptive Clonoseq at 10^-5 threshold. | Up to Approximately 5 Years | 
| Change from Baseline in Disease Symptoms as Measured by the Disease Symptoms Domain of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Multiple Myeloma Module (EORTC QLQ-MY20) | The disease symptoms domain of EORTC QLQ-MY20 is a 6-item questionnaire to assess the physical function of the participant, with a higher score indicating a higher level of symptoms. | Up to 6 Months | 
| Change from Baseline in Physical Functioning as Measured by the Physical Functioning Domain of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) | The physical functioning domain of EORTC QLQ-C30 is a 5-item questionnaire to assess the physical function of the participant, with a higher score indicating worse functioning. | Up to 6 Months | 
| Time to Response (TTR) | TTR is defined as the number of months from the date of first dose to the date of best overall response of CR or PR ('responders') determined by IMWG criteria as assessed by IRC. | Up to Approximately 5 Years | 
| Duration of Response (DOR) | DOR is defined as the number of days from the day the response criteria are met to the date that disease progression as determined by the IRC. | Up to Approximately 5 Years | 
| Time-to-Progression (TTP) | TTP is defined as the number of days from the date of first dose to the date of earliest disease progression as determined by the IRC. | Up to Approximately 5 Years | 
| Time to Next Anti-lymphoma Therapy (TTNT) | TTNT is defined as the time from randomization to first documented administration of subsequent anti-lymphoma therapy. | Up to Approximately 5 Years | 
| Number of Participants with Event-free Survival (EFS) | EFS is defined as the time from randomization until adverse event determined by the IRC, or death, whichever occurs first. | Up to Approximately 5 Years | 
| Change from Baseline in Patient-Reported Outcomes Measurement Information System Fatigue Short Form 7a (PROMIS Fatigue SF 7a) | The PROMIS Fatigue SF7a is a 7-item short form that assesses the impact and experience of fatigue in the past 7 days. For each item, 5-point rating scales are used to measure frequency (Never, Rarely, Sometimes, Often, or Always) with a higher score indicating a greater impact. | Up to Approximately 6 Months | 
| Change from Baseline in Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) | The PRO-CTCAE is a patient-reported outcome measurement system developed to assess symptomatic toxicity in participants in cancer clinical trials. PRO-CTCAE items are scored from 0 to 4 to evaluate common symptoms from study treatment on their frequency, severity, interference, amount, presence/absence. | Up to Approximately 6 Months | 
| Change from Baseline in Remaining Items in the EORTC QLQ-C30 | The EORTC QLQ-C30 assesses health-related quality of life in cancer patients participating in clinical trials. The EORTC QLQ-C30 comprises 5 functional scales (physical, role, emotional, social, cognitive), 8 single-item symptom scales (fatigue, pain, nausea/vomiting, appetite loss, constipation, diarrhea, insomnia, and dyspnea), as well as subscales assessing global health/quality of life and financial impact. Raw scores are transformed to a scale of 0 to 100, with higher scores representing better functioning/quality of life and greater symptom burden. | Up to Approximately 6 Months | 
| Change from Baseline in Remaining Items in the EORTC QLQ-MY20 | The EORTC QLQ-MY20 consists of four scales: two symptom scales (Disease Symptoms [6 items] and Side Effects of Treatment [10 items]), one function scale (Future Perspective [3 items]), and one single item (Body Image). Each item has four response options: Not at all, A little, Quite a bit, or Very much. All scores are then linearly transformed to a 0 to 100 scale. A higher score on the symptom scales indicates a higher level of symptoms, whereas higher scores on future perspective and body image indicate good functioning or support. | Up to Approximately 6 Months | 
| Change from Baseline in European Quality-of-Life 5-dimensional-5-level (EQ-5D-5L) | The EQ-5D-5L is a standardized, non-disease specific instrument used to measure health-related quality of life. The EQ-5D-5L assesses general health on 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/ depression). Each dimension has 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems). The scores for the 5 dimensions are used to compute a single utility index score ranging from 0 to 1 representing the general health status of the individual, with higher scores indicating better health state. | Up to Approximately 6 Months | 
| Change from Baseline in Patient Global Impression of Severity (PGIS) | The self-report measure PGIS reflects a participant's belief about their lymphoma symptoms over the past 7 days. The PGIS is a 5-point scale depicting a participant's rating of overall severity. | Up to Approximately 6 Months | 
| Change from Baseline in Patient Global Impression of Change (PGIC) | The self-report measure PGIC reflects a participant's belief about the efficacy of treatment. The PGIC is a 7-point scale depicting a participant's rating of overall improvement since start of treatment. Participants rate their change as very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse. | Up to Approximately 6 Months | 
| Number of Participants with Skeletal-Related Event (SRE) | SREs are defined as the presence of any of the following spinal cord compression, pathologic fracture, surgery to bone, or radiation to bone. | Up to Approximately 5 Years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cervino, Multiple Myeloma, ABBV-383, Carfilzomib, Pomalidomide, Elotuzumab, Selinexor, Bortezomib, Dexamethasone