Business decision (no enrollment)

The main aim is to show that long-term use of ixazomib can improve symptoms of multiple myeloma and provide an effective long-term alternative treatment.

Participants will take ixazomib orally (by mouth) with pomalidomide and dexamethasone or lenalidomide and dexamethasone in 28-day treatment cycles. Participants will be treated for a maximum of 39 cycles but may continue to receive ixazomib beyond 39 cycles if they are benefiting from it. A follow-up study visit will occur 30 days after the last dose of ixazomib. Participants will be monitored for up to 3 years.

The main objective is to determine whether an in-class transition (iCT) from a parenteral proteasome inhibitor (PI) regimen to an all-oral ixazomib(NINLARO) regimen can improve outcomes and provide an effective long-term alternative treatment for participants with relapsed and/or refractory multiple myeloma.

The drug being tested in this study is called ixazomib (NINLARO). Ixazomib is being tested to treat people who have relapsed and/or refractory multiple myeloma (R/R MM). This study will look at the efficacy and safety of ixazomib in participants with R/R MM who were previously receiving parenteral proteasome inhibitor (PI)-based therapy in combination with pomalidomide or with lenalidomide, and who undergo in-class transition to an oral ixazomib-based combination containing either pomalidomide (cohort A) or lenalidomide (cohort B).

The study will enroll approximately 140 patients. Participants will be enrolled to one of the two treatment groups, depending on whether they are transitioning from a pomalidomide- or lenalidomide- based regimen:

• Cohort A: Ixazomib 4 mg + Pomalidomide 4 mg + Dexamethasone 40 mg
• Cohort B: Ixazomib 4 mg + Lenalidomide 25 mg + Dexamethasone 40 mg

Participants who are >75 years of age at time of enrollment will be instructed to take 20 mg dexamethasone. For participants with moderate or severe hepatic impairment, severe renal impairment, or end-stage renal disease requiring dialysis, the recommended starting dose of ixazomib is 3 mg which can be further reduced to 2.3 mg at investigator's discretion.

This multi-center trial will be conducted at approximately 30 study centers across the United States. The overall duration of this study is approximately 5 years or until all participants have died, have been lost to follow-up, or completion of the study by the sponsor, whichever occurs first.

Inclusion Criteria

1. Has a diagnosis of multiple myeloma (MM) using current IMWG diagnostic criteria, and are relapsed or refractory to 1 to 3 prior lines of therapy*.

   a. Has completed 3 or 4 cycles of a parenteral proteasome inhibitor (PI), and lenalidomide- or pomalidomide-based regimen and achieved a response of ≥ partial response (PR) with no evidence of disease progression as defined by IMWG criteria. This lead-in therapy to in-class transition (iCT) is not included as part of the 1 to 3 prior lines and should be completed no more than 28 days prior to initiation of IRd or IPd in this study.

   Those with light chain myeloma and free light chain (FLC) only may be enrolled if they previously met or currently meet the criteria for a diagnosis of MM.

   *A line of therapy is defined as one or more cycles of a planned treatment program. This may consist of one or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem-cell transplantation, followed by maintenance is considered one line of therapy. Autologous and allogenic transplants are permitted.

2. Has a diagnosis of non-secretory disease as long as the participant has a marker of disease that can be followed serially and assessed for response.

3. Has an Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status of 0, 1, or 2 at the time of enrollment.

Exclusion criteria

1. Has Grade >2 peripheral neuropathy (PN), or Grade 2 PN with pain on clinical examination.
2. Has not adequately recovered from other non-neuropathy AEs related to prior therapy in the opinion of the investigator at the time of enrollment.
3. Is pomalidomide refractory.
4. Has primary light chain amyloidosis (AL). Those with MM and concurrent AL are allowed.
5. Has known central nervous system involvement by MM.
6. Has infection requiring systemic antibiotic therapy or other serious infection within 14 days before enrollment.
7. Has ongoing or active systemic infection, active hepatitis B or C virus infection, or known positive status for human immunodeficiency virus.
8. Has been diagnosed or treated for another malignancy within 2 years before enrollment or has previously been diagnosed with another malignancy and has any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
9. Has previously been treated with ixazomib or participated in a study with ixazomib whether treated with ixazomib or not.

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/ For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.