General Key
Inclusion Criteria:
1. Eastern Cooperative Oncology Group (ECOG) performance status ≤1. 2. Participants must have measurable disease as defined in the protocol according to
International Myeloma Working Group (IMWG) consensus criteria. 3. Adequate creatinine clearance, hematologic function and hepatic function, as defined
in protocol. 4. Life expectancy of at least 6 months.
Cohort Specific
Inclusion Criteria:
For the below cohorts, each participant must have RRMM with progression following at least
3 lines of therapy, or at least 2 lines of therapy and either prior exposure to at least 1
anti-CD38 antibody, 1 immunomodulatory imide drug (IMiD) and 1 proteasome inhibitor (PI),
or double-refractory to 1 PI and 1 IMiD, or the combination of 1 PI and 1 IMiD.
Cohort 1: Prior treatment with daratumumab is allowed if previously tolerated. However,
participants enrolled in the expansion portion cannot be refractory to an anti-CD38
antibody containing regimen. In addition, all participants must have at least a 6-month
washout from prior anti-CD38 antibody therapy.
Cohort 2: Prior treatment with carfilzomib is allowed if previously tolerated at the
approved full dose. Carfilzomib-refractory participants may enroll in the dose finding
portion provided they are triple-class refractory (PI, IMiD, anti-CD38 antibody). However,
participants enrolled in the dose expansion portion cannot be refractory to carfilzomib. In
addition, all participants must have at least a 6-month washout from prior carfilzomib
therapy.
Cohort 3: Prior treatment with lenalidomide is allowed if previously tolerated at the
approved full dose. However, a participant cannot be refractory to any combination regimen
that included 25 mg of lenalidomide. In addition, participants must have at least a 6-month
washout from any prior lenalidomide therapy (including maintenance therapy).
Cohort 4: Prior treatment with bortezomib is allowed if previously tolerated at the
approved full dose. Bortezomib-refractory participants may enroll in the dose finding
portion provided they are triple-class refractory (PI, IMiD, anti-CD38 antibody). However,
participants enrolled in the dose expansion portion cannot be refractory to bortezomib. In
addition, all participants must have at least a 6-month washout from prior bortezomib
therapy.
Cohort 5: Prior treatment with pomalidomide is allowed if previously tolerated at the
approved full dose. Additionally, participants must undergo at least a 6-month washout
following prior pomalidomide therapy before enrollment.
Cohort 6: Prior treatment with isatuximab is allowed if previously tolerated. Additionally,
participants must undergo at least a 3-month washout following prior anti-CD38 antibody
therapy before enrollment.
Cohort 7 and 8: RRMM with progressive disease and one of the following:
- - Received at least 3 lines of therapy including exposure to at least 1 anti-CD38
antibody, 1IMiD, and 1 PI or.
- - Triple-class refractory disease (anti-CD38 antibody, IMiD, PI)
Cohort 9: each participant must have progressive RRMM and the following:
- Received at least 3 lines of therapy and.
- - Triple-class refractory disease (anti-CD38 antibody, IMiD, PI)
General Key
Exclusion Criteria:
1.
Diagnosis of plasma cell leukemia, primary light-chain amyloidosis (excluding myeloma
associated amyloidosis), Waldenström macroglobulinemia (lymphoplasmacytic lymphoma),
or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein,
and skin changes)
2. Participants with known MM brain lesions or meningeal involvement. 3. Treatment with any systemic anti-myeloma therapy within 5 half-lives or within 21 days
prior to first administration of study drug regimen, whichever is shorter. 4. History of allogeneic stem cell transplantation, or autologous stem cell
transplantation within 12 weeks of the start of study drug regimen. 5. Unless stated otherwise in a specific sub-protocol, prior treatment with BCMA-directed
immunotherapies, including BCMA bispecific antibodies and bispecific T-cell engagers
(BiTEs), and BCMA chimeric antigen receptor (CAR) T cells (Note: BCMA antibody-drug
conjugates are not excluded)
6. History of progressive multifocal leukoencephalopathy, neurodegenerative condition or
central nervous system (CNS) movement disorder or participants with a history of
seizure within 12 months prior to study enrollment are excluded. 7. Live or attenuated vaccination within 28 days prior to first study drug regimen
administration with a vector that has replicative potential. 8. Cardiac ejection fraction <40% by echocardiogram (Echo) or multigated acquisition
(MUGA) scan.
Cohort Specific
Exclusion Criteria:
Cohort 3:
1. Known malabsorption syndrome or pre-existing gastrointestinal (GI) conditions that may
impair absorption of lenalidomide (eg, gastric bypass, lap band, or other gastric
procedures that would alter absorption); delivery of lenalidomide via nasogastric tube or
gastrostomy tube is not allowed.
Cohort 4:
1. Peripheral neuropathy grade ≥2. Cohort 5:
1. Known malabsorption syndrome or pre-existing GI conditions that may impair absorption of
pomalidomide (eg, gastric bypass, lap band, or other gastric procedures that would alter
absorption); delivery of pomalidomide via nasogastric tube or gastrostomy tube is not
allowed.
Cohort 7:
1. Prior treatment with anti-lymphocyte activation gene 3 (LAG-3) agents. Prior exposure
to vaccine therapies or other immune checkpoint modulating therapies such as
anti-programmed cell death protein 1 (PD-1) antibodies is permitted, as described in
the protocol.
2. Ongoing or recent (within 2 years) evidence of an autoimmune disease that has required
systemic treatment with immunosuppressive agents, as described in the protocol.
3. Prior solid organ transplant.
4. History of grade ≥3 immune-mediated adverse events (with the exclusion of
endocrinopathies that are fully controlled by hormone replacement) from prior
checkpoint inhibitor therapies.
Cohort 8:
1. Prior treatment with anti-PD-1 or anti-PD-L1 agents. Prior exposure to vaccine
therapies or other immune checkpoint modulating therapies such as anti-cytotoxic T
lymphocyte-associated antigen 4 (CTLA-4) antibodies is permitted, as described in the
protocol.
2. Encephalitis or meningitis in the year prior to enrollment.
3. History of interstitial lung disease (eg, idiopathic pulmonary fibrosis or organizing
pneumonia), of active, noninfectious pneumonitis that required immune-suppressive
doses of glucocorticoids to assist with management, or of pneumonitis within the last
5 years. A history of radiation pneumonitis in the radiation field is permitted as
long as pneumonitis resolved ≥6 months prior to enrollment.
4. Ongoing or recent (within 2 years) evidence of an autoimmune disease that has required
systemic treatment with immunosuppressive agents, as described in the protocol.
5. Prior solid organ transplant.
6. History of grade ≥3 immune-mediated adverse events (with the exclusion of
endocrinopathies that are fully controlled by hormone replacement) from prior
checkpoint inhibitor therapies.
Cohort 9:
1. Abnormal QT interval corrected by Fridericia's formula (QTcF), as described in the
protocol. 2. Use of concomitant medications that are known to prolong the QT/QTcF interval
including Class Ia and Class III antiarrhythmics at the time of informed consent. 3. Ongoing use or anticipated use of food or drugs that are known strong/moderate
cytochrome P450 (CYP)3A4 inhibitors, or strong CYP3A inducers within 14 days prior to
first dose of nirogacestat. 4. Known malabsorption syndrome or existing gastrointestinal GI conditions that may
impair absorption of nirogacestat (eg, gastric bypass, lap band, or other gastric
procedures that would alter absorption); delivery of nirogacestat via nasogastric tube
or gastrostomy tube is not allowed.
NOTE: Other protocol defined inclusion/exclusion criteria apply
