No prior proteasome inhibitor or immune-modulating drug (IMiD) use
Proteasome inhibitor naive or sensitive disease; proteasome inhibitor sensitive disease is defined as a PR or better to prior proteasome inhibitor-based therapy that is maintained for >= 60 days from the last dose of the proteasome inhibitor\r\n* A patient who receives induction therapy with lenalidomide, bortezomib and dexamethasone and achieves a PR or better but subsequently progresses on continued lenalidomide or lenalidomide-dexamethasone would be eligible provided the progression occurs 60 days or more after discontinuation of the bortezomib; similarly, ixazomib exposure is allowed provided they meet the definition of proteasome inhibitor sensitive disease
Participant must have received at least one prior line of treatment of multiple myeloma; for pomalidomide-containing arm(s), patients must have received at least one prior line of treatment and must have undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of proteasome inhibitor (either in separate regimens or within the same regimen) unless not a candidate
A regimen that included an immunomodulatory agent (eg, thalidomide, lenalidomide, pomalidomide) and a proteasome inhibitor (eg, bortezomib, carfilzomib, ixazomib), either alone or in combination
Participant is refractory to any proteasome inhibitor, defined as progression on or within 60 days of the last dose of a proteasome inhibitor-containing regimen.
Participant has had prior treatment with proteasome inhibitor within 60 days prior to first dose of study drug.
Must have relapsed and/or refractory MM, having received treatment with proteasome inhibitor and IMiD
Proteasome inhibitor therapy (e.g. bortezomib or carfilzomib) -2 weeks
Prior treatment with or intolerance to proteasome inhibitor and immunomodulator
Subjects known to be refractory to any proteasome inhibitor other than bortezomib or carfilzomib, including but not limited to MLN9708, CEP-18770, ONX 0912, and SalmosporamideA; refractory will be defined as a history of progression on or within 60 days after completing a regimen containing the proteasome inhibitor for a minimum of 2 cycles at either approved or considered effective or best tolerated doses
Patients must not have other therapeutic options known to provide clinical benefit in MM available to them. Prior lines of therapy must include at least a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody.
Is either refractory to or intolerant of at least one proteasome inhibitor and a least one immunomodulatory drug. In addition, after the MTD/OBD is defined, must also be either refractory to of at least one anti-CD38 monoclonal antibody.
Prior treatment with any investigational proteasome inhibitor within 6 months of study entry
Diagnosis of multiple myeloma previously treated with at least one prior line of therapy. Induction therapy followed by stem cell transplant and maintenance therapy will be considered a single line of therapy. For Safety Expansion, subjects must have been previously treated with a proteasome inhibitor (e.g., bortezomib) and an immunomodulatory agent (e.g., thalidomide, lenalidomide). For Venetoclax-Dexamethasone Combination, subjects must have been been previously treated with a proteasome inhibitor (e.g., bortezomib) and an immunomodulatory agent (e.g., thalidomide, lenalidomide) AND have t(11;14)-positive multiple myeloma per the central lab testing. For Phase 2, subjects must have documented MM positive for t(11;14) translocation. If testing has been performed by non-central lab, retesting must be confirmed by central lab. Subjects must have evidence of disease progression on or within 60 days of last dose of most recent previous treatment based on IMWG criteria AND subjects must have previously received at least 2 lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, daratumumab, and glucocorticosteroids. Daratumumab combination regimen must be one of the prior lines of therapy (for this study, daratumumab plus corticosteroids will not be considered a combination regimen) given alone or in combination, OR, subjects must be refractory to glucocorticosteroid and to the most recent immunomodulatory drug, proteasome inhibitor and daratumumab given alone or in combination.
Patients who have previously received bortezomib or other proteasome inhibitors that did not have a response while receiving the inhibitor are not eligible; patients that responded but had a subsequent relapse are eligible
Must have relapsed or refractory disease after treatments including three therapies: proteasome inhibitors, immunomodulatory imide drugs (IMiDs), and anti-CD38 antibody
Have relapsed or treatment refractory disease with ? 10% CD138+ malignant plasma cells immunohistochemistry (IHC) on BM core biopsy, either: \r\n* Following autologous stem-cell transplantation (ASCT)\r\n* Or, if a patient has not yet undergone ASCT, the individual must:\r\n** Be transplant ineligible, due to age, comorbidity, patient choice, insurance reasons, concerns of rapidly progressive disease, and/or discretion of attending physician, and,\r\n** Demonstrate disease that persists after > 4 cycles of induction therapy and that is double refractory (persistence/progression) after therapy with both a proteasome inhibitor and immunomodulatory drug (IMiD) administered either in tandem, or in sequence, or demonstrate intolerance to both classes of agents (IMiD and proteasome inhibitor [PI])
Symptomatic multiple myeloma (MM) having progressed on >= 2 prior therapies including proteasome inhibitor (i.e. bortezomib, carfilzomib ixazomib), immunomodulatory drug (i.e., thalidomide, lenalidomide, pomalidomide), and daratumumab or other CD38 targeting monoclonal antibody. Subjects who are refractory to proteasome inhibitors or ONC201 are eligible. Subjects must not be candidates for treatment regimens known to provide clinical benefit to be eligible for this study
Relapsed or refractory MM after adequate exposure to and therapeutic response (following IMWG response criteria) to at least one line of treatment with one or more active agents, including alkylating drugs, corticosteroids, immunomodulatory drugs (IMiD: thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, cartilzomib), and monoclonal antibodies (daratumumab, elotuzumab, ixazomab);
Received at least 3 prior lines of therapy including a proteasome inhibitor (PI) (greater than or equal to [>=] 2 cycles or 2 months of treatment) and an immunomodulatory drug (IMiD) (>=2 cycles or 2 months of treatment) in any order during the course of treatment (except for participants who discontinued either of these treatments due to a severe allergic reaction within the first 2 cycles/months). A single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of corticosteroids (no more than the equivalent of dexamethasone 40 milligram/day [mg/day] for 4 days) would not be considered prior lines of therapy
Must have received at least 3 prior lines of therapy to include treatment with a proteasome inhibitor (eg, bortezomib, carfilzomib, or ixazomib) and an immunomodulatory agent (eg, lenalidomide, pomalidomide) unless double-refractory to both; and a hematopoietic stem cell transplant (HSCT), for those subjects considered HSCT-eligible.
Receipt of 2, but not more that 3 prior lines of therapy that must have included a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) (alone or in combination, and are refractory to the last line of treatment(Cohort D2)
Prior refractoriness to proteasome inhibitor or immunomodulatory drugs (IMiD)
Patient must have a diagnosis of symptomatic multiple myeloma, who relapses or is refractory after previous treatment with a proteasome inhibitor (bortezomib or carfilzomib) and an immunomodulatory agent (thalidomide, lenalidomide or pomalidomide)
Subjects must have relapsed or refractory disease after either one of the following:\r\n* At least 3 prior regimens, which must have contained an alkylating agent, proteasome inhibitor, and immunomodulatory agent (IMiD)\r\nOR\r\n* At least 2 prior regimens if “double-refractory” to a proteasome inhibitor and IMiD, defined as progression on or within 60 days of treatment with these agents; Note: induction therapy, stem cell transplant, and maintenance therapy, if given sequentially without intervening progression, should be considered as 1 “regimen”
Must have failed prior anti-myeloma treatments that have included an immunomodulatory drug (IMiD) (pomalidomide, lenalidomide, or thalidomide) AND proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) alone or in combination DLBCL Participants:
Patients must be relapsed or are refractory to at least 3 prior lines of therapy, including both a proteasome inhibitor an immunomodulatory drug (IMiD), and for whom a transplant is not recommended (induction therapy and stem cell transplant +/- maintenance will be considered as one regimen)
Patients must be at least 2 weeks from last treatment with a proteasome inhibitor (e.g., bortezomib, carfilzomib) at time of treatment on this protocol
For the bortezomib arm of the study, prior therapy with a proteasome inhibitor if discontinued due to toxicity
Have received ? 2 lines of prior therapy which must have included an immune modulatory drug (IMiD) and a proteasome inhibitor alone or in combination
Phase 1: Relapsed MM with at least one prior line of therapy and should have received a proteasome inhibitor and an immunomodulatory drug
Phase 2: 1-3 prior lines of therapy and should have received a proteasome inhibitor and an immunomodulatory drug
Patients must have received prior treatment with an immunomodulatory drug (IMiD) (for ?2 cycles or ?2 months of treatment) and a proteasome inhibitor (PI) (for ?2 cycles or ?2 months of treatment).
Patients who have had prior exposure to romidepsin or any proteasome inhibitor are NOT eligible for participation
Patient must have received ? 2 prior anti-myeloma regimens including a proteasome inhibitor and/or immunomodulatory agent.
Did not receive chemotherapy (including systemic steroids), immunotherapy (interferon), Imids (thalidomide/lenalidomide), proteasome inhibitors (bortezomib), or radiotherapy for at least 21 days prior to Day 1 of Cycle 1
Histologically or cytologically confirmed diagnosis of MM as defined according to International Myeloma Working Group (IMWG). The subject has undergone stem cell transplant or is considered transplant ineligible and has failed at least 3 prior lines of anti-myeloma treatments, including an anti-CD38 antibody (example [e.g.], daratumumab) alone or in combination, and is refractory to an Immunomodulatory drugs (IMiD) (that is [i.e.], lenalidomide or pomalidomide), and to a proteasome inhibitor (i.e., bortezomib, ixazomib or carfilzomib).
Has received at least 2 consecutive cycles of a proteasome inhibitor (PI).
Pathologically-documented diagnosis of multiple myeloma that has relapsed after prior lines of therapy that must include a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and, where approved and available, anti-CD38 therapy in any order OR that is refractory to PI, IMiD, and anti-CD38 therapy. ?Subjects who could not tolerate a PI, IMiDs, or a CD38-directed therapeutic antibody due to unacceptable toxicities are eligible to enroll in the study.
Prior treatment: Treated with at least three prior lines of multiple myeloma therapy including a proteasome inhibitor and an immuno modulatory agent or who are double refractory to a proteasome inhibitor and an immuno modulatory agent. Prior anti-CD38 antibody (e.g., daratumumab, isatuximab) treatment is acceptable only for participants receiving monotherapy treatment.
Diagnosis of relapsed or relapsed and refractory multiple myeloma following at least 2 prior therapies which must include at least one immunomodulatory drug (e.g., thalidomide, lenalidomide or pomalidomide) and one proteasome inhibitor (e.g., bortezomib or carfilzomib). Patients must not be candidates for regimens known to provide clinical benefit.
Patient must have relapsed or refractory disease according to international uniform response criteria and must have previously received therapy with a proteasome inhibitor and an immunomodulatory imide drug (IMiD)
Patients must have previously received lenalidomide and a proteasome inhibitor
Received at least 2 prior lines of therapy for MM including an immunomodulatory drug and a proteasome inhibitor.
Prior anti-myeloma treatments must have included an immunomodulatory drug (IMiD) AND proteasome inhibitor alone or in combination and participant must have failed therapy with an IMiD OR proteasome inhibitor
Participant must not have been previously treated with proteasome inhibitors. (The sponsor reserves the right to open the study to proteasome inhibitor-exposed participants in the future, at some time point after the first interim analysis (IA). In that case, the participant may not be refractory to proteasome inhibitor therapy.)
Patient had received at least two previous therapies including lenalidomide and proteasome inhibitor and have demonstrated disease progression on therapy or after completion of the last therapy.
Prior anti-myeloma treatments must have included a lenalidomide AND proteasome inhibitor alone or in combination.
Must have undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of proteasome inhibitor unless not a candidate.
No prior treatment with MRZ or any other proteasome inhibitors or any other anti-angiogenic agents.
Patients must have received at least 2 prior lines of anti-myeloma therapy, which must include at least 2 consecutive cycles of lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib or ixazomib) given alone or in combination.
Patients must have failed treatment with lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) alone or in combination.
Prior treatment with bortezomib or other proteasome inhibitor is allowed, provided ALL of the following criteria are met: Disease is NOT refractory to any proteasome inhibitor, defined as no disease progression (i.e., PD, per IMWG or European Society for Blood and Marrow Transplantation [EBMT] criteria) while receiving proteasome inhibitor therapy or within 60 days after the last dose, AND best response achieved with any proteasome inhibitor therapy (alone or in combination) was at least a PR, AND participant did not discontinue any proteasome inhibitor due to intolerance or greater than or equal to Grade 3 related toxicity.
Participant is refractory to any proteasome inhibitor, defined as progression on or within 60 days of the last dose of a proteasome inhibitor-containing regimen.
Participant has had prior treatment with proteasome inhibitor within 60 days prior to first dose of study drug.
Subjects must have received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory (IMID) agent OR were double-refractory to both an IMID and a PI. Refractory is defined as progressing on-treatment or within 60 days of the last dose.
Prior treatment with less than or equal to (>=) 2 treatment lines of anti-myeloma therapy. Prior lines of therapy must include a proteasome inhibitor (PI) (eg, bortezomib, carfilzomib) and an immunomodulatory drug (IMiD) (example, thalidomide, lenalidomide, pomalidomide) in any order during the course of treatment. Each prior line of therapy may consist of one or more agents and may include induction, hematopoietic stem cell transplantation, and/or maintenance therapy. Radiotherapy, bisphosphonates, or a single short course of steroids is not considered a prior line of therapy
Have received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) in any order during the course of treatment for multiple myeloma or have disease that is refractory to both a PI and an IMiD
Prior therapy for SMM with a proteasome inhibitor
Prior exposure to an immunomodulatory agent (IMiD)
Prior exposure to a proteasome inhibitor (PI)
Prior therapy with a proteasome inhibitor if discontinued due to toxicity
Received two lines of prior therapy that includes an immune-related inflammatory disease (IMiD) (lenalidomide or thalidomide) and a proteasome inhibitor (bortezomib and/or carfilzomib) (used either separately or in combination); prior pomalidomide therapy is permitted, provided the patient achieved at least a partial remission and had not progressed for 3 months after stopping therapy
Prior treatment: no previous cytotoxic chemotherapy within 4 weeks prior to initiation of therapy; (this does not include immunomodulatory drugs [IMIDs], proteasome inhibitors, monoclonal antibodies or steroids)
Must have undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of a proteasome inhibitor (either in separate regimens or within the same regimen)
includes an IMiD and proteasome inhibitor as separate lines or a combined line of therapy
Diagnosis of multiple myeloma previously treated with at least 1 prior line of therapy (dose escalation only) or (safety expansion only) received treatment with a proteasome inhibitor or an IMiD(r) or immunomodulatory agent (e.g., thalidomide, lenalidomide). Induction therapy and following stem cell transplant are considered a single line of therapy.
Prior therapy with any proteasome inhibitor other than bortezomib or carfilzomib
Previous therapy with IMiD compounds (thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib), and corticosteroids must be discontinued at least 14 days before entry onto this study
MSKCC confirmed diagnosis of multiple myeloma that has relapsed or is resistant after therapy with at least one immunomodulatory drug (i.e. lenalidomide, thalidomide) and at least one proteasome inhibitor
Proteasome inhibitors within 14 days
Must have received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or those who are double refractory to a PI and an immunomodulatory agent and have demonstrated disease progression (DP) on or within 60 days of completion of the last therapy; participants previously treated with an alkylating agent, in addition to an IMiD or proteasome inhibitor, are allowed to enroll in the trial
Participants who will receive combination therapy with Pomalidomide/Dexamethasone must have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy
Must have received at least 3 of the following classes of anti-myeloma agents either alone or in combination: glucocorticoids, immunomodulatory drugs such as thalidomide, proteasome inhibitors, alkylating chemotherapy, or anthracyclines
Prior treatment with a proteasome inhibitor
Patients with a confirmed diagnosis of multiple myeloma who have received two or more lines of therapy and are refractory to their most recent line of therapy, as defined as relapse while on therapy or within 60 days from their last line of therapy. If patient has not received either an immunomodulatory drug (IMID) or proteasome inhibitor as a prior therapy then Investigator must notify Novartis prior to the patient enrollment. Patients who have received a prior bone marrow transplant and otherwise meet the inclusion criteria are eligible for this study
Patients must have received at least one prior line of therapy and also must have received at least one proteasome inhibitor and one immunomodulatory agent (IMiD); for example; one prior line of therapy may consist of all predetermined components of induction followed by autologous stem cell transplantation and maintenance
Patient received prior treatment for MM with a proteasome inhibitor and an immunomodulatory drug, unless not a candidate for a proteasome inhibitor or an immunomodulatory drug.
a. ?2 prior therapies including proteasome inhibitor and immunomodulatory agent (IMiD)
Must have received ? 2 prior anti-MM therapies including a proteasome inhibitor and an IMiD. The most recent proteasome inhibitor must not have been carfilzomib.
Have received at least 3 prior lines of therapy, including a proteasome inhibitor [PI] and an immunomodulatory agent [IMiD] OR have disease that is double refractory to a PI and IMiD
Prior exposure to approved or investigational treatments for SMM or MM (including but not limited to conventional chemotherapies, immunomodulatory agent [IMiDs], or proteasome inhibitor [PIs]). Stable standard dosing of bisphosphonate as indicated for osteoporosis is acceptable
Relapsed after > or = 2 lines of prior therapy that must include a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and, where approved and available, a CD38-directed cytolytic antibody in any order during the course of treatment OR refractory to PI, IMiD, and CD38- directed cytolytic antibody,
Diagnosis of MM with relapsed or refractory disease and have had at least 3 different prior lines of therapy including proteasome inhibitor (e.g., bortezomib or carfilzomib) and immunomodulatory therapy (IMiD; e.g., lenalidomide or pomalidomide), or have double refractory disease to a proteasome inhibitor and IMiD, defined as progression on or within 60 days of treatment with these agents.
Prior treatment with bortezomib or other Proteasome Inhibitor (PI) is allowed, provided all of the following criteria are met: Best response achieved with prior bortezomib at any time was ? PR and with the last PI (PI therapy (alone or in combination) was ? PR, AND Participant did not discontinue bortezomib due to ? Grade 3 related toxicity, AND Must have had at least a 6-month PI-treatment-free interval prior to Cycle 1 Day 1 (C1D1) of study treatment.
Prior therapy should include at least a proteasome inhibitor (PI), an immunomodulatory drug (IMid), an alkylating agent, and a steroid and should be refractory or intolerant to at least 1 PI and at least 1 IMid.
Minimum of 3 prior lines of therapy including an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI)