Thalidomide: 7 days
Immunomodulator therapy (IMiD e.g. lenalidomide or thalidomide) -1 week
History of allergy to mannitol or prior hypersensitivity to thalidomide, lenalidomide or pomalidomide
Prior treatment with lenalidomide; patients previously treated with thalidomide who discontinued treatment for reasons aside from an adverse reaction to thalidomide are permitted
Known hypersensitivity to thalidomide or lenalidomide
Patients who experienced thromboembolic events while on full anticoagulation during prior therapy with lenalidomide or thalidomide.
Any prior treatment with pomalidomide. Subjects who have prior treatment with other immunomodulatory compounds (thalidomide, lenalidomide) ARE eligible if they meet all other eligibility criteria and did not have allergic reactions or other \significant toxicity\ per Investigator discretion associated with lenalidomide or thalidomide use.
Lenalidomide, thalidomide or other immunomodulatory drugs (IMiDs)
Prior therapy with elotuzumab or any immunomodulatory drug (IMiD) (including pomalidomide), except for prior thalidomide or lenalidomide (as defined in inclusion criteria)
History of grade 4 rash associated with thalidomide treatment
Known hypersensitivity to lenalidomide or thalidomide, ibrutinib, rituximab, etoposide, vincristine,\r\ndoxorubicin, cyclophosphamide, or prednisone
History of hypersensitivity of lenalidomide or thalidomide
Patients with history of previous immunomodulatory therapy (not including lenalidomide or thalidomide)
Lenalidomide, thalidomide and pomalidomide
Known hypersensitivity to thalidomide or lenalidomide
Known hypersensitivity to thalidomide, lenalidomide or ipilimumab
Known hypersensitivity or desquamating rash to either thalidomide or lenalidomide
Known hypersensitivity to thalidomide or lenalidomide
Subject has known hypersensitivity to dexamethasone, clarithromycin, lenalidomide, or thalidomide
Hypersensitivity to thalidomide, lenalidomide, pomalidomide, bortezomib, or dexamethasone (such as Stevens-Johnson syndrome); rash to immunomodulatory drug that can be medically managed is allowable
History of erythema multiforme or severe hypersensitivity to prior IMiD’s such as thalidomide and lenalidomide
Had rash ? Grade 3 during prior thalidomide, lenalidomide, or pomalidomide therapy
Has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, POM, or dex
Prior thalidomide is allowed, however, patients must not have prior >= grade-3 allergic reactions to thalidomide
History of erythema multiforme, Grade >= 3 rash, or blistering following prior treatment with immunomodulatory derivatives such as thalidomide and lenalidomide
Hypersensitivity to thalidomide, lenalidomide, pomalidomide, or dexamethasone
For MM-2 cohort only: Hypersensitivity (eg, Rash Grade 3 or 4) to thalidomide, lenalidomide, or dexamethasone (MM-2b).
Hypersensitivity to IMiDs (thalidomide or lenalidomide) defined as any hypersensitivity reaction leading to stop IMiDs within the 2 first cycles or toxicity, which does meet intolerance definition.
Arm A only: ImiDs (eg, lenalidomide, thalidomide);
Prior therapy with thalidomide in combination with ruxolitinib
Known hypersensitivity to thalidomide or lenalidomide
Patients with a prior history of serious allergic reactions associated with thalidomide or lenalidomide
Patients who have received pomalidomide in the past are not eligible; patients who have prior treatment with other immunomodulatory drugs (IMiDs) (thalidomide, lenalidomide) ARE eligible if they meet all other eligibility criteria and did not have \significant toxicity\ associated with lenalidomide or thalidomide use; a “significant” toxicity will be defined as one that required a dose reduction or discontinuation due to toxicity; please discuss any questions with the PI
Known hypersensitivity to thalidomide or lenalidomide
Known hypersensitivity to thalidomide or lenalidomide
Patients who have received hydroxyurea alone or have received non-cytotoxic therapies previously for treatment of MDS or myeloproliferative neoplasm (MPN) (e.g. azacitidine, decitabine, histone deacetylase inhibitors, tyrosine kinase inhibitors, hematopoietic growth factors, interferon, lenalidomide, thalidomide) will be eligible for this trial as long as immunomodulatory drugs (e.g. lenalidomide, thalidomide) have not been used in the past 3 months
Hypersensitivity to thalidomide, lenalidomide, or dexamethasone (such as Steven Johnson Syndrome). Hypersensitivity, such as rash, that can be medically managed is allowable
Hypersensitivity to previous lenalidomide or thalidomide
Patients with a prior history of grade 4 rash associated with thalidomide treatment
Hypersensitivity to thalidomide, lenalidomide or pomalidomide
Known hypersensitivity to thalidomide or lenalidomide (if applicable)
Known hypersensitivity to thalidomide or lenalidomide.
Known hypersensitivity to thalidomide or lenalidomide
Known hypersensitivity to thalidomide or lenalidomide.
Prior therapy with thalidomide and lenalidomide is allowed
Must have received at least one (1) prior line of systemic treatment that has included either lenalidomide or thalidomide.
Known hypersensitivity to thalidomide, lenalidomide, azacitidine, or mannitol
Known hypersensitivity to thalidomide or lenalidomide (if applicable)
Grade 4 rash due to prior thalidomide treatment
Have known hypersensitivity to thalidomide or lenalidomide
Patients with known hypersensitivity to thalidomide or lenalidomide or pomalidomide
Known hypersensitivity to thalidomide or lenalidomide
Patients who were previously exposed and who developed severe adverse events, hypersensitivity or desquamating rash to either thalidomide or lenalidomide
History of hypersensitivity to IMiDs® (lenalidomide, pomalidomide, thalidomide).
Known hypersensitivity to thalidomide or lenalidomide (if applicable)
Known hypersensitivity to thalidomide or Revlimid (if applicable)
Known hypersensitivity to thalidomide or lenalidomide
Known history of resistance to thalidomide
Lenalidomide, thalidomide and pomalidomide
Subjects must have received prior treatment with bortezomib, and either thalidomide or lenalidomide
Known hypersensitivity to lenalidomide or thalidomide
Hypersensitivity to thalidomide, lenalidomide, or dexamethasone
Prior Therapy with thalidomide, lenalidomide or pomalidomide
Prior therapy with histone deacetylase (HDAC) inhibitors or immunomodulatory drugs (IMDs) (lenalidomide or thalidomide)
Known hypersensitivity to thalidomide or lenalidomide (if applicable)
Known hypersensitivity to thalidomide or lenalidomide
Known sensitivity to lenalidomide or other thalidomide derivatives
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)
Carfilzomib: 7 days
Plans to receive maintenance treatment within 100 days post-engraftment (e.g. Lenalidomide, Bortezomib, Pomalidomide, Thalidomide, Carfilzomib, etc.)
Patients not able to tolerate lenalidomide or carfilzomib or dexamethasone
ARM 1: Must have prior exposure to an immunomodulatory drug (IMiD) and proteasome inhibitor (PI) and have had 2 prior regimens/lines of therapy; but there is no maximum number of prior regimens, and prior autologous bone marrow transplant is acceptable if > 12 weeks from transplantation; patients may have received prior carfilzomib (sensitive, relapsed and refractory [having progressed while receiving carfilzomib or within 60 days of stopping carfilzomib] are all eligible), but must be > 4 weeks from last dosing of carfilzomib
ARM 2: Must have had at least 1 but no more than 3 prior lines of anti-myeloma therapy; may be refractory to lenalidomide but sensitive to carfilzomib; prior exposure to carfilzomib is allowed but may not be refractory to carfilzomib; subjects must be >= 8 weeks from last carfilzomib therapy
Patients may have received prior carfilzomib (sensitive, relapsed and refractory all eligible);  response and duration of prior carfilzomib therapy must be known
Male subjects must agree to practice contraception for at least 90 days after the last dose of carfilzomib, and must agree not to donate sperm for at least 90 days after the last dose of carfilzomib
Prior treatment with carfilzomib for lymphoma
Male subjects must agree not to donate semen or sperm while taking pomalidomide and/or carfilzomib until at least 28 days after the last pomalidomide/carfilzomib dose
Pts who have received prior treatment with carfilzomib (Phase II only)
Pts who have received prior treatment with both carfilzomib & pomalidomide (Phase I only)
For patients that relapse following a response to prior treatment with bortezomib or carfilzomib, six months must have elapsed since the last dose of treatment
The patient is refractory to carfilzomib or bortezomib; (refractory is defined as patients who never achieved a response and progressed while on carfilzomib or bortezomib or within 60 days of completing treatment)
Patients must have been previously treated with an immunomodulatory drug (IMiD) and proteasome inhibitor, must be refractory to carfilzomib defined as progression on or within 2 months of a carfilzomib-containing therapy, and must be progressing
Patients eligible for this trial will be those who have failed carfilzomib either as a single agent as the last form of therapy, or carfilzomib in combination with dexamethasone, or carfilzomib in combination with revlimid and dexamethasone; given the potential for compounding/worsening toxicities with the addition of cabozantinib to carfilzomib, patients eligible for the trial will have to have had very good tolerance to carfilzomib in the context of described regimens, with resolved prior toxicity to grade 1 or better, and no toxicities due to carfilzomib that required dose reductions to less than 27 mg/m^2
Allergy to carfilzomib or cabozantinib or any excipients
Subjects who have carfilzomib-related posterior reversible encephalopathy syndrome (PRES) and thrombotic microangiopathy (TMA) should not be challenged with carfilzomib
Must have received at least 2 consecutive cycles of a bortezomib- or carfilzomib-containing regimen, and either:
Achieved at least a partial response (PR) and did not have PD during treatment with or within 60 days after the last dose of bortezomib or carfilzomib, OR
Had bortezomib and/or carfilzomib intolerance (defined as discontinuation because of drug-related adverse events (AEs) before completion of the planned treatment course) without PD before the start of the next regimen.
Subjects not able to tolerate elotuzumab, lenalidomide, carfilzomib, or dexamethasone
Prior treatment with carfilzomib
No prior irinotecan or carfilzomib
Are refractory to bortezomib or carfilzomib at the last exposure before this study (defined as participants having PD while receiving bortezomib or carfilzomib therapy or within 60 days after ending bortezomib or carfilzomib therapy).
Criteria 5 Prior therapy with carfilzomib is allowed as long as the patient had at least a PR to most recent therapy with carfilzomib, was not removed due to toxicity, did not relapse within 60 days from discontinuation of carfilzomib, and will have at least a 6-month carfilzomib treatment-free interval from last dose received until first study treatment. (Patients may receive maintenance therapy with drugs that are not proteasome inhibitors or CD38 antibodies during this 6-month carfilzomib treatment free interval)
Subjects must have been treated with at least 2 prior therapies including a proteasome inhibitor and a cereblon-binding agent\r\n* Subjects who are refractory to carfilzomib may enroll throughout the trial; carfilzomib refractory status is defined by IMWG criteria: disease that is nonresponsive while on salvage therapy, or progresses within 60 days of last therapy in patients who have achieved minimal response (MR) or better at some point previously before then progressing in their disease course\r\n* In the twice weekly dosing cohort of the study, enrollment will be limited to patients meeting carfilzomib refractory status\r\n* In the weekly dosing cohort, it will be required that one of the expansion cohorts (20 subjects) enrolls carfilzomib refractory subjects and the other (20 subjects) enrolls carfilzomib/proteasome inhibitor (PI) naive/sensitive subjects
Male patients must agree not to donate semen or sperm while they are taking carfilzomib and 28 days after the last carfilzomib dose.
Patients may not have received any prior carfilzomib treatment
Patient must have been eligible for and initially randomized to Arm 1 (low dose carfilzomib), begun cycle 2 of treatment, and progressed prior to completing 12 cycles of protocol therapy
Patients must have begun cycle 2 (carfilzomib – 27 mg/m^2) and must not have received any dose reduction for toxicity in the last cycle of treatment, immediately preceding progression
Subject must have received a regimen containing carfilzomib in combination with dexamethasone as their most recent line of therapy and have:
For carfilzomib-lenalidomide-dexamethasone (KRd) regimen: newly diagnosed myeloma. For carfilzomib-dexamethasone (CFZ-dex) regimen: relapsed or refractory disease
Subjects with relapsed/refractory MM who have received at least two prior lines of therapy including lenalidomide and either bortezomib or carfilzomib and have demonstrated disease progression on or within 60 days of the completion of the most recent treatment regimen.
Any prior treatment with carfilzomib
Prior treatment with carfilzomib or oprozomib
Is refractory to VELCADE or another PI, like ixazomib and carfilzomib (had progression of disease while receiving VELCADE therapy or within 60 days of ending VELCADE therapy or another PI therapy, like ixazomib and carfilzomib
Prior treatment with either carfilzomib or oprozomib
Prior therapy with carfilzomib if discontinued due to toxicity
Intolerance to previous bendamustine, carfilzomib or dexamethasone or mannitol; subjects who are allergic to bortezomib are not excluded
Prior dose limiting toxicity from carfilzomib or lenalidomide
Prior carfizolmib is not required but is allowed if a patient had at least 2 cycles of carfilzomib alone or in combination with a dose of at least 20/27 mg/m2, as long as the patient :
Had at least a partial response to prior carfilzomib therapy
Was not removed from carfilzomib therapy due to toxicity, unless approved by the medical monitor
Male subjects must agree not to donate semen or sperm while taking lenalidomide and/or carfilzomib and 28 days after the last lenalidomide/carfilzomib dose
Patients should be proteasome inhibitor naive (including bortezomib and carfilzomib) OR have received less than 6 cycles of therapy with a bortezomib or carfilzomib containing regimen and were not refractory to the bortezomib or carfilzomib based regimen (less than a PR or progression on or within 60 days of discontinuation)
Confirmed relapsed or refractory multiple myeloma (MM) or plasma cell leukemia (PCL); patients should have received at least 1 prior treatment regimen; prior treatment must have included at least one full cycle of a proteasome inhibitor (e.g., bortezomib) and at least one full cycle of an immunomodulatory (IMiD) (e.g., thalidomide, lenalidomide or pomalidomide); patients who have had prior ARRY-520 and carfilzomib will be allowed in the dose escalation phase, however prior ARRY-520 and carfilzomib will be excluded in the dose expansion cohort 1 of part A; there will be 2 cohorts in the dose expansion of part A: cohort 1 will be patients who are carfilzomib sensitive; cohort 2 will be patients who are carfilzomib refractory
Patients who have received any previous carfilzomib treatment
Prior treatment with carfilzomib, filanesib, or any other KSP inhibitor.
Known hypersensitivity to carfilzomib
Subjects must have progressed on standard dose/schedule of carfilzomib without having had any carfilzomib related grade 3 or 4 toxicities
Prior therapy with carfilzomib is allowed as long as the patient had at least a PR to prior carfilzomib therapy, was not removed from carfilzomib therapy due to toxicity, and had at least a 6-month carfilzomib treatment-free interval from last dose received until first study treatment. (Patients may receive maintenance therapy with drugs that are not in the proteasome inhibitor class during this 6 month carfilzomib treatment-free interval). The exception to this is patients randomized or previously randomized in any other Onyx-Sponsored Phase 3 trial.
c. carfilzomib. Demonstrated disease progression on or within 60d of completion of carfilzomib therapy
Prior carfilzomib treatment
Not received carfilzomib within 6 months (183 days) of Cycle 1 Day 1 (C1D1), and
Carfilzomib was not part of their most recent therapy for the treatment of MM, and
Did not discontinue carfilzomib treatment because of adverse effects.
For Concomitant Treatment: No prior treatment with MRZ or any other PIs, including BTZ, carfilzomib (CFZ), or ixazomib (IXZ)