STEP I: Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse, while taking lenalidomide and for 28 days after stopping lenalidomide; male subjects must also agree to abstain from donating blood, semen, or sperm during study participation and for at least 28 days after discontinuation from lenalidomide; male subjects must be willing to use condoms for 90 days after discontinuation of carfilzomib
STEP II: Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse, while taking lenalidomide and for 28 days after stopping lenalidomide; male subjects must also agree to abstain from donating blood, semen, or sperm during study participation and for at least 28 days after discontinuation from lenalidomide; males must agree to use contraception and agree to not donate sperm for at least 90 days after the last day of carfilzomib
Progression on lenalidomide as part of first line therapy (lenalidomide-refractory disease)\r\n* Lenalidomide-refractory disease is defined as disease progression on or progression within 60 days of the last dose of a lenalidomide-based treatment; patients should have received at least 2 cycles of a lenalidomide-based regimen to be evaluable for refractoriness; examples: 1) progression on lenalidomide maintenance therapy after initial induction +/- consolidation; 2) initial response followed by progression on continuous lenalidomide-dexamethasone +/- elotuzumab or daratumumab
Lenalidomide: 7 days
Received >6 cycles lifetime exposure to Lenalidomide.
Received 2-4 prior lines of therapy, including lenalidomide and a PI, either sequential or in the same line, and is refractory (relapsed and refractory or refractory) to lenalidomide in the last line. Refractory status to lenalidomide is defined as progression while on lenalidomide therapy or within 60 days of last dose, following at least 2 cycles of lenalidomide with at least 14 doses of lenalidomide per cycle.
Patients with 5q del MDS unless failed on Revlimid (lenalidomide)
ARM 3: Must have had at least 1 but no more than 3 prior lines of anti-myeloma therapy; exposure to carfilzomib and lenalidomide is allowed but must not be refractory to either drug; must be 6 months from prior therapeutic lenalidomide (> 4 weeks if lenalidomide used as maintenance [dose < 15 mg]) and ?8 weeks from prior carfilzomib
All subjects must have failed 1+ prior treatment, one of which must include lenalidomide therapy\r\n* Patients requiring second (2nd) line of therapy must meet criteria of lenalidomide-refractory disease defined as a history of progression on or within 60 days of completion of a regimen of a minimum of 2 cycles containing full or maximally tolerated dose of lenalidomide\r\n** Patients progressing on lenalidomide maintenance in the first line of therapy will be eligible provided that they have received at least 2 cycles of lenalidomide at established standard maintenance dosing schedule; maintenance dosing and schedule must be documented and approved by lead principal investigator prior to enrollment \r\n* For patients requiring third (3rd) or higher line of therapy, history of treatment with lenalidomide is required but lenalidomide-refractory status is not\r\n* In addition, subjects also refractory to pomalidomide, carfilzomib, or bortezomib are permitted limited to 10 subjects per group
Nursing women (lactating females are eligible provided that they agree not to breast feed while taking lenalidomide)
Patients with 5q- syndrome should have failed to respond to or progressed on treatment with lenalidomide, where available and indicated
Women of childbearing potential and sexually active males must agree to use 2 methods of an accepted and effective method of contraception and counseled on the potential teratogenic effects of lenalidomide; effective contraception must be used by patients for at least 4 weeks before beginning lenalidomide therapy, during lenalidomide therapy, during dose interruptions and for 4 weeks following discontinuation of lenalidomide therapy; reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal naturally for at least 24 consecutive months; two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method; females of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed; sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be females of childbearing potential; it is not known whether CC-5013 (lenalidomide) is present in the semen of patients receiving the drug; therefore, males receiving CC-5013 (lenalidomide) must always use a latex condom during any sexual contact with females of childbearing potential even if they have undergone a successful vasectomy
Patients must not have received prior therapy with lenalidomide (for more than 2 months) nor eltrombopag
Able to take aspirin (81 or 325 mg) daily or for thromboprophylaxis with lenalidomide.
Nursing women (lactating females are eligible provided that they agree not to breast feed while taking lenalidomide)
Prior therapy with lenalidomide
Patients who previously received lenalidomide and have experienced toxicities resulting in treatment discontinuation.
Must be refractory to lenalidomide, defined as having received at least 2 consecutive cycles of lenalidomide as a single agent or within a lenalidomide-containing regimen and having had PD during treatment with or within 60 days after the last dose of lenalidomide. The starting dose of lenalidomide should have been 25 mg (or as low as 10 mg in the case of renal function impairment or other safety concern), and the final dose should have been a minimum of 10 mg.
Patients who previously had any intolerance to lenalidomide 10 mg or who have a contraindication to lenalidomide will not be eligible for concomitant treatment with lenalidomide but will remain eligible for CAR T cell therapy without lenalidomide
Has progressed on prior therapy with lenalidomide
Prior venetoclax or other BCL-2 family inhibitors or prior lenalidomide is not permitted
Newly diagnosed, previously untreated myeloma requiring systemic chemotherapy\r\n* Prior treatment of hypercalcemia or spinal cord compression or active and/or aggressively progressing myeloma with corticosteroids and/or lenalidomide and/or bortezomib/principal investigator (PI)-based regimens does not disqualify the subject (the corticosteroid treatment dose should not exceed the equivalent of 160 mg of dexamethasone in a 4 week period or not more than 1 cycle of lenalidomide and/or PI-based therapy)
Currently using lenalidomide or hypomethylating agents (HMA)
Breast feeding (if lactating, must agree not to breast feed while taking lenalidomide); breastfeeding should be discontinued if the mother is treated with lenalidomide
Subject has received > 6 months of lenalidomide (Revlimid) therapy prior to stem cell collection
Prior lenalidomide exposure is permitted only if the subject did not discontinue lenalidomide due to a related, grade >= 3 adverse event (AE)
Patients with history prior to transplant of progression on lenalidomide therapy
Failed 2 or more prior standard MM therapies, and >100 days post autologous bone marrow transplant prior to first dose for transplanted subjects. Prior lenalidomide is permitted.
History of hypersensitivity to lenalidomide (Part B only)
Patients who completed induction treatment followed by autologous stem cell transplant as initial therapy for symptomatic myeloma as per IMWG criteria and are considered for single agent lenalidomide (Revlimid) maintenance or initiated single agent Revlimid maintenance\r\n* Patients will be eligible for enrollment in the first 0-4 months of lenalidomide maintenance provided that lenalidomide maintenance has been initiated on days 60 - 120 after transplant\r\n* Patients must be receiving lenalidomide 10 mg or 15 mg and be able to tolerate dose escalation to 25 mg daily\r\n* Patients receiving lenalidomide maintenance cannot exceed 4 months of lenalidomide post-transplant
Previous treatment with lenalidomide for AML
All patients must have received prior lenalidomide therapy and been determined to be refractory; refractory will be defined as a history of progression on a regimen containing full or maximally tolerated dose of lenalidomide administered for a minimum of at least two completed cycles of therapy
Prior to enrollment, sites must provide evidence of myeloma progression/relapse and evidence of being refractory to lenalidomide, with start and stop dates of lenalidomide therapy and the most recent treatment regimen, as well as best tumor response to all prior treatment regimens
Any prior use of lenalidomide.
Has received at least 2 consecutive cycles of lenalidomide and be refractory to lenalidomide, as defined per protocol.
Previously treated relapsed and refractory multiple myeloma\r\n* Patients must have received at least one prior line of therapy\r\n* Prior therapy must include at least 2 cycles of lenalidomide and at least 2 cycles of a proteasome inhibitor (either in separate regimens or within the same regimen)\r\n* Patients must be refractory and/or relapsed/refractory to lenalidomide or prior lenalidomide\r\n* Disease progression on or within 60 days of completion of last therapy
Patients must be lenalidomide failures: disease progression on a prior lenalidomide-based therapy or progression within 60 days of the last dose of a lenalidomide; patients should have received at least 2 cycles of a lenalidomide-based regimen at standard doses to be evaluable for refractoriness; prior intolerance to lenalidomide does not exclude participation in the study except in cases of severe allergic reaction
Patient must agree to take lenalidomide with low dose dexamethasone as their initial therapy
Subject must be at least 2 months (from first dose of lenalidomide) from stem cell infusion.
Subject has isolated Central Nervous System (CNS) involvement or extramedullary relapse. (Subjects with combined CNS/marrow relapse may be Subject has had prior treatment with cytotoxic chemotherapy within 2 weeks of the first dose of lenalidomide with the exception of hydroxyurea (allowed prior to the first dose of lenalidomide and through Day 14 of Cycle 1) and intrathecal (IT) cytarabine will be administered within 2 weeks prior to administration of lenalidomide.
Prior treatment with azacitidine, decitabine, other hypomethylating agents and lenalidomide ( for lenalidomide : unless the last dose received is >= 8 weeks prior to inclusion into the study).
? 2 prior lines of therapy which must have included at least 2 consecutive cycles of lenalidomide and a proteosome inhibitor alone or in combination
Refractory to proteosome inhibitor and lenalidomide, and to last treatment
Patients must not have prior therapy with lenalidomide
Patients must have completed 16 weeks of monotherapy with lenalidomide
Patients must not have a limiting unresolved grade 3 or greater toxicity from lenalidomide monotherapy or drug intolerance preventing continuation of lenalidomide treatment
Agreement to comply with all local requirements of the lenalidomide risk minimization plan
History of resistance to lenalidomide or response duration of <1 year
Patients may have received prior lenalidomide as long as it has been at least two years since exposure and the patient may not have experienced a progression while receiving lenalidomide previously
Prior therapy with lenalidomide
Prior treatment with lenalidomide
Have currently active gastrointestinal disease, or prior surgery that may affect the ability of the patient to absorb oral lenalidomide
Patients must have also undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of a proteosome inhibitor (either in separate regimens or within the same regimen).
Any prior use of lenalidomide
Del(5q) karyotype unless treatment with lenalidomide has failed. Failure is defined as either: 1) having received at least 3 months of lenalidomide treatment without RBC transfusion benefit (International Working Group [IWG] 2006); 2) progression or relapse after hematologic improvement with lenalidomide (IWG 2006); 3) discontinuation of lenalidomide due to toxicity; or 4) unable to receive lenalidomide due to a contraindication. Source documentation for lenalidomide treatment failure must be verified by the sponsor
Prior use of lenalidomide
If treated with a lenalidomide and dexamethasone combination, progression during the first 3 months after initiating treatment.
Any progression during treatment if the lenalidomide and dexamethasone regimen was the most recent line of therapy.
Prior use of lenalidomide.
Pregnancy tests must occur within 10-14 days and again within 24 hours prior to initiation of cycle 1 of lenalidomide; females of childbearing potential (FCBP) with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on lenalidomide therapy (including breaks in therapy); at discontinuation of lenalidomide and at day 28 post the last dose of lenalidomide; females with irregular menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while on lenalidomide therapy (including breaks in therapy), at discontinuation of lenalidomide and at day 14 and day 28 post the last dose of lenalidomide
Females of childbearing potential must have a negative serum pregnancy test with a minimum sensitivity of 50 mIU/mL and agree to use two medically accepted forms of contraception from the time of initial screening through completion of the study or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: \r\n* For at least 28 days before starting lenalidomide \r\n* Throughout the entire duration of lenalidomide treatment\r\n* During dose interruptions\r\n* For at least 28 days after lenalidomide discontinuation.
Prior use of lenalidomide if discontinued due to toxicity
Patients must have had therapy with a proteasome inhibitor and lenalidomide and be refractory to lenalidomide according to the International Myeloma Working Group (IMWG) criteria definition of refractory disease (progressive disease on or within 60 days of stopping lenalidomide)
Patients must not have had progression of disease on lenalidomide 25 mg; stable disease on lenalidomide is permitted
Disease shows evidence of refractoriness or intolerance to lenalidomide or if previously treated with a lenalidomide-containing regimen the participant is excluded if he or she discontinued due to any adverse event related to prior lenalidomide treatment
Disease progression as defined by International Myeloma Working (IMW) Criteria on the combination of carfilzomib, lenalidomide and dexamethasone (patients with progression on lenalidomide maintenance after completion of carfilzomib, lenalidomide and dexamethasone combination therapy will be eligible)
Prior use of lenalidomide if discontinued due to toxicity
History of hypersensitivity to lenalidomide
Patients who are post auto-SCT as primary therapy must have received maintenance therapy with lenalidomide
Patients must be registered within 6 months of last dose of lenalidomide
All subjects must have received prior treatment with a lenalidomide containing regimen for at least 2 consecutive cycles.
Have discontinued lenalidomide due to any treatment-related adverse event or be refractory to any dose of lenalidomide. Refractory to lenalidomide is defined as either, participants whose disease progresses within 60 days of lenalidomide, or participants whose disease is nonresponsive while on any dose of lenalidomide. Nonresponsive disease is defined as either failure to achieve at least an minimal response (MR) or development of progressive disease (PD) while on lenalidomide
Calculated creatinine clearance ? 30 mL/min NOTE: Participants with a low creatinine clearance ? 60 mL/min (or ? 50 mL/min, according to lenalidomide prescribing information/local practice) were to receive a reduced lenalidomide dose of 10 mg once daily (QD) on Days 1 through 21 of a 28-day cycle. The lenalidomide dose may have been escalated to 15 mg QD after 2 cycles if the participant was not responding to treatment and was tolerating the treatment. If renal function normalized (ie, creatinine clearance >60 mL/min or >50 mL/min, according to lenalidomide prescribing information/local practice) and the participant continued to tolerate this treatment, lenalidomide may then have been escalated to 25 mg QD.
Any prior use of lenalidomide
Any prior use of lenalidomide.
Patients may have received lenalidomide and/or dexamethasone
Prior treatment with Lenalidomide permitted if:
Subject did not receive more than 9 cycles of Lenalidomide and had at least 9 months between the last dose of Lenalidomide and progression
Patient has any prior use of lenalidomide
Patients with MDS should have failed prior therapy with a hypomethylating agent or, if associated with a 5q- chromosomal abnormality, lenalidomide. NOTE: Patients with 5q- unable to receive or intolerant to lenalidomide are also eligible.
History of intolerance or resistance to lenalidomide
Any prior use of lenalidomide
Active infection at the start of lenalidomide
Must agree to receive counseling related to teratogenic and other risks of lenalidomide.
Prior therapy with lenalidomide.
Prior therapy with lenalidomide.
Received prior treatment for MDS with lenalidomide or hypomethylating agents (HMAs).
Treatment with investigational GVHD prophylactic agents (eg, CCR5 inhibitors; lenalidomide; and/or bortezomib) within the 7 days prior to the 1st dose of neihulizumab
ELIGIBILITY FOR VACCINE AND LENALIDOMIDE ADMINISTRATION (PROTOCOL ENTRY)
Refractory to lenalidomide in the most recent line of therapy, as defined by the International Myeloma Consensus Panel criteria as failure to achieve minimal response or development of progressive disease while on lenalidomide or within 30 days of lenalidomide therapy
If previously received lenalidomide, demonstration of clinical response of any duration or stable disease with progression-free interval of ?6 months from start of that therapy.
Patients must have received previous bortezomib-containing and lenalidomide-containing regimens (or thalidomide where lenalidomide is not available)
Lenalidomide must have been used for at least 6 months after autologous hematopoietic stem cell transplantation with the current dose of lenalidomide 15 mg/day or less
Relapsed myeloma that previously became refractory to lenalidomide, after initial response of partial response or better to the drug; refractory is defined as progression on treatment with a dose of at least 10 mg daily for lenalidomide; greater than or equal to 180 days must have elapsed since previous lenalidomide therapy was stopped
Prior treatment with lenalidomide
Patients must be suitable for treatment or re-treatment with lenalidomide & dexamethasone; Note: patients previously treated with lenalidomide & dexamethasone are eligible to participate in the trial
All patients must agree to follow the requirements for lenalidomide counseling, pregnancy testing and birth control; for women of childbearing potential (WOCBP) this includes pregnancy testing prior to prescribing lenalidomide and to either commit to continued\r\nabstinence from heterosexual intercourse or begin acceptable methods of birth control for 28 days prior to prescribing lenalidomide, during therapy and for 28 days after the last dose of lenalidomide; WOCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a WOCBP even if they have had a successful vasectomy and must agree not to donate semen during study drug therapy and for a period of time after therapy; all patients must abstain from donating blood, agree not to share lenalidomide with others and be counseled about the risks of lenalidomide
Prior Lenalidomide exposure is permitted only if the subject did not discontinue Lenalidomide due to a Grade ?3 related Adverse Event (AE)
All subjects must have received at least 2 consecutive cycles of prior treatment that included lenalidomide and bortezomib
All subjects must have failed treatment with both lenalidomide and bortezomib in one of the following ways: 1) Documented progressive disease on or within 60 days of completing treatment with lenalidomide and/or bortezomib, or 2) In case of prior response [? partial response (PR)] to lenalidomide or bortezomib, subjects must have relapsed within 6 months after stopping treatment with lenalidomide and/or bortezomib-containing regimens, or 3) Subjects who have not had a ? minimal response (MR) and have developed intolerance/toxicity after a minimum of two cycles of lenalidomide- and/or bortezomib-containing regimen
Prior treatment with lenalidomide or everolimus
Discontinuation of previous lenalidomide or dexamethasone due to intolerance; subjects intolerant to bortezomib are not excluded
Subjects must agree to receive counseling related to pregnancy precautions, teratogenic and other risks of lenalidomide
Prior lenalidomide therapy.
Patients must be suitable for treatment with lenalidomide & dexamethasone.
Both men and women in the lenalidomide combination arm (Cohort D) must adhere to the guidelines of the RevAssist program (United States participants) or, if not using commercial supplies, must adhere to the Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the Study Manual.
For participant in the lenalidomide combination arm, demonstrated hypersensitivity (example, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide.
Platelet count =< 50 x 10^9/L untransfused of at least 2 weeks duration, secondary to prior chemotherapy; if there is a platelet count of > or = 50 x 10^9/L after a transfusion, that value will be discounted; this may include a combination regimen including lenalidomide; these regimens will include dexamethasone, cyclophosphamide, etoposide, cisplatin (DCEP), Velcade with Doxil, Cytoxan and/or lenalidomide; patients who have thrombocytopenia (CIT) from lenalidomide or from radiation therapy alone will not be allowed; patients may be retreated with Nplate within 6 months of their initial response, with a different chemotherapy regimen
Patients receiving maintenance therapy with myelosuppressive medications such as lenalidomide will be excluded
Lenalidomide naïve; relapsed or refractory CD20-positive follicular lymphoma (Grade 1, 2, or 3a) following at least one prior standard systemic treatment regimen including systemic chemo-, immune-; or chemo-immunotherapy and at least one prior line of salvage therapy with no prior exposure to lenalidomide, or double-refractory FL subjects with no prior exposure to lenalidomide (FL-1 cohort)
Lenalidomide exposed: relapsed or refractory CD20-positive follicular lymphoma (Grade 1, 2, or 3a) previously treated with at least two cycles of lenalidomide-containing regimen (FL-2 cohort), either as a single agent or in combination
Recommended to start lenalidomide