Clinical Trials in Myeloma and Related Disorders at PMH (Version: May 2018)

Transcription

1 Clinical Trials in Myeloma and Related Disorders at PMH (Version: May 2018) NEWLY DIAGNOSED MULTIPLE MYELOMA Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib Maintenance Therapy After Initial Therapy in Patients With Newly Diagnosed Multiple Myeloma Not Treated With Stem Cell Transplantation (Protocol Number: C16021) Inclusion Criteria Each patient must meet all the following inclusion criteria to be randomized to treatment: 1. Adult male or female patients aged 18 years or older with a confirmed diagnosis of symptomatic NDMM according to standard criteria. 2. Completed 6 to 12 months (+/- 2 weeks) of initial therapy, during which the patient was treated to best response, defined as the best response maintained for 2 cycles after the M-protein nadir is reached. 3. Documented major response (PR, VGPR, and CR) according to the IMWG uniform response criteria, version 2011, after this initial therapy. 4. Female patients who: Are postmenopausal for at least 1 year before the screening visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, post ovulation methods] and withdrawal are not acceptable methods of contraception.) Male patients, even if surgically sterilized (ie, status postvasectomy), who: Agree to practice effective barrier contraception during the entire study Treatment period and through 90 days after the last dose of study drug, or agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post ovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.) 5. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. 6. Complete documentation of the details of the initial therapy before randomization including cytogenetics and ISS is available. 7. Eastern Cooperative Oncology Group Performance Status of 0 to 2.

2 8. Suitable venous access for the study-required blood sampling and consent for the specific amounts that will be taken. 9. Patient is willing and able to adhere to the study visit schedule and other protocol requirements including blood sampling and bone marrow aspiration. 10. Patients must meet the following clinical laboratory criteria at study entry: Absolute neutrophil count (ANC) 1,000/mm3 without growth factor support and platelet count 75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before randomization. Total bilirubin 1.5 X the upper limit of the normal range (ULN). Alanine aminotransferase and aspartate amino transferase 3 X ULN. Calculated creatinine clearance 30 ml/min (using the Cockroft-Gault equation Exclusion Criteria Patients meeting any of the following exclusion criteria are not to be randomized to treatment: 1. Multiple myeloma that has relapsed after, or was not responsive to, initial therapy. 2. Prior SCT. 3. Radiotherapy within 14 days before randomization. 4. Diagnosed or treated for another malignancy within 5 years before randomization or previous diagnosis with another malignancy. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. 5. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period. 6. Major surgery within 14 days before randomization. 7. Central nervous system involvement. 8. Infection requiring IV antibiotic therapy or other serious infection within 14 days before randomization. 9. Diagnosis of Waldenstrom s Macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome. 10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, uncontrolled congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. 11. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, Voriconazole, ketoconazole, nefazodone, posaconazole), or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) or use of Ginkgo biloba or St. John s wort within 14 days before randomization. 12. Ongoing or active infection, known human immunodeficiency virus positive, active hepatitis B or C infection. 2

3 Clinical-grade Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies (Protocol MMRF-002; Non-Interventional) Inclusion Criteria: 1. Patients must have a diagnosis of multiple myeloma or related plasma cells malignancies 2. Patients are undergoing standard of care bone marrow aspirates. 3. Patients (male or female) from any race or ethnicity must be 18 years of age at the time of registration 4. Procedure-specific signed informed consent form (ICF) prior to initiation of any study-related procedures. Exclusion Criteria: 1. It is the enrolling study physician s discretion to decide if a patient is not fit enough to undergo tissue biopsy. 2. Patients who are incarcerated are not eligible to participate. 3. Women who are pregnant. 4. Patients who have had another malignancy within the last five (5) years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix) Health-related quality of life and caregiver burden assessment in multiple myeloma and lymphoma patients and their caregivers undergoing outpatient autologous stem cell transplantation as compared to inpatient transplantations: a needs assessment (Non-Interventional) Inclusion criteria: 1. Males or females aged 18 years or older undergoing an autologous stem cell transplant for multiple myeloma, or Hodgkin or Non-Hodgkin Lymphoma 2. Able to provide consent 3. Able to read, write and speak English 4. Available primary caregiver for the caregiver QOL and burden component of study who is able to provide consent and read, write and speak English Exclusion criteria: 1. Geographically inaccessible/will not be followed at Princess Margaret Cancer Centre for the 100d period posttransplant. 2. Unable to provide consent. 3

4 The Terry Fox Pan-Canadian Multiple Myeloma Molecular Monitoring Cohort Study (The M4 Study; Non-Interventional) Inclusion criteria: 1. Age 19 years 2. Ability to give informed consent 3. Diagnosed with active multiple myeloma (refer to Appendix I for IMWG definition) 4. Also enrolling in the CMM-DB project; and 5. Previously untreated and eligible for autologous stem-cell transplantation (ASCT) 6. Patients who are going to be treated on a clinical trial are also eligible to participate in this study if they meet the other eligibility criteria. Detection of AL amyloid fibrils and oligomers in blood plasma of Multiple Myeloma and Related Plasma Cell Dyscrasias using Immuno-Gold Electron Microscopy (Non-Interventional) Inclusion criteria: 1. Patients must have or be suspected of a diagnosis of AL amyloidosis, MM, or related clonal plasma cell disorder (PCD) such as smoldering myeloma or MGUS. 2. Patient must be 18 years old. 3. Patients are undergoing standard of care blood draw. 4. All patients must have signed and dated an informed consent form. Healthy Subject Inclusion Criteria years old lbs. and above 3. Not pregnant 4. Not known to be anemic

5 Phase 1/2 Multicenter, Open-Label Study to Determine the Recommended Dose and Regimen of Durvalumab (Medi4736) In Combination with Lenalidomide (Len) With and Without Dexamethasone (Dex) In Subjects with Newly Diagnosed Multiple Myeloma (Protocol: MEDI4736-MM-002) Inclusion criteria 1. Subjects must satisfy the following criteria to be enrolled into the study: Subject is 18 years of age at the time of signing the informed consent form (ICF) Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted Subject is willing and able to adhere to the study visit schedule and other protocol requirements Subject must have documented diagnosis with previously untreated (for cohort C, the induction and consolidation treatment along with the first ASCT are allowed), symptomatic MM as defined by the criteria below (Rajkumar, 2014; NCCN-MM, 2015): 2. MM diagnostic criteria (all 3 required); Monoclonal protein present in the serum and/or urine Clonal bone marrow plasma cells 10% or biopsy-proven bony or extramedullary plasmacytoma* Any one or more of the following myeloma defining events: i. One or more of the following Myeloma-related organ dysfunction (at least one o [C] Calcium elevation (serum calcium >11.5 mg/dl) [> 2.65 mmol/l] o [R] Renal insufficiency (serum creatinine >2 mg/dl) [177 µmol/l or more] or creatinine clearance < 40 ml/min o [A] Anemia (hemoglobin <10 g/dl or >2 g /dl below the lower limit of laboratory normal) o [B] Bone lesions (lytic or osteopenic) one or more bone lesions on skeletal radiography, CT, or PET-CT ii. One or more of the following biomarkers of malignancy: o Clonal bone marrow plasma cell percentage* 60% o Abnormal serum free light-chain ratio 100 (involved kappa) or < 0.01 (involved lambda) o >1 focal lesions detected by functional imaging including PET/CT and/or whole body magnetic resonance imaging (MRI) AND have measurable disease by protein electrophoresis analyses as defined by the following: o IgG MM: Serum monoclonal paraprotein (M-protein) level 1.0 g/dl or urine M protein level 200 mg/24 hours o IgA MM: Serum M-protein level 0.5 g/dl or urine M-protein level 200 mg/24 hours o IgM MM (IgM M-protein plus lytic bone disease documented by skeletal survey plain films): Serum M-protein level 1.0 g/dl or urine M-protein level 200 mg/24 hours o IgD MM: Serum M-protein level 0.05 g/dl or urine M-protein level 200 mg/24 hours o Light chain MM: Serum M-protein level 1.0 g/dl or urine M-protein level 200mg/24 hours 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 4. Females of childbearing potential (FCBP1) must: Have two negative pregnancy tests as verified by the investigator prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence2 from heterosexual contact.

6 She must either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and be source documented) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study treatment, during the study therapy (including dose interruptions), and for 90 days after discontinuation of study treatment. Refrain from egg cell and blood donation for 90 days after the final dose of Durvalumab. 5. Male subjects must: Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions and for at least 90 days following study treatment discontinuation, even if he has undergone a successful vasectomy. Refrain from sperm and blood donation for at least 90 days after the final dose of Durvalumab 6. For Cohort A subject must be transplant non-eligible (TNE) and meet at least one of the following high risk factors: Cytogenetic abnormalities finding in malignant myeloma clone with t(4; 14); and / or del(17p); and / or 1q rearrangement; and / or t(14:16); or ISS Stage III; or Serum LDH > 2 x ULN; 7. For Cohort B subject must be 65 years of age at the time of signing the informed consent form (ICF) and transplant non-eligible (TNE); excluding the subjects who meet the Cohort A criteria 8. For Cohort C subject must be after first autologous stem cell transplantation (ASCT) for NDMM and meet the following criteria: Have a post-transplant response as PR or better at the time of enrollment to this study; Have one of the following high risk factors at the time of NDMM diagnosis; i. Cytogenetic abnormalities finding in malignant myeloma clone with t(4; 14); and / or del(17p); and / or 1q rearrangement; and / or t(14; 16); or ii. ISS stage III; or iii. Serum LDH > 2 x ULN; 9. MRD positive (defined as more than 1 malignant cell in 105 cells) measured by ClonoSIGHT NGS assay of a BMA sample) at the time of enrollment to this study; BMA sample collected at the time of multiple myeloma diagnosis, prior to induction therapy available for central MRD assessment by ClonoSIGHT NGS assay Exclusion criteria The presence of any of the following will exclude a subject from enrollment: 1. Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid [ie, less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 14 days of Cycle 1 Day 1], for Cohort C, the induction and consolidation treatment along with the first ASCT are allowed) 2. Any of the following laboratory abnormalities: Absolute neutrophil count (ANC) < 1,000/μL Untransfused platelet count < 75,000 cells/µl Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (SGOT/AST) or alanine aminotransferase (SGPT/ALT) > 2.5 upper limit of normal (ULN) Serum total bilirubin > 1.5 ULN or > 3.0 mg/dl for subjects with documented Gilbert s syndrome Corrected serum calcium >13.5 mg/dl (> 3.4 mmol/l) 3. Renal failure requiring hemodialysis or peritoneal dialysis

7 4. Any serious medical condition that places the subject at an unacceptable risk if he or she participates in this study. Examples of such a medical condition are, but are not limited to, subject with unstable cardiac disease as defined by: cardiac events such as myocardial infarction (MI) within the past 6 months, NYHA (New York Heart Association) heart failure class III-IV, uncontrolled atrial fibrillation or hypertension; subjects with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment 5. Peripheral neuropathy Grade 2 6. Primary AL (immunoglobulin light-chain) amyloidosis and myeloma complicated by amyloidosis 7. Prior history of malignancies, other than MM, unless the subject has been free of the disease for 5 years with the exception of the following non-invasive malignancies: Basal cell carcinoma of the skin Squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative 8. Subjects is positive for human immunodeficiency virus (HIV); chronic or active hepatitis B or active hepatitis A, or C 9. Subject had prior exposure to immunotherapy, including, but not limited to, other anti-ctla-4, anti-pd-1, anti-pd-l1 monoclonal antibody or inhibitor, cell-based therapies, or cancer vaccines 10. Subjects has history of organ or allogeneic stem cell transplantation 11. Subjects who have had clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS multiple myeloma, or plasma cell leukemia 12. Known or suspected hypersensitivity to the excipients contained in the formulation of 13. Durvalumab, lenalidomide, or dexamethasone 14. Major surgery (as defined by the investigator) within the 28 days prior to the first dose of study treatment 15. Received prior treatment (for any reason) with a monoclonal antibody within 5 half-lives of initiating study treatment 16. Use of any investigational agents within 28 days or 5 half-lives (whichever is longer) of initiating study treatment.

8 RELAPSED OR REFRACTORY MULTIPLE MYELOMA A Phase 2, Multicenter Study to Determine the Efficacy and Safety of bb2121 in Subjects with Relapsed and Refractory Multiple Myeloma (Protocol Number: BB2121-MM-001) Inclusion Criteria 1. Documented diagnosis of multiple myeloma 2. Must have received at least 3 prior MM treatment regimens. 3. Must have undergone at least 2 consecutive cycles of treatment for each regimen, unless PD was the best response to the regimen. 4. Must have received a proteasome inhibitor, an immunomodulatory agent and an anti-cd38 antibody. 5. Must be refractory to the last treatment regimen. Refractory is defined as documented progressive disease during or within 60 days (measured from the last dose) of completing treatment with the last anti-myeloma drug regimen before study entry. 6. Subjects must have measurable disease, including at least one of the criteria below: Serum M-protein greater or equal to 1.0 g/dl Urine M-protein greater or equal to 200 mg/24 h Serum free light chain (FLC) assay: involved FLC level greater or equal to 10 mg/dl (100 mg/l) provided serum FLC ratio is abnormal (Clarification by Medical Monitor: Measurable FLC would count for eligibility. However, if patient has disease that is followed by M-protein in serum for response, they need to progress by serum M protein. They cannot progress by FLC alone if the disease has always been followed by serum m protein) Exclusion Criteria: 1. Subjects with solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease 2. Inadequate bone marrow function defined by: ANC < 1000 cells/mm3 in the absence of growth factor support (Filgrastim within 7 days or pegfilgrastim within 14 days of screening) Platelet count < 50,000 mm3 in the absence of transfusion support (platelet transfusion within 7 days of screening). 3. Inadequate renal function defined by CrCl 45 ml/min using Cockcroft-Gault equation. 4. International ratio (INR) or partial thromboplastin time (PTT) > 1.5 ULN, 5. Echocardiogram or MUGA with LVEF < 45%. 6. Inadequate pulmonary function (oxygen saturation (Sa02) < 92 % on room air). 7. Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine or systemic steroids at any dose). Intermittent topical, inhaled or intranasal corticosteroids are allowed. 8. Following transmissible disease tests will be done as part of the screening for this study: HIV 1 and 2 antibody/p24 antigen combination, Hepatitis B Surface Antibody (HBsAb), Hepatitis B Surface Antigen (HBsAg), Hepatitis B Core Antibody (HBcAb), Hepatitis C antibody (HCV antibody), syphilis (by CMIA), HTLV 1 & 2 antibody, HBV DNA and HCV RNA testing. West Nile Virus; CMV, EBV (Dr. Reece s agreement to Bio- Safety Committee) 9. Patients with positive tests for following diseases will be excluded from this study (as per protocol): HIV; hepatitis B virus (HBV); hepatitis C virus. 10. Patient will be verbally screened for the history of travelling in the Zika Virus affected area. If an assay for antibody titer is positive for Zika virus. Patient will be excluded from the study (Dr. Reece s agreement to Bio-Safety Committee) 2

9 11. Dr. Reece has agreed to follow the BMT program protocol for patient s eligibility in addition to protocol (patients with West Nile virus and Syphilis will be excluded). 12. Subject requires ongoing treatment with chronic, therapeutic dosing of anti-coagulants (eg, warfarin, low molecular weight heparin, or Factor Xa inhibitors). 13. Washout-page 53: Any prior systemic therapy for MM within 7 days prior to scheduled protocol required leukapheresis. Experimental agents within 4 weeks prior to leukapheresis unless no response or PD is documented on the experimental therapy (Clarification: If patient s best response to an Investigational Agent (e.g. anti-pdl1) is progressive disease, then 7 days. If not, then 28 days for this experimental agent. Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis. AN OPEN-LABEL, MULTICENTER, PHASE I TRIAL EVALUATING THE SAFETY AND PHARMACOKINETICS OF ESCALATING DOSES OF BFCR4350A IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA (Protocol Number: GO39775) Key Inclusion Criteria 1. Patients must have R/R MM for which no established therapy for MM is appropriate and available or be intolerant to those established therapies 2. Agreement to provide bone marrow biopsy and aspirate samples as per protocol 3. Adverse events from prior anti-cancer therapy resolved to Grade 1, with the following exceptions: Any grade alopecia, peripheral sensory or motor neuropathy must have resolved to Grade 2 Measurable disease defined as at least one of the following: Serum monoclonal protein (M-protein) 0.5 g/dl ( 5 g/l) Urine M-protein 200 mg/24 hr. Serum free light chain (SFLC) assay: Involved SFLCs 10 mg/dl ( 100 mg/l) and an abnormal SFLC ratio (< 0.26 or > 1.65) 4. Laboratory values: Hepatic function: AST and ALT 3 ULN; Total bilirubin 1.5 ULN; patients with a documented history of Gilbert syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible. Hematologic function: Platelet count 75,000/mm3 without transfusion within 14 days prior to first dose of BFCR4350A, ANC 1000/mm3, Total hemoglobin 8 g/dl Creatinine 2.0 ml/dl and creatinine clearance (CrCl) 30 ml/min (either calculated or per 24-hr urine collection) Serum calcium (corrected for albumin) level at or below the ULN 5. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of BFCR4350A and tocilizumab (if applicable) 6. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm Key Exclusion Criteria 1. Prior use of any monoclonal antibody, radioimmunoconjugate, or antibody-drug conjugate within 4 weeks before first BFCR4350A infusion 2. Prior treatment with systemic immunotherapeutic agents, including, but not limited to, cytokine therapy and anti- CTLA4, anti PD-1, and anti PD-L1 therapeutic antibodies, within 12 weeks or 5 half-lives of the drug, whichever is shorter, before first BFCR4350A infusion 3. Treatment-related, immune-mediated adverse events associated with prior immunotherapeutic agents as follows: Grade 3 adverse events with the exception of Grade 3 endocrinopathy managed with replacement therapy 3

10 Grade 1 2 adverse events that did not resolve to baseline after treatment discontinuation 4. Treatment with radiotherapy, any chemotherapeutic agent, or treatment with any other anti-cancer agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to first BFCR4350A infusion 5. Autologous stem cell transplantation (SCT) within 100 days prior to first BFCR4350A infusion 6. Prior allogeneic SCT 7. Primary or secondary plasma cell leukemia as defined by an absolute plasma cell count exceeding 2000/μL or 20% of the peripheral blood white cells 8. Prior solid organ transplantation 9. History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener s granulomatosis, Sjögren s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study. 10. Patients with history of confirmed progressive multifocal leukoencephalopathy 11. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibodyrelated fusion proteins) 12. History of other malignancy that could affect compliance with the protocol or interpretation of results. - Patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are allowed. Patients with a malignancy that has been treated with curative intent will also be allowed if the malignancy has been in remission without treatment for 2 years prior to first BFCR4350A infusion. 13. Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, neurodegenerative disease, or CNS involvement by MM Patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits as judged by the investigator are allowed. Patients with a history of epilepsy who have had no seizures in the past 2 years while not receiving any antiepileptic medications are allowed. 14. Significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) 15. Significant active pulmonary disease (e.g., bronchospasm and/or obstructive pulmonary disease) 16. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics within 4 weeks prior to first BFCR4350A infusion 17. Known or suspected chronic active EBV infection. 18. Recent major surgery within 4 weeks prior to first BFCR4350A infusion 19. Positive serologic or PCR test results for acute or chronic HBV infection: Patients whose HBV infection status cannot be determined by serologic test results 20. Acute or chronic HCV infection 21. Known history of HIV seropositivity 22. Administration of a live, attenuated vaccine within 4 weeks before first BFCR4350A infusion or anticipation that such a live attenuated vaccine will be required during the study. 23. Received systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) with the exception of corticosteroid treatment 10 mg/day prednisone or equivalent within 2 weeks prior to first dose of BFCR4350A 4

11 Patients who received acute, low-dose, systemic immunosuppressant medications (e.g., single dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval of the Medical Monitor The use of inhaled corticosteroids, mineralocorticoids for management of orthostatic hypotension, physiologic doses of corticosteroids for management of adrenal insufficiency is permitted. 24. History of illicit drug or alcohol abuse within 12 months prior to screening, MCRN 004 The LAURENTIANS Trial: A Randomized Phase II, Open Label, Study of Daratumumab, Weekly Low-Dose Oral Dexamethasone and Cyclophosphamide with or Without Pomalidomide in Patients with Relapsed and Refractory Multiple Myeloma Inclusion Criteria 1. Males or females, age 18 years or older. 2. ECOG performance status score of 0, 1 or Life expectancy of at least 3 months 4. Measurable disease according to the IMWG criteria defined as Serum monoclonal paraprotein (M-protein) 10 g/l (if IgG) or 5g/L (if IgA, D, E or M). Urine M-protein 200 mg/24 h. Serum free light chains (FLC) assay: Involved FLC level 100 mg/l and an abnormal serum free light chain ratio (< 0.26 or > 1.65) if disease otherwise unmeasurable by a and b. 5. Relapsed or relapsed and refractory disease defined as documented disease progression during or after completing their last treatment line and it must have contained either bortezomib and/or lenalidomide. The only exception for non-refractory patients is when re-treatment with these agents is medically contra-indicated. 6. Have undergone at least 1 prior line of therapy. Induction therapy followed by ASCT and consolidation/maintenance will be considered as one line. 7. Have achieved at least a Minimal Response (MR) or better to at least one previous line of therapy. 8. Have received at least 2 consecutive cycles of prior treatment that have included lenalidomide or bortezomib, either alone or in combination regimens, unless intolerant to these agents. 9. Subjects must be eligible for pomalidomide reimbursement by their provincial jurisdictions or by the criteria of their private insurance companies. 10. Have the following laboratory values: ANC 1.0 x 109/L Hemoglobin 80 g/l Platelets 70 x 109/L (or 50 x 109/L if 50% plasmacytosis in bone marrow. Calculated CrCl 45 ml/min AST and ALT 3.0 x ULN Total bilirubin 2 x ULN unless known to have Gilbert s disease Corrected serum calcium 3.5 mmol/l 11. Have signed the informed consent documents indicating that the subject understands the purpose of the procedures required for the study and is willing to participate and adhere to the study protocol. 12. Females with child-bearing potential (FCBP ) must agree to use 2 reliable forms of contraception* simultaneously or practice complete abstinence from heterosexual contact for at least 28 days before starting study drug, while participating in the study (including during dose interruptions), and for at least 90 days after study treatment discontinuation. 13. Females must agree to abstain from breastfeeding during study participation and 90 days after study drug discontinuation. 5

12 14. Males must agree to use a latex condom during any sexual contact with FCBP while participating in the study and for 90 days following discontinuation from this study, even if he has undergone a successful vasectomy. 15. Males must also agree to refrain from donating semen or sperm during the treatment phase and for 90 days after discontinuation from this study treatment. 16. All subjects must agree to refrain from donating blood while on study therapy and for 28 days after discontinuation from this study treatment. 17. All subjects must be eligible for enrollment and enrolled in the RevAid program (refer to for RevAid eligibility). Exclusion Criteria 1. Prior exposure to daratumumab (or other anti-cd38 monoclonal antibody) or pomalidomide 2. History of prior allogeneic stem cell transplantation and showing evidence of active graft-versus-host disease or graft-versus-host disease that requires immunosuppressive therapy. 3. Chemotherapy or other anti-myeloma therapy within 14 days prior to the first dose of study drug. 4. Treatment-related toxicity that has not recovered Grade 1 unless deemed to be irreversible (an example of an irreversible toxicity would include steroid induced cataracts). Peripheral neuropathy > Grade 2 or Grade 2 with pain will be excluded. 5. Subjects who have received steroids within 2 weeks prior to starting study treatment or who have not recovered from side effects of such therapy. Concomitant therapy medications that include corticosteroids are allowed if subject receive 10 mg of prednisone per day, or equivalent, as indicated for other medical conditions, or up to 100 mg of hydrocortisone as pre-medication for administration of certain medications or blood products prior to enrolment in this study. 6. Subjects who have received any investigational agents within 28 days or 5 half-lives (whichever is longer) of the first dose (Cycle 1, Day 1). 7. Prior history of malignancies, other than MM, unless the subject has been free of the disease for 3 years or longer. Exceptions include the following: Basal or squamous cell carcinoma of the skin Carcinoma in situ of the cervix or breast Adenocarcinoma of the prostate (TNM stage of T1a or T1b) 8. Other concurrent severe and/or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection, acute diffuse pulmonary disease, pericardial disease, uncontrolled thyroid dysfunction) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol. 9. Known chronic obstructive pulmonary disease (COPD), defined as a FEV1 < 50% predicted value. 10. Known moderate or severe persistent asthma within the last 2 years, or currently has uncontrolled asthma of any classification. 11. History of or current uncontrolled cardiovascular disease including: Unstable angina, myocardial infarction, or known congestive heart failure Class III/IV (Appendix 5) within the preceding 12 months Transient ischemic attack within the preceding 3 months, pulmonary embolism within the preceding 2 months. Any of the following: sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes, cardiac arrest, Mobitz II second degree heart block or third degree heart block; known presence of dilated, hypertrophic, or restrictive cardiomyopathy. QTc prolongation as confirmed by ECG assessment at screening (QTc >470 milliseconds). 12. Women who are pregnant, breastfeeding or planning to become pregnant while enrolled in this study, or within 90 days after the last dose of study medications. Male subject who plans to father a child while enrolled in this study, within 90 days after the last dose of study medications. 13. Known HIV positivity or active infectious hepatitis B or C 14. Known allergies, hypersensitivity to mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to the Daratumumab IB), or known sensitivity to mammalian-derived products 6

13 15. Known CNS involvement, plasma cell leukemia or amyloidosis. 16. Subjects who are receiving any other investigational agent 17. Autologous, peripheral stem cell transplant within 12 weeks of the first dose of study drug 18. Any other condition that, in the Investigator s opinion, would contraindicate the patient s participation in the clinical study due to safety concerns or compliance with clinical study procedures. Phase 3, Randomized Multicenter Study of Subcutaneous vs. Intravenous Administration of Daratumumab in Subjects with Relapsed of Refractory Multiple Myeloma (Study Number: MMY3012) Inclusion Criteria 1. At least 18 years of age. 2. Documented multiple myeloma as defined by the criteria below: Multiple myeloma diagnosis according to the IMWG diagnostic criteria (refer to Attachment 1). Measurable disease at Screening as defined by any of the following: IgG multiple myeloma: Serum M-protein level 1.0 g/dl or urine M-protein level 200 mg/24 hours; or IgA, IgD, IgE, IgM multiple myeloma: serum M-protein level 0.5 g/dl or urine M-protein level 200 mg/24 hours; or Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin FLC 10 mg/dl and abnormal serum immunoglobulin Kappa lambda FLC ratio. 3. Evidence of a response (PR or better based on investigator s determination of response by IMWG criteria) to at least 1 prior treatment regimen. 4. Relapsed or refractory disease as defined below: Relapsed disease is defined as an initial response to previous treatment, followed by Confirmed PD by IMWG criteria >60 days after cessation of treatment. Refractory disease is defined as <25% reduction in M-protein or confirmed PD by IMWG criteria during previous treatment or 60 days after cessation of treatment. 5. Received at least 3 prior lines of therapy (refer to Attachment 2) including a PI ( 2 cycles or 2 months of treatment) and an IMiD ( 2 cycles or 2 months of treatment) in any order during the course of treatment (except for subjects 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 mg/day for 4 days) would not be considered prior lines of therapy. or Refractory to both a PI and an IMiD. For subjects who have received more than 1 type of PI, their disease must be refractory to the most recent one. Similarly, for those who have received more than 1 type of IMiD, their disease must be refractory to the most recent one. 6. ECOG Performance Status score of 0, 1, or 2 (refer to Attachment 3). 7. Pretreatment clinical laboratory values meeting the following criteria during the Screening Phase: hemoglobin 7.5 g/dl ( mmol/l) (without prior red blood cells [RBC] transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted); absolute neutrophil count /L (prior growth factor support is permitted); platelet count /L (transfusions are not permitted within 7 days of testing to achieve this minimum platelet count); aspartate aminotransferase (AST) 2.5 upper limit of normal (ULN); alanine aminotransferase (ALT) 2.5 ULN; 7

14 total bilirubin 2.0 ULN; except in subjects with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin 2.0 ULN is required); estimated creatinine clearance ml/min per 1.73m2 (refer to Attachment 4); albumin-corrected serum calcium 14 mg/dl ( 3.5 mmol/l) or free ionized calcium 6.5 mg/dl ( 1.6 mmol/l) (refer to Attachment 5). 8. Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. 9. Women of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to randomization. 10. Each subject (or their legally acceptable representative) must sign an Informed Consent Form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF. Exclusion Criteria 1. Received daratumumab or other anti-cd38 therapies previously. 2. Received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before the date of randomization. The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days [refer to Attachment 6]) before treatment. A list of anti-myeloma treatments with the corresponding pharmacokinetic half-lives is provided in the Site Investigational Product Procedures Manual. 3. Received autologous stem cell transplant within 12 weeks before the date of randomization, or the subject has previously received allogeneic stem cell transplant (regardless of timing). 4. Plans to undergo a stem cell transplant prior to progression of disease on this study (these subjects should not be enrolled to reduce disease burden prior to transplant). 5. History of malignancy (other than multiple myeloma) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or breast, or other noninvasive lesion, that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years). 6. Clinical signs of meningeal involvement of multiple myeloma. 7. Either of the following: Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) is <50% of predicted normal. Note that FEV1 testing also is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% of predicted normal. Known moderate or severe persistent asthma, or a history of asthma within the last 2 years, or currently has uncontrolled asthma of any classification (refer to Attachment 7). (Subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.) 8. Any of the following: Known to be seropositive for human immunodeficiency virus (HIV) Known to be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]) or with known prior hepatitis B infection without evidence of immunity (ie, patients who are positive for antibodies to hepatitis B core antigen [anti- HBc] but negative for antibodies to hepatitis B surface antigen [anti-hbs]) Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy). 8

15 9. Concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study. 10. Clinically significant cardiac disease, including: Myocardial infarction within 6 months before date of randomization, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV [refer to Attachment 8]). Uncontrolled cardiac arrhythmia (Grade 2 or higher by NCI-CTCAE Version 4.03) or clinically significant ECG abnormalities. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula >470 msec. 11. Known allergies, hypersensitivity, or intolerance to any of the study drugs, hyaluronidase, mabs, human proteins, or their excipients (refer to daratumumab IB10), or known sensitivity to mammalian-derived products. 12. Plasma cell leukemia (> /L circulating plasma cells by standard differential) or Waldenstrom s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) or amyloidosis. 13. Known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments. 14. Pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug. 15. Plans to father a child while enrolled in this study or within 3 months after the last dose of study drug. 16. Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before the planned first dose of study drug (except for investigational anti-myeloma treatments, which cannot be taken within 2 weeks before Cycle 1 Day 1). 17. Major surgery within 2 weeks before randomization, or has not fully recovered from an earlier surgery, or has major surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration. Kyphoplasty or vertebroplasty are not considered major surgery. Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate. If there is a question whether a procedure is considered a major surgery, the investigator must consult with the appropriate sponsor representative and resolve any issues before enrolling a subject in the study. 18. Plasmapheresis within 28 days before randomization. Phase 1/2 Trial of Idasanutlin in combination with Ixazomib and dexamethasone in patients with 17p deleted, relapsed multiple myeloma (MC1582/MMRC-061; Protocol#: MC1582/MMRC-061) Inclusion Criteria 1. Diagnosis of MM with deletion 17p (del17p) or monosomy 17 by FISH who have received at least one line of therapy. 2. The following laboratory values obtained 14 days prior to registration. Calculated creatinine clearance 30 ml/min AST (SGOT) and ALT (SGPT) 3.0 x upper limit of normal (ULN) Total bilirubin 1.5 the upper limit of the normal range (ULN) Absolute neutrophil count (ANC) 1500/mm3 Platelet count 75,000/mm3 Hemoglobin 8.0 g/dl NOTE: White blood count and platelet count criteria must be met without any transfusion or growth factor support. 9

16 3. Patients with measurable disease defined as at least one of the following: Serum monoclonal protein 1.0 g/dl by protein electrophoresis >200 mg of monoclonal protein in the urine on 24-hour electrophoresis Serum immunoglobulin free light chain 10 mg/dl AND abnormal serum immunoglobulin kappa to lambda free light chain ratio. 4. ECOG performance status 0, 1 or 2 Exclusion Criteria 1. Other malignancy requiring active therapy. EXCEPTIONS: Non-melanoma skin cancer, DCIS or carcinoma-in-situ of the cervix. NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer 2. Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational. NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment. 3. Patient has >Grade 2 peripheral neuropathy, or Grade 1 with pain on clinical examination during the screening period. 4. All CYP2C8 inhibitors, inducers, and substrates should be discontinued 7 days prior to registration. Systemic treatment with CYP2C8 inhibitors (anastrozole, montelukast, quercetin, trimethoprim, gemfibrozil, rosiglitazone, pioglitazone), inducers (carbamazepine, phenytoin, rifabutin, rifampin), or substrates (amiodarone, repaglinide, rosiglitazone, sorafenib, torsemide) should be discontinued 7 days prior to registration. 5. Systemic treatment with strong inhibitors of CYP3A4 (clarithromycin, telithromycin, itraconazole, Voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A4 inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, Gingko biloba, St. John s wort) are not allowed 14 days before registration. 6. Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 6 months. Note: Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant. 7. QTc >470 milliseconds (msec) on a 12-lead ECG obtained during the Screening period. 8. Known human immunodeficiency virus (HIV) positive. 9. Known hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection 10. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib or idasanutlin including difficulty swallowing 11. Diarrhea >Grade 1, based on the NCI CTCAE grading, or currently taking antidiarrheals 12. Need for ongoing therapeutic anticoagulation. 13. Patients that have previously been treated with ixazomib, or who participated in a blinded study with ixazomib (whether treated with ixazomib or not). A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of Oprozomib in Combination with Pomalidomide and Dexamethasone in Subjects with Relapsed or Refractory Multiple Myeloma (Protocol: ) Inclusion Criteria 1. Subject must have a pathologically documented, definitively diagnosed, multiple myeloma relapse, or refractory progressive disease after at least 2 lines of therapy for multiple myeloma. Prior therapeutic treatment or regimens must include a proteasome inhibitor and lenalidomide 2. Measurable disease (assessed within 28 days prior to day 1), as indicated by one or more of the following: Serum M-protein 0.5 g/dl

17 Urine M-protein 200 mg/24 hours In subjects without detectable serum or urine M-protein: serum Free Light Chain (sflc) 10 mg/dl ( 100 mg/l) and an abnormal sflc ratio 3. Eastern Cooperative Oncology Group (ECOG) performance status of 2 4. Hematological function, as follows, without transfusion support: Absolute neutrophil count 1.0 X 10 9 /L Platelet count 75 X 10 9 /L (in patients with < 50% of bone marrow nucleated cells were plasma cells) or 50 X 10 9 /L (in patients with 50% of bone marrow nucleated cells were plasma cells) without transfusion or growth factor support Hemoglobin > 8 g/dl (> 80 g/l) Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed, however most recent RBC transfusion must not be within 7 days prior to obtaining screening hemoglobin 5. Coagulation function as follows: PT/INR and PTT < 1.5 x Institutional Upper Limit of Normal (ULN) 6. Renal function as follows: estimated glomerular filtration rate based on Modification of Diet in Renal Disease calculation (MDRD) > 30 ml/min/1.73 m2 7. Hepatic function, as follows: AST and ALT < 3 x ULN, Total bilirubin < 1.5 x ULN (except subjects with Gilbert s syndrome) Exclusion Criteria 1. Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study(s) 2. Previously received an allogeneic stem cell transplant and the occurrence of one or more of the following: Received the transplant within 6 months prior to study day 1 Received immunosuppressive therapy within the last 3 months prior to study day Having signs or symptoms of acute or chronic graft-versus-host disease 3. Autologous stem cell transplant < 90 days prior to study day 1 4. Multiple myeloma with IgM subtype 5. POEM syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 6. Plasma cell leukemia (> 2.0 X109/L circulating plasma cells by standard differential) 7. Waldenstrom s macroglobulinemia, Amyloidosis 8. Requirement for plasmapheresis during the screening period 9. Dexamethasone at cumulative doses of greater than 160 mg or equivalent within 21 days prior to study day 1 is not allowed. Use of topical or inhaled steroids is Acceptable 10. History of other malignancy, except: Current use of therapeutic doses of anticoagulation unless agreed upon by the investigator and the Amgen Medical Monitor. Please note: thromboprophylaxis is recommended with pomalidomide treatment 11. History of clinically significant GI hemorrhage (Grade 2) in the 6 months prior to study day 1, unless agreed upon by the investigator and the Amgen Medical Monitor 12. Known positive results for Human Immunodeficiency Virus (HIV) 13. Prior systemic radiation therapy must have been completed at least 28 days before study day 1. Prior focal radiotherapy completed at least 14 days before study day Prior use of pomalidomide if subjects required pomalidomide dose reduction or pomalidomide discontinuation due to toxicity 2