clinical study protocol
5.4.4 treatment discontinuation

Administration of Carfilzomib, lenalidomide and dexamethasone can be discontinued permanently in the event of a treatment-related toxicity at the Treating Investigator's discretion. If a delay of starting a new cycle is greater than 21 days, the subject should be discontinued from treatment, unless continuing treatment is mutually agreed upon by the Treating Investigator and the Lead Principal Investigator. If either carfilzomib or lenalidomide requires permanent discontinuation before Cycle 4 induction, the subject's treatment will be discontinued at the end of Cycle 4 induction. If either carfilzomib or lenalidomide requires permanent discontinuation during consolidation or maintenance cycles, the subject may remain on study with the remaining drug(s). Dexamethasone may be discontinued without the subject discontinuing study treatment.
clinical study protocol
5.5 concomitant medications

Concomitant medication is defined as any prescription or over-the-counter preparation, including vitamins and supplements. All concomitant medications must be recorded on the concomitant medications case report form from 21 days before Day 1 through 30 days following the last dose of study drugs.
clinical study protocol
5.5.1 required concomitant medications

- Valacyclovir or similar anti-varicella (anti-herpes) agent HZV prophylaxis  
- Aspirin for VTE prophylaxis.
Instructions for their administration are found in Section 5.2.1. Note: If a subject is allergic to aspirin, low-molecular-weight heparin or clopidogrel may be used. In subjects with a prior history of venous thrombosis, low-molecular-weight heparin or therapeutic doses of warfarin (target INR 2-3) are required.
clinical study protocol
5.5.2 optional and allowed concomitant

In view of emerging data that pneumocystis pneumonia (PCP) is unlikely in patients treated with low dose dexamethasone, the use of Pentamidine or Bactrim will be optional in CRd.  
Of these medications, use of Pentamidine is recommended as the PCP prophylaxis of choice for CRd patients. Use of Dapsone for PCP prophylaxis will require approval of the Lead Principal Investigator, in view of the potential for hemolysis in this subset of patients. Mycostatin and lansoprazole or other proton pump inhibitor or an H2 antagonist are recommended but NOT required and considered optional medications. Marketed bisphosphonates are allowed. Subjects may receive anti-emetics and antidiarrheal agents as necessary. Colony-stimulating factors may be used if neutropenia occurs but should not be given prophylactically. Subjects may receive RBC or platelet transfusions if clinically indicated in accordance with institutional guidelines, however screening platelet count must be independent of platelet transfusions for at least 2 weeks (Section 3.6). Subjects who require repeated platelet transfusion support should be discussed with the Lead Principal Investigator. Allopurinol (for use only in subjects at risk for TLS due to high tumor burden) is optional and will be prescribed at the Treating Investigator's discretion. These subjects may receive allopurinol 300 mg PO BID (Cycle 1 Day -2, Day -1), continuing for 2 days after Cycle 1 Day 1 (total of 4 days), then reduce dose to 300 mg PO QD, continuing through Day 17 of Cycle 1. Allopurinol dose should be adjusted according to the package insert. Subjects who do not tolerate allopurinol and are at risk for TLS should be discussed with the Lead Principal Investigator in order to discuss alternatives. If signs of tumor flare are present, split dosing of dexamethasone may be implemented so that subjects may be given 4 mg dexamethasone PO or IV on Days 2, 9 and 16 in Cycles 1 and 2 prior to carfilzomib infusion. The total dose of dexamethasone prior to carfilzomib should not exceed 40 mg weekly therefore it is recommended that the dose is split between days of carfilzomib administration, for example 36mg Day 1 and 4mg Day 2.. This will be prescribed at the Treating Investigator's discretion. Subjects believed to be at high risk for bacterial infection may receive antibiotic prophylaxis as per institutional guidelines. Radiation therapy to a localized mass for subjects on CRd therapy is acceptable with prior approval of the Lead Principal Investigator. Corticosteroids for non-malignant conditions (e.g., asthma, inflammatory bowel disease) equivalent to a dexamethasone dose ≤ 4 mg/day or prednisone ≤ 20 mg/day are permitted
clinical study protocol
5.5.3 excluded concomitant medications

Concurrent therapy with a marketed or investigational anticancer therapeutic is not allowed. Corticosteroids for non-malignant conditions (e.g., asthma, inflammatory bowel disease) equivalent to a dexamethasone dose > 4 mg/day or prednisone > 20 mg/day are not permitted. Other investigational agents are not to be used during the study.
clinical study protocol
5.6 safety guidance for investigators

A "first dose" effect has been encountered early in carfilzomib treatment, characterized by fever, chills, rigors, and/or dyspnea occurring during the evening following the first day of infusion and an increase in creatinine on Day 2, which may be the clinical sequelae of rapid tumor lysis and/or cytokine release. Should a "first dose" effect occur, treatment with glucocorticoids is recommended. In addition IV fluids, vasopressors, oxygen, bronchodilators, and acetaminophen should be available for immediate use and instituted as medically indicated.
clinical study protocol
5.6.2 tumor lysis syndrome

Tumor lysis syndrome, which may be associated with multi-organ failure, has been observed in Cycles 1 and 2 of some subjects with multiple myeloma treated with carfilzomib. In addition, multiple myeloma subjects with high tumor burden (e.g., Durie-Salmon or ISS Stage II/III) or rapidly increasing M-protein or light chains or compromised renal function (GFR < 50 mL/min) should be considered to be at particularly high risk. All such subjects should be identified at screening. During Cycles 1 and 2, serum electrolytes and chemistries are closely monitored as outlined in Section 7.2. Subjects with laboratory abnormalities consistent with lysis of tumor cells (e.g., serum creatinine ≥ 50% increase, LDH ≥ 2-fold increase, uric acid ≥ 50% increase, phosphate ≥ 50% increase, potassium ≥ 30% increase, calcium ≥ 20% decrease) prior to dosing should not receive the scheduled dose. Subjects with such abnormalities should be re-evaluated as clinically indicated. The Lead Principal Investigator should be consulted if there are further delays. Subjects should be informed of signs and symptoms that may be indicative of tumor lysis syndrome, such as fevers, chills/rigors, nausea, vomiting, muscle tetany, weakness, or cramping, seizures, and decreased urine output; subjects should be instructed to report such symptoms immediately and seek medical attention. In the event tumor lysis syndrome manifests, cardiac rhythm, fluid, and serial laboratory monitoring should be instituted. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer therapeutic and supportive care, including dialysis, as clinically indicated. All cases of tumor lysis syndrome must be reported to The University of Chicago as a Serious Adverse Event (SAE) as outlined in Section 8.5.
clinical study protocol
5.6.3 renal function

Carfilzomib has not been fully characterized in subjects with creatinine clearance < 30 mL/min. It is critical that the subject's renal function is known at the time of dosing. Renal function, serum creatinine, and serum uric acid should be monitored closely as outlined in Section 6. See Section 5.4.2 and Table 5-5 for guidance regarding dose reduction in subjects with compromised renal function.
clinical study protocol
5.6.4 hydration

All subjects should be well-hydrated. However, over-hydration without matching output should be avoided with use of diuretics as needed. Carfilzomib treatment can cause nausea, vomiting, diarrhea, or constipation sometimes requiring the use of antiemetics or antidiarrheal agents. Fluid and electrolyte replacement should be administered as outlined in Section 5.2.1
clinical study protocol
6 study tests and observations

All protocol-required tests and observations along with their chronology are summarized in Appendix A.
clinical study protocol
6.1 screening (days -21 to

Written informed consent must be obtained before any protocol-specific tests or procedures may be conducted. The consent may be obtained within 30-days of Cycle 1 Day 1 however the following screening assessments will be performed between Days -21 and –1 unless otherwise stated: General
- Medical history (review of systems, prior treatments for all significant conditions including  
neuropathy)
- Complete physical examination (including vital signs [systolic and diastolic blood pressure, respiration, pulse, oral temperature], height, weight, calculation of body surface area [BSA], and ECOG score). Height outside of the 21-day window is acceptable.  
- Skeletal survey (lateral radiograph of the skull, anteroposterior and lateral views of the spine, and anteroposterior views of the pelvis, ribs, femora, and humeri). May be within 30 days of planned Day 1 of Cycle 1. Skeletal surveys performed outside of the 30 day window may be considered for inclusion. Please contact the Lead Principal Investigator on a case-by-case basis.
clinical study protocol
- 12-lead ecg including qtc

- Neurologic assessment, consisting of neurologic exam (to detect peripheral neuropathy and/or changes in pre-existing neuropathy) and completion of the neurologic questionnaire by the subject.  
- Record all concomitant medications starting 21 days before planned Day 1 of Cycle 1.
Laboratory  
- Pregnancy test (FCBP must have a negative serum or urine pregnancy test, with a sensitivity of at least 50 mIU/mL, within 10-14 days before and again within 24 hours before lenalidomide is prescribed for Day 1 of Cycle 1). See also Appendix F.  
- Urinalysis - Serum chemistries (see Section 6.2 for list of analytes). Creatinine clearance calculated by Cockroft-Gault (See Appendix G)
- Hematology (hemoglobin, hematocrit, WBC with complete differential, RBC, platelets)
- Coagulation tests (prothrombin time, activated partial thromboplastin time, and international normalized ratio)
Disease-related
- M-protein determination using both of the following procedures:  
o Serum protein electrophoresis (SPEP) and serum protein immunofixation
- Pre-treatment serum M-protein baseline level from outside institution must be well documented and recorded and required for eligibility o Urine protein electrophoresis (UPEP), urine protein immunofixation (using 24-hour urine collection above) and total protein in urine. SPEP will be used serially during the study if the baseline value for M-protein is > 0.5 g/dL. UPEP will be used if the baseline value is
> 200 mg per 24 hours. If both tests are positive at baseline, both will be performed at each required time point.  
- Pre-treatment urine M-protein baseline level from outside institution (light chain 24 hr quantitation) must be well documented and recorded. If not available but the patient has pre-treatment measurable serum M-protein, lack of pre-treatment 24 hr urine results is not an exclusion  
- Plasmacytoma evaluation (either physical exam or imaging where applicable and at treating investigator's discretion)
- Serum quantitative immunoglobulins
- Serum β2 microglobulin - Serum free light chains (SFLC) - Bone marrow aspirate and biopsy - quantify percent myeloma cell involvement, and obtain bone marrow aspirate for cytogenetics [i.e. diploidy, del 13] and fluorescent in situ hybridization (FISH) studies [i.e. t(4:14); t(11:14); del 17p]. Cytogenetics is only required  
at screening.
o All patients are required to have two samples for MRD analysis centrally (by Flow cytometry at the University of Chicago and by Next Generation Sequencing (NGS) at Adaptive Biotechnologies) collected at 1) Screening (for calibration for MRD by gene sequencing), 2) Pre-transplant (end of cycle 4), 3) Post-transplant (preconsolidation), 4) End of Cycle 8, 5) End of Treatment, 6) 1, 2, 3, and 5 years after EOT. In the event that a superfluous bone marrow aspirate (BMA) sample from screening was not available, slides of BMA smear or clot from a time prior to enrollment can be used.  
- CT-PET - Performed to confirm MRD-negative disease per Standard of Care, at every time-point when MRD is checked.  
- CRP levels
- If pre-treatment serum β2 microglobulin, serum free light chains (SFLC), and cytogenetics are missing, this is not an exclusion.
clinical study protocol
6.2 treatment cycles 1 through

- Complete physical examination (including vital signs [systolic and diastolic blood pressure, respiration, pulse, oral temperature], weight, calculation of body surface area [BSA]) and ECOG score) on Day 1 of each cycle. Abbreviated (i.e., symptom-directed) exams may be performed on Days 8 and 15 if indicated. For Cycle 1, the screening physical may be used if it was within 7 days before Day 1.  
- Vital signs within 1 hour before the dose of carfilzomib on Days 1, 2, 8, 9, 15, and 16 during Cycles 1-8 and on Days 1, 2, 15, and 16 during Cycles 9-18.  
- Hematology Days 1 and 15 of each cycle during Cycles 1-8 and on Day 8 of Cycles 1 and 2 only. On cycles 9-18 hematology should be done on day 1 only. Results must be available before the dose of carfilzomib is given (hence may be performed the day before planned dosing).  
- Full serum chemistry panel on Days 1, 8, and 15 of Cycles 1 through 8 and on Day 1 of Cycles 9-18, plus abbreviated panel (see below) on Days 2, 9, and 16 of Cycles 1 and 2 only and only if clinically indicated as per institutional standards of care (i.e., subject at risk for tumor lysis syndrome).
Results must be available before the dose of carfilzomib is given (hence may be performed the day before planned dosing). Results must be consistent with eligibility criteria prior to dosing on Cycle 1 Day 1.  
| Full Chemistry Panel                                                                         | Abbreviated                                                                    |                                                                        |
|----------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------|------------------------------------------------------------------------|
| Chemistry Panel                                                                              |                                                                                |                                                                        |
| sodium potassium chloride bicarbonate BUN creatinine glucose uric acid total protein albumin | calcium Phosphorus Magnesium total bilirubin alkaline  phosphatase ALT AST LDH | sodium potassium chloride bicarbonate BUN creatinine glucose uric acid |  
- FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 28 days while on study, at study discontinuation, and at day 28 following discontinuation from the study. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study discontinuation, and 14 and 28 days after discontinuation from the study. Patients already on lenalidomide at the initiation of CRd therapy, may continue with the regularly scheduled pregnancy testing schedule as long as there has been no interruption in the testing schedule and use of birth control measures, rather that repeating the cycle 1 weekly testing. In addition to the above, at each visit the Treating Investigator must confirm that FCBP are continuing to use 2 reliable methods of birth control. Pregnancy testing and counseling must be performed if a subject misses her period or if her pregnancy test or her cycle is abnormal. See also Appendix F.  
- Disease-related tests (M-protein by SPEP and/or UPEP [requires 24-hour urine collection] as appropriate, quantitative immunoglobulins, and plasmacytoma as appropriate) on Day 1 of each cycle. For cycle 1, screening values may be used if within 7 days of Day 1. In Cycle 1 only, these tests are repeated on Day 15 to assess possible onset of early response.  
- Neurologic assessment as before on Day 1 of every cycle. This includes subject completion of the neurologic questionnaire.
- All patients are required to have two samples for MRD analysis centrally (by Flow cytometry at the University of Chicago and by Next Generation Sequencing (NGS) at Adaptive Biotechnologies) collected at 1) Screening (for calibration for MRD by gene sequencing), 2) Pre-transplant (end of cycle 4), 3) Post-transplant (pre-consolidation), 4) End of Cycle 8, 5) End of Treatment, 6) 1, 2, 3, and 5 years after EOT. In the event that a superfluous bone marrow aspirate (BMA) sample from screening was not available, slides of BMA smear or clot from a time prior to enrollment can be used.  
- CT-PET - Performed to confirm MRD-negative disease per Standard of Care, at every time-point when MRD is checked.
clinical study protocol
6.3 end of cycle 4

After 4 cycles of induction treatment, disease status including bone marrow for pre-transplant assessment will be assessed as described in Section 6.8.Bone marrow biopsy and aspirate must include two research samples for MRD by flow and by NGS. Also at this point of the study, subjects will proceed to stem cell collection and then ASCT. A CT-PET must be performed to confirm MRD-negative disease per Standard of Care, at every time-point when MRD is checked.
clinical study protocol
6.4 stem cell collection and

Thirty days after the last dose of CRd treatment, or at the start of stem cell collection (whichever occurs first), subjects will no longer be followed for adverse events and will be considered offtreatment for the remainder of the transplant period. Treating Investigators should follow their institution's standard practice for SCC and mobilization however section 6.4.1 should be referenced for guidance and recommendations. Section 6.4.2 should be followed for autologous stem cell transplant along with standard practice.
clinical study protocol
6.4.1 mobilization and collection of

Mobilization with G-CSF should start 2-4 weeks from the last dose of lenalidomide (i.e., 2-4 weeks after Cycle 4 Day 21). In general, scheduling of stem cell collection should assure as limited break as possible between the last dose of CRd treatment and ASCT, which should not exceed 6 weeks. Neupogen (G-CSF) should be used for stem cell mobilization according to standard practice. If G- CSF alone is not sufficient for mobilization, the addition of plerixafor (Mozibil) should be used or as per the institution's standard. During the apheresis procedure, correction of cytopenias and electrolyte abnormalities will be performed as per standard unit policy.
clinical study protocol
6.4.2 autologous stem cell transplant

Patients will be admitted to the inpatient stem cell transplant unit at the treating institution.  
Conditioning chemotherapy will consist of melphalan 200mg/m2 IV. If melphalan at 200mg/m2 cannot be administered because it is not tolerated or it is against institutional guidelines for reasons such as the patient's age, than the patient is not considered suitable for transplant per protocol and should not be enrolled to the trial. Sites should follow their standard protocol for hydration and antiemetic prophylaxis prior to melphalan infusion, antibiotic prophylaxis, platelet and packed red blood cell transfusions, and standard laboratory testing. Administration of autologous peripheral stem cells will take place on day 0 according to standard unit protocol. Patients will be monitored inpatient per standard protocol until criteria for discharge are met.
clinical study protocol
6.5 3 months post transplant

After recovery from ASCT toxicities (day 70-90 but not more than 120 and prior to initiation of CRd consolidation), disease status will be assessed as described in section 6.8 and Appendix E and bone marrow biopsy and aspirate must include two samples for MRD by flow and by NGS. Patients who have established sCR earlier with negative MRD can have bone marrow biopsy waived after discussion with study Lead Principal Investigator. A CT-PET must be performed to confirm MRD-negative disease per Standard of Care, at every time-point when MRD is checked.
clinical study protocol
6.6 end of cycle 8

After completion of 8 cycles, disease status will be assessed as described in section 6.8 and Appendix E and bone marrow biopsy and aspirate including two samples for MRD by flow and by NGS. Patients who have established sCR earlier with negative MRD can have bone marrow biopsy waived after discussion with study Lead Principal Investigator. A CT-PET must be performed to confirm MRD-negative disease per Standard of Care, at every time-point when MRD is checked.
clinical study protocol
6.7 long-term follow-up

Subjects who did not progress while on study, including subjects on lenalidomide maintenance, will be followed every 3 months for 5 years from the safety follow-up visit (28 days post last dose of study treatment) to document progression-free survival and development of any new cancers. Progression-free survival (PFS) and overall survival (OS) will be calculated every 6 months. When the median PFS/OS is reached, follow-up can be stopped. For subjects who are in CR or better at the end of 18 cycles (± 30 days), a repeat bone marrow aspirate and biopsy should be collected for Minimal Residual Disease (MRD) at the end of study treatment visit done in central labs. One sample will be analyzed by Flow cytometry at the University of Chicago and the other by Next Generation Sequencing (NGS) at Adaptive Biotechnologies). A bone marrow aspirate and biopsy with two aspirates for MRD analysis should be collected 1, 2, 3, and 5 years after EOT for central analysis at UC and at Adaptive Biotechnologies.  
Fresh Bone Marrow aspirate for MRD analysis by **flow cytometry** will be shipped at ambient temperature on the same day of the procedure directly to the University of Chicago Hematology lab. Please refer to the lab manual for shipping details. On the other hand, fresh Bone Marrow aspirate MRD analysis by NGS by Adaptive Biotechnologies, will be shipped at ambient temperature on the same day of the procedure directly to the University of Chicago **Multiple Myeloma lab** for processing and later batched shipping.  
Please refer to the lab manual for shipping details.
clinical study protocol
6.8 tumor response assessment

Subjects will be evaluated under Treating Investigator review for disease response according to the International Myeloma Working Group (IMWG) uniform response criteria Appendix E. Response categories include sCR, CR, nCR, VGPR, PR, SD, and progressive disease (PD).In addition, minimal response (MR) will be evaluated as an alternate response following EBMT modified criteria (Appendix E). For subjects in whom achievement of a sCR, CR, or nCR is suspected, a repeat bone marrow biopsy and aspirate (showing < 5% myeloma cells in the marrow, in addition to the other criteria in Appendix E) will be required to document the initial response. For confirmation of response, an aspirate but not a biopsy is required. All response categories (sCR, CR, nCR, and VGPR) require 2 consecutive assessments made after baseline and before the start of new therapy. If a subject is being followed by serum M-protein only, a response must be confirmed by a negative UPEP even if negative at baseline. SFLC will be repeated to confirm an MR or better. PD requires 2 consecutive assessments made at any time before classification as relapse or progression and/or the institution of new therapy when clinically possible.
clinical study protocol
6.9 optional correlative studies

In addition to the required bone marrow aspirate samples for MRD analysis [1) Screening 2) Pretransplant, 3) Post-transplant), 4) End of Cycle 8, 5) End of Treatment, 6) 1, 2, 3, and 5 years after EOT], for patients who consent additional samples will be collected including bone marrow aspirate, peripheral blood, and buccal swabs. As a companion study to the proposed clinical trial, studies will be conducted aimed at identifying markers of response to the CRd regimen. The correlative studies will focus on the (1) evaluations of markers of response, and (2) pre-treatment myeloma cell characteristics. Briefly, we will collect samples prior to treatment and at indicated time points. The first objective is to determine tumor characteristics, which predict at least very good partial response (VGPR). VGPR has been associated with longer progression survival and overall survival.25,26 The results will complement ongoing efforts to identify markers of VGPR
using samples already collected from VDD, RVD, RVDD, and CRd frontline clinical trials, with a broader goal to provide rationale for individualized therapy as a method of improving VGPR or CR/nCR. In addition to global assessment of pretreatment profiling and genetic variants, which Page 70 will be correlated with a response, we will prospectively evaluate selected characteristics and markers of response identified in our proteomics studies to date, and other emerging markers of response including Cereblon. If the subject provides additional consent, please obtain research samples (peripheral blood and bone marrow aspirates) at the time points below. In the event that adequate sample cannot be obtained, these studies may be run using any superfluous sample obtained from the required samples for MRD analysis for patients who have given consent
- Screening* - Pre-transplant/Post-transplant - End of C8 - Time of response (to confirm complete response), and/or End of Treatment visit *Please also obtain a buccal mucosa swab at screening. Assays may include: 1. Proteomics 2. Tumor cell
- Gene micro array - SNP analysis - Analysis of genetic variants 2. Additional Biomarker Studies
- Cereblon expression Specimen Collection Instructions:
- BM aspirate) - Peripheral blood Serum - Buccal swab Please note that supplies for correlative sample collection will not be provided Please refer to the Laboratory Manual for detailed collection, processing and shipping instructions. Label all specimens with the following:
1. Subject initials  
2. Subject study number (will include protocol number) 3. Visit at which sample was drawn (i.e. C1D4) 4. Date sample drawn (i.e. mm/dd/yyyy) 5. Time sample drawn (24 hour clock) 6. Sample type (eg. plasma, serum, bone marrow cells, tumor cells)
Shipping Instructions:  
1. An inventory sheet provided in the lab manual including a complete list of samples shipped
(patient number, timepoint, study \#) must accompany each shipment.  
2. An electronic copy (Word or Excel) of the sample list must also be sent via email. The listing must also include a contact name, address and phone number of the person who is responsible for the shipment. They should sign and date the form.  
3. Please email the Myeloma Lab at the University of Chicago (myelomalab@bsd.uchicago.edu) as notification of an incoming shipment.  
4. Please ship Monday, Tuesday, Wednesday or Thursday, as shipments cannot be received on weekends and/or on holidays.  
- Disease progression - Noncompliance with study procedures - Requirement for alternative therapy - Subject no longer consents to participate in the study
clinical study protocol
7 study discontinuation

Please note that collection and processing supplies will not be provided however a FedEx account number will be provided for shipments. Andrzej J Jakubowiak, MD, PhD 900 E 57th St KCBD 7240 LB17 Chicago, IL 60637 Business Phone (773) 702-1345 or 773-834-1592 Business Fax 773-248-330-6027 Note: Please follow your institution's policy regarding destruction of patient samples upon withdrawal of informed consent. Subjects may withdraw from the study at any time. Subjects who withdraw will be monitored for AEs, as described in Section 8.3. The Lead Principal Investigator may elect to discontinue the study at any time. The Treating Investigator may remove a subject from the study for the following reasons:
- Intercurrent illness that interferes with study assessments - Incidence or severity of AEs that indicates a potential health hazard to the subject - Suspected pregnancy or positive pregnancy - Death  
- Reports of any death should include date of death and specific cause (disease under study of specific other cause) and information about autopsy if the cause of death was unknown
The Lead Principal Investigator must be contacted to discuss any impending discontinuation of a study subject/patient prior to withdrawal from the study. If withdrawal occurs prior to discussion with the Lead Principal Investigator, they must be notified within 24 hours via email with a copy to the University of Chicago CRA. If the reason for withdrawal is the occurrence of an AE, the subject will be followed until such events resolve, stabilize, and, according to the Treating Investigator's judgment, there is no need of further follow-up. The reason for withdrawal from the study will be documented in the case report form.
clinical study protocol
8 adverse events 8.1 adverse

An adverse event (AE) is any untoward medical occurrence in a study subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. An AE therefore can be any unfavorable and unintended sign (including laboratory finding), symptom or disease temporally associated with participation in an investigational study, whether or not considered drug-related. In addition to new events, any increase in the severity or frequency of a pre-existing condition that occurs after the subject signs a consent form for participation is considered an AE. This includes any side effect, injury, toxicity, or sensitivity reaction. An unexpected AE is any adverse drug event, the specificity or severity of which is not consistent with the current IB or prescribing information for a marketed compound. Also, reports which add significant information on specificity or severity of a known, already documented AE constitute unexpected AEs. For example, an event more specific or more severe than described in the IB would be considered "unexpected". Whenever possible, the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 should be used to describe the event and for assessing the severity of AEs (see Appendix D). Any events representing a change in the CTCAE Grade need to be reported on the AE case report form. This includes any change in laboratory values. For AEs not adequately addressed in the CTCAE, the severity table below may be used:
clinical study protocol
table 5-7

| Severity                                               | Description Transient or mild discomfort; no limitation in                                                                                                                                                                                                                                         |    |         |                      |
|--------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|---------|----------------------|
| GRADE 1 - Mild                                         | activity;                                                                                                                                                                                                                                                                                          | no | medical | intervention/therapy |
| required. Mild to moderate limitation in activity—some |                                                                                                                                                                                                                                                                                                    |    |         |                      |
| GRADE 2 - Moderate                                     | assistance may be needed; no or minimal  medical intervention/therapy required. Marked limitation in activity, some assistance                                                                                                                                                                     |    |         |                      |
| GRADE 3 - Severe                                       | usually required; medical intervention/therapy  required, hospitalizations possible. Extreme limitation in activity, significant  assistance required; life-threatening (immediate  risk of death); significant medical  intervention/therapy required, hospitalization or  hospice care probable. |    |         |                      |
| GRADE 5 - Fatal                                        | Death                                                                                                                                                                                                                                                                                              |    |         |                      |
| GRADE 4 - Lifethreatening                                                        |                                                                                                                                                                                                                                                                                                    |    |         |                      |  
Any condition, laboratory abnormality, or physical finding with an onset date prior to the subject signing consent for study participation is considered to be pre-existing in nature and part of the subject's medical history and are considered AEs only if they worsen.
clinical study protocol
8.2 causality

Using the following criteria, the relationship of the AE to the study drug should be assessed as follows: Definite, Probable, Possible, Unlikely, Unrelated.
clinical study protocol
8.3 adverse events reporting procedures

Information about all AEs, whether volunteered by the subject, discovered by investigator questioning, or detected through physical examination, laboratory tests or other means, will be collected and recorded and followed as appropriate. All AEs (e.g., any new event or worsening in severity or frequency of a pre-existing condition or laboratory finding) with an onset date on or after Cycle 1 Day 1 of treatment must be documented on the appropriate CRF. Adverse Events which occur after consent but prior to the start of treatment must be reported if they are considered related to study procedures. Details of the event must include severity, relationship to study drug, duration, action taken, and outcome. Serious adverse events (SAEs) will be recorded on the appropriate SAE form. All AEs that are considered related to study drug must be followed to resolution or stabilization if improvement is not expected. AEs should be reported from Day 1 of treatment through 30 days post-last dose of study drug (Carfilzomib) or initiation of a new anti-cancer therapy, whichever occurs first. For subjects who continue to ASCT, AEs will be recorded for 30 days post last dose of Cycle 4 or until the start of stem cell collection if earlier. AEs will not be recorded during the transplant period (stem cell collection through start of consolidation) but should be collected again starting at Cycle 5 Day 1 or the first cycle of consolidation following ASCT. In addition, the Treating Investigator should report any AE that may occur after this time period that is believed to have a reasonable possibility of being associated with study drug. If a subject is enrolled but discontinues study prior to receiving any study drug, only SAEs that are considered related to study procedures must be reported through the end-of-study visit. AEs which completely resolve and then recur should be recorded as a new AE. For subjects who complete the end of study visit less than 30 days following their last dose of study drug, a follow up of ongoing AEs should be attempted by telephone, and documented in the subject's source. AEs continuing at 30 days post-last dose should have a comment in the source by the Treating Investigator that the event has stabilized or is not expected to improve. The Treating Investigator is responsible for evaluating all AEs for relationship to study drug and for seriousness, obtaining supporting documents, and determining that documentation of the event is adequate. Adverse events will be assigned a severity grade using the NCI-CTCAE grading scale Page 75 v4.0. The treating investigator must assess all abnormal laboratory results for their clinical significance. If any abnormal laboratory result is considered clinically significant, the treating investigator must provide details about the action taken with respect to the test drug and about the patient's outcome. All Grade 3 and 4 laboratory abnormalities must be recorded as AEs on the CRF. Grade 1 and 2 abnormalities should only be recorded if they require treatment or are otherwise considered clinically significant by the Treating Investigator. The Site or Lead Principal Investigator may delegate these duties to Sub-investigators and must ensure that these Sub-investigators are qualified to perform these duties under the supervision of the Principal Investigator and that they are listed on the FDA Form 1572 and delegation log.
clinical study protocol
8.4 serious adverse events

Information about all serious adverse events (SAE) will be collected and recorded on the appropriate SAE form. To ensure patient safety, each serious adverse event must be reported to the Lead Investigator and the University of Chicago Comprehensive Cancer Center (via paper SAE form and electronic submission in Velos) within 24 hours of learning of its occurrence.
clinical study protocol
- death

- Life threatening experience defined as any adverse experience that places the subject, in the view of the Treating Investigator, at immediate risk of death at the time of occurrence; i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death.  
- Requires inpatient hospitalization or prolongation of an existing hospitalization (except scheduled hospitalizations for non-acute, unrelated cause such as an elective surgery)
- Results in persistent or significant disability/incapacity - Is a congenital anomaly/birth defect in the offspring of an exposed subject - Important medical events that may not result in death, be life-threatening, or require hospitalization, may be considered an SAE, when, based upon appropriate medical judgment, it jeopardizes the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
Any death occurring within 30 days of the subject receiving study drug, regardless of the subject having discontinued from the study must be reported to the Lead Investigator/ University of Chicago Comprehensive Cancer Center as an SAE. 8.4.2 **SERIOUS AND UNEXPECTED SUSPECTED ADVERSE REACTION (SUSAR)** A serious adverse event is considered to be a suspected adverse reaction if there is evidence to suggest a causal relationship to the study agent. This may include a single occurrence of an event strongly associated with drug exposure (e.g. Stevens Johnson Syndrome), one or more occurrence of an event otherwise uncommon in the study population, or an aggregate analysis of specific events occurring at greater frequency than expected from historical controls.  
Unexpected events are those not listed at the observed specificity or severity in the protocol, consent, investigator brochure, FDA approved package insert, or elsewhere in the current IND application. This includes adverse events listed in the protocol, consent or IND as occurring within the class of drugs or otherwise expected from the drug's pharmacological properties but which have not been previously observed with this investigational agent. **ALL serious and unexpected**
suspected adverse reactions (SUSARs) **occurring on this clinical trial must be reported to the** FDA. Refer to section 8.5 for reporting guidelines. The lead institution (University of Chicago) is responsible for notifying the appropriate Regulatory Agencies, when required, and in accordance with applicable laws and regulations of any Expedited Safety Reports. Generally, these are all SAEs that are judged to be unexpected and related to study drug(s), as specified in ICH E2B guidelines: Clinical Safety Data Management Data Elements for Transmission of Individual Case Safety Reports. However, certain Regulatory Agencies may have additional requirements for expedited safety report submissions. ALL Serious Adverse Events, whether or not they are considered related to the study agent MUST be reported to the Lead Principal Investigator **and to the University of Chicago** Comprehensive Cancer Center (via entry on the SAE form in Velos). Refer to Section 8.5 for reporting guidelines.
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8.5 serious adverse event reporting

All SAEs (except those that occur during ASCT more than 30 days after the last dose of CRd at cycle 4 unless considered to be related to CRd treatment) from the time that the subject signs consent for study participation through 30 days after the last administered dose of study drug must be reported to the Lead Principal Investigator and to the University of Chicago Comprehensive Cancer Center via paper submission. The SAE should also be entered electronically as soon as possible. All SAEs regardless of relationship to study drug must be followed to resolution or to stabilization if improvement or resolution is not expected. If a subject is permanently withdrawn from the study because of a SAE, this information must be included in the initial or follow-up SAE report as well as the appropriate form for Study Discontinuation. A copy of the SAE form (found in Velos) should be sent via fax or via email to the University of Chicago Cancer Clinical Trials Office (fax number 773-702-1561 or email to qaccto@bsd.uchicago.edu) according to the timeframe in section 8.6.1. All MedWatch Form 3500A SAE forms must include the patient number, age, sex, weight, severity of reaction (e.g. mild, moderate, severe), relationship to study drug(s) (e.g. probably related, unknown relationship, definitely not related), date and time of administration of study drug(s) and all concomitant medications and medical treatment provided. The Treating Investigator is responsible for evaluating all adverse events to determine whether criteria for "serious" as defined above are present. If a subject is permanently withdrawn from the study because of a SAE, this information must be included in the initial or follow-up SAE report form as well as the Study Discontinuation report form. The appropriate University of Chicago coordinator will be responsible for notifying the Regulatory Agencies as required. 8.5.1 **EXPEDITED REPORTING BY LEAD PRINCIPAL INVESTIGATOR TO ONYX** The University of Chicago CRA will inform Onyx in writing by email or facsimile of any SAE within 24 hours of being aware of the event. The date of awareness should be noted on the report. This must be documented on a MedWatch Form 3500A. This form will be supplied to Onyx within 24 hours/1 business day or at the latest on the following working day. The initial report must be as complete as possible, including details of the current illness and (serious) adverse event, and an assessment of the causal relationship between the event and the investigational product(s). Information not available at the time of the initial report (e.g., an end date for the adverse event or laboratory values received after the report) must be documented on a follow-up FDA MedWatch Form 3500A. A final report to document resolution of the SAE is required.  
The Onyx protocol number **(IST-CAR-578)** and the institutional protocol number should be included on SAE reports to Onyx. A copy of the fax transmission or email confirmation of the SAE report (or on the fax cover letter) sent to Onyx should be attached to the SAE and retained with the patient records Onyx Drug Safety and Pharmacovigilance Contact Information: Fax: 800-783-7954 or 650-266-0501 SAE Hotline: 650-266-2501 Email: adverse.events@onyx.com
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8.5.2 investigator reporting responsibilites

The conduct of the study will comply with all applicable safety reporting requirements. All adverse experience reports must include the patient number, age, sex, weight, event diagnosis (if known) or signs/symptoms, severity of reaction (mild, moderate, severe), relationship to study drug (probably related, unknown relationship, definitely not related), date and time of administration of test medications and all concomitant medications, and medical treatment provided. The Treating Investigator is responsible for evaluating all adverse events to determine whether criteria for "serious" and as defined above are present. Participating sites are responsible for reporting all SAEs to the Lead Principal Investigator. The Lead Principal Investigator will be responsible for reporting SAEs to Onyx (as outlined above) and the FDA. The Treating Investigator is responsible for notifying their respective Institutional Review Board (IRB) or Independent Ethics Committee (IEC) in accordance with local regulations of all SAEs. Events occurring at a participating site should be reported to the local IRB of record according to their policies and procedures and may be reported to the University of Chicago IRB if they meet current reporting criteria. It is the responsibility of the University of Chicago coordinator on behalf of the Lead Principal Investigator to notify all participating sites of all serious unexpected suspected adverse reactions that occur on this clinical trial and which are reported to the FDA as an IND Safety Report (21 CFR 312.32). A copy of the completed Form 3500A (MedWatch) and/or IND Safety Report Narrative will be provided to the responsible Regulatory Manager by the IND coordinator for distribution to all participating sites.
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8.5.3 fda reporting by the

This study will be conducted under an IND held by Andrzej Jakubowiak at the University of Chicago. Current FDA regulations require that all SUSARs (see definition in section 8.4.1) occurring on this trial, other findings that suggest a significant risk to humans exposed to the investigational drug (e.g. information from pooled analysis of multiple studies), and any clinically significant increase in the rate of an expected serious adverse reaction be reported as an IND Safety Report. In order to meet these requirements, the lead principal investigator will review all reported serious adverse events as they occur to determine if FDA reporting is required and will conduct a literature search to seek new safety information and review and analyze all safety information from this clinical trial at least annually and more frequently as appropriate. Individual Event Reports: FDA Form 3500A (MedWatch) will be completed for all SAEs that require FDA reporting. This will be completed by the designated research staff at each site. The completed MedWatch form for fatal or life-threatening events must be returned to the Lead Investigator/ University of Chicago CRA within 4 calendar days. All other events must be received within 10 calendar days.  
Other findings that suggest significant risks *to the subject*: A narrative description summarizing all relevant findings will be provided by the lead principal investigator along with a copy of any relevant publications (if applicable). Clinically Significant Increase in Frequency of Events: A narrative description summarizing all relevant findings will be provided by the lead principal investigator along with details of individual cases (if applicable). All MedWatch reports are due to the designated University of Chicago CRA (and will be forwarded to the University of Chicago Clinical Trials Office IND coordinator) according to the specified timeline regardless of whether or not all information regarding this event is available. If applicable, a follow-up report should be provided to the University of Chicago CRA/ IND coordinator once additional information on the event is available. The completed MedWatch form and/or safety narrative will be forwarded to the FDA by the University of Chicago Comprehensive Cancer Center - Cancer Clinical Trials Office (CCTO) on behalf of the IND Holder within the appropriate timeframes as designated in 21 CRF 312.32. 8.5.4 **ADVERSE EVENT UPDATES/IND SAFETY REPORTS** Onyx shall notify the Treating Investigator via an IND Safety Report of the following information:  
- Any AE associated with the use of the drug in this study or other studies that is both serious and unexpected
- Any findings from tests in laboratory animals that suggest a significant risk for human subjects including reports of mutagenicity, teratogenicity or carcinogenicity.  
The Treating Investigator shall notify his/her IRB/IEC promptly of these new serious and unexpected AEs or significant risks to subjects in accordance with their policies. The Lead Principal Investigator must keep copies of all AE information, including correspondence with Onyx and the IRB/IEC on file (see Section 12.2.3 for records retention information).
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8.6 pregnancy

Pregnancy of a female subject or the female partner of a male subject occurring while the subject is on treatment or within 4 weeks after the subject's last dose of study drug are considered expedited reportable events. Study drugs—both lenalidomide and carfilzomib—are to be discontinued immediately and the subject instructed to return any unused lenalidomide to the Treating Investigator. The pregnancy must be reported within 24 hours of the Treating Investigator's knowledge of the pregnancy by phone and facsimile using the SAE form (Velos SAE form as well as FDA MedWatch 3500A) to the University of Chicago CRA either by fax or by email. The Treating Investigator must inform the University of Chicago in writing by email or facsimile of any pregnancy within 24 hours / 1 business day at the latest on the following workday of being aware of the event. The University of Chicago must report pregnancy as an SAE directly to Onyx Drug Safety as well, using expedited reporting procedures listed in Section 8.5. The Treating Investigator will follow the pregnant female until completion of the pregnancy, and must notify the Lead Principal Investigator at the University of Chicago. It is the responsibility of the coordinator on behalf of the Lead Principal Investigator to notify Onyx Drug Safety of the outcome as specified below. The Treating Investigator will provide this information as a followup to the initial SAE. If the outcome of the pregnancy meets a criterion for immediate classification as an SAE— spontaneous abortion (any congenital anomaly detected in an aborted fetus is to be documented), stillbirth, neonatal death, or congenital anomaly—the Treating Investigator should repeat the procedures for expedited reporting of SAEs as outlined above. Any suspected fetal exposure to lenalidomide must be reported to Celgene and Onyx within 24 hours of the Lead Principal Investigator being made aware of the event. The pregnant female should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. All neonatal deaths that occur within 30 days of birth should be reported, without regard to causality, as SAEs. In addition, any infant death after 30 days that the Treating Investigator suspects may be related to the in utero exposure to lenalidomide should also be reported to the Lead Principal Investigator and subsequently to Celgene and Onyx by the University of Chicago coordinator. In the event of a live "normal" birth, Celgene and Onyx Drug Safety should be advised as soon as the information is available.
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9 statistical methods and data

9.1.1 **PRIMARY OBJECTIVES**
The primary objective of this Phase 2 trial is to determine the efficacy of the CRd combination regimen as measured by response, defined as the rate of stringent CR (sCR) after 8 cycles of CRd (4 cycles of induction + ASCT + 4 cycles of CRd consolidation).
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9.1.2 secondary objectives

Secondary objectives include determining the best objective overall response rate (ORR) defined as partial response or better (>PR), the rate of VGPR or better, near complete response or better (sCR/CR/nCR), the time to progressive disease, duration of response, and progression-free and overall patient survival distributions.
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9.1.3 exploratory objectives

Additional exploratory objective include evaluation of the status of minimal residual disease in patients who achieve a CR 1) after induction (first 4 cycles), 2) post-transplant, 3) after 8 cycles, 4) end of CRd treatment (cycle 18) 5) or any point that bone marrow is performed for assessment of CR response on CRd therapy. Additional prospective evaluation of candidate markers of response to CRd established in ongoing frontline CRd trial in newly diagnosed myeloma will be completed (Jakubowiak et al, ASH 2011, ASCO 2012, Blood 2012). In addition, we will ask patients to consent to provide research samples for additional evaluations of prognostic markers with a goal to established marker-based individualized therapy with CRd with or without transplant. Bone marrow biopsies are optional with patient consent for research purposes at the end induction, post-transplant, end of 8 cycles of CRd (end of cycle 4 CRd consolidation), and end of treatment, per section 6.6. In order to accrue an adequate sample size for MRD assessment in patients who are suspected of having a sCR, CR, or nCR at this time given other diseaserelated tests, we will over-accrue above the original sample size, N = 53, to N=70. Given this additional sample size, we hypothesize a 65-70% consent rate for the necessary optional marrow biopsies. A 65-70% consent rate would afford a total sample size of approximately 45-49 patients, which would afford interrogation of the hypothesis that this regimen will improve the rate of MRD after 4 CRD induction cycles, ASCT, and 4 cycles of CRD consolidation from 25% estimated MRD rate in the CRD trial without transplant to 45% with transplant, with approximately 80% power with 5% type II error.
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9.2 population for analysis

The Intent-to-Treat (ITT) population of patients will be defined as all patients who receive at least one dose of carfilzomib and lenalidomide. If a patient fails to receive these drugs, the patient will be replaced. The primary efficacy results in the study will be based on data from this population. Patients in this population who have inadequate data to assess efficacy according to the criteria for response in section 8 will be considered treatment failures for this analysis. Patients in this population will be analyzed according to the treatment they were actually scheduled to receive, regardless of any errors of dosing or dose modifications. Analysis of safety will be performed on the set of patients who receive any study drug, formally the same group as comprises the ITT population.
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9.3 study design and sample

This is single-arm, open label phase II study to determine the rate of sCR after a total of 8 cycles of CRd (i.e. 4 cycles of CRd induction and 4 cycles post ASCT consolidation) in patients who were enrolled into initial treatment with CRd and received at least one dose of carfilzomib and/or lenalidomide. The historical comparison population is the recently completed CRd phase I/II frontline therapy study which incorporated a deferred transplant design. The response rate determined in the current trial will be compared to, and be expected to exceed, the rate of sCR after the same duration of CRd therapy, 8 cycles. Mature data from the recently completed CRd phase I/II trial indicates that 13 of 44 (30%) patient attained a sCR when receiving 8 cycles of CRd frontline therapy. For primary objective of the study, at least 53 and up to 70 patients will be enrolled to the CRd induction phase of this trial, with the expectation that the patients will receive ASCT, CRd consolidation, CRd maintenance, and recommended lenalidomide maintenance off protocol if able. To minimize the sample size, the study was originally designed as a Simon 2-stage study design with interim analysis after the enrollment of the first 27 patients, with the trial to continue enrollment if 12 of the first 27 patients achieved sCR at the end of 4 cycles of consolidation (or after a total of 4 cycles before and 4 cycles post-transplant). This design did not take into account that it takes approximately 1 year for each subject to reach the primary end-point evaluation, which would require either extended study delay or the study would complete enrollment by the time 27 patients were evaluable for this interim primary end-point. Therefore, the study is revised to a single-stage. The sample size was increased to 53 patients, and further to 70 for MRD assessment, based upon the updated mature results of our prior CRd trial for patient at the completion of 8 cycles of frontline therapy without transplant and the consent rate for optional bone marrow biopsy for MRD assessment in the early portion of conducting this trial, respectively.. The sample size of 53 minimally necessary to test whether the rate of sCR would be 50% or greater in the current trial after 8 cycles of CRd ((i.e. 4 cycles of CRd induction and 4 cycles post ASCT consolidation) versus 30%, the sCR rate after 8 induction cycles in the historical comparison population. This trial will have 5% type I error (1-sided) and 10% type II error (90% power) to interrogate the stated hypothesis. With 70 patients, this trial will have 10% type II error (90% power) with 5% type I error (2-sided) to interrogate the stated hypothesis.
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analysis plan 9.3.1 primary objective

The study's primary endpoint, attainment of sCR will be assessed at the completion of the 8 cycle of CRd (at the conclusion of the 4th consolidation cycle). All patients enrolled and receiving any CRd treatment will be evaluable for this endpoint, with the exception of patients that decline to receive transplant for reasons unrelated to toxicity and/or efficacy. Patients in that category will be replaced. All other patients who discontinue treatment before receiving 4 cycles of CRd induction and transplantation will be considered treatment failures for assessment of the study's primary endpoint. Patients who receive less than 4 cycles of consolidation will be evaluable for primary end point provided that they received at least lenalidomide and/or carfilzomib in posttransplant period for at least 4 months at the completion of 4 months of post-transplant treatment. Patients not meeting the minimum consolidation therapy as just described will be considered treatment failures for the study's primary endpoint.
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9.3.2 secondary objectives

Secondary objectives include the overall response rate, defined as at least a partial response to therapy (>PR), at least VGPR and at least nCR rate, time to progression, duration of response, and progression-free and overall survival. The rate of overall response will be reported along with its exact 95% binomial confidence interval. Time to event endpoints will be estimated using the product-limit method of Kaplan and Meier. Follow-up time for these endpoints will be calculated from the date of first treatment (D1C1 of CRd induction). For time to progression, patients that do not experience progression during follow-up will be censored on the date of their last clinical examination. Duration of response will be assessed conditional upon achieving at least a partial response. Follow-up time for this endpoint will be calculated from the date of the clinical examination which confirmed the response, until the date of disease progression, or censoring at the date of last clinical follow-up. For progression-free survival, follow-up time will continue from the date of first therapy until the date of documented disease progression or death. Patients not reach either milestone during follow-up will be censored on their date of last clinical assessment.
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9.3.3 exploratory objectives

Patients first enrolled onto this trial who achieve suspected CR will be evaluated for minimal residual disease using multicolor flow cytometry and gene sequencing (Sequenta, Inc). Patients with marker characteristics determined to predict response to CRd will be evaluated for time to events. The rate of MRD in those with at least a CR after 8 cycles of CRD (4 induction cycles, ASCT, and 4 consolidation cycles) will be estimated along with 95% confidence intervals.The proportion of patients alive and free of disease progression at 2 years post ASCT, will be estimated using the product limit method of Kaplan and Meier.
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9.3.4 safety analysis

Safety analysis will be based on the incidence, intensity, and type of adverse events, and clinically significant changes in the patient's physical examination, vital signs, and clinical laboratory results. Safety variables will be tabulated and presented for all patients in the study. Exposure to study drug and reasons for discontinuation of study treatment will be tabulated. All adverse events occurring on study will be listed in by-patient data listings. Treatment emergent events will be tabulated, where treatment emergent is defined as any adverse event that occurs after administration of the first dose of study drug and through the End of Study visit or up through 30 days after the last dose of study drug, any event that is considered drug-related regardless of the start date of the event, or any event that is present at baseline but worsens in intensity or is subsequently considered drug-related by the Treating investigator and/or Lead Principal Investigator. Events that are considered related to treatment (possibly, probably or definitely drugrelated) will also be tabulated. Deaths, serious adverse events and events resulting in study discontinuation will be tabulated. Of note 30 days following the last dose of CRd, during ASCT period patients will be considered to be off-study so no toxicities will be recorded from that period. Change from baseline in clinical laboratory parameters will be summarized across time on study, and the frequency of clinically significant abnormal laboratory values will be tabulated. Similarly, changes in vital sign parameters will be summarized over time, and any abnormal values will be tabulated.
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10 investigational product 10.1 carfilzomib

Please refer to the Carfilzomib manual provided by Onyx for detailed information. Carfilzomib is a synthetic small molecule peptide bearing the chemical name (2S)-N-((S)-1-((S)-4-methyl-1- ((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. The molecular formula isC40H57N5O7 and the molecular weight is 719.91. It specifically functions as an inhibitor of the chymotrypsin-like activity of the 20S proteasome which leads to the accumulation of protein substrates within the cell and induction of apoptosis.
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10.1.1 formulation

Carfilzomib for Injection will be provided as a lyophilized powder which, when reconstituted, contains 2 mg/mL isotonic solution of carfilzomib Free Base in 10 mM sodium citrate buffer
(pH 3.5) containing 10% (w/v) sulfobutylether--cyclodextrin (SBE--CD, Captisol®).
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10.1.2 storage

Lyophilized Carfilzomib for Injection must be stored at 2–8ºC under the conditions outlined in the separate Pharmacy Manual, in a securely locked area to which access is limited to appropriate study personnel.
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10.1.3 accountability

Onyx, Inc. and the Lead and Site Principal Investigator will maintain records of each shipment of investigational product. The records will document shipment dates, method of shipment, batch numbers, and quantity of vials contained in the shipment. Upon receipt of the investigational product, the designated recipient at the study site will inspect the shipment, verify the number and condition of the vials, and prepare an inventory or drug accountability record. Drug accountability records must be readily available for inspection by representatives of Onyx and by regulatory authorities. Empty and partially used vials should be accounted for and destroyed at the study site in accordance with the internal standard operating procedures. Drug destruction records must be readily available for inspection by representatives of Onyx and by regulatory authorities. Only sites that cannot destroy unused drug on-site will be required to return their unused supply of investigational product.
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10.1.4 carfilzomib ordering

Carfilzomib will be provided at no cost by Onyx Pharmaceuticals. Drug orders will be made by the institution's investigational drug services. After full IRB approval and study activation including site initiation, the following documents need to be submitted to Onyx Clinical Research:
- 1572 (including investigational pharmacy shipping address as identification in section 7)
- Principal Investigator's current CV and license - IRB letter of approval for protocol and consent
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- onyx site contact information

After the site receives approval for drug shipment, drug orders can be placed directly using the Onyx Pharmaceuticals Carfilzomib Drug order form for IST-CAR-578.
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10.2 lenalidomide 10.2.1 description

Lenalidomide, a thalidomide analogue, is an immunomodulatory agent with anti-angiogenic and anti-neoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione. The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3. Lenalidomide is off-white to pale-yellow solid powder. It is soluble in organic solvent/ water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/mL. Lenalidomide has an asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero. Lenalidomide is available in 5 mg, 10 mg, 15 mg and 25 mg capsules for PO administration. Each capsule contains lenalidomide as the active ingredient and the following inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 5 mg and 25 mg capsule shell contains gelatin, titanium dioxide and black ink. The 10 mg capsule shell contains gelatin, FD&C blue \#2, yellow iron oxide, titanium dioxide and black ink. The 15 mg capsule shell contains gelatin, FD&C blue \#2, titanium dioxide and black ink.
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10.2.2 supply

Commercially available REVLIMID® (lenalidomide) capsules are supplied through the Revlimid REMS® program as the drug is approved for indications in this study. Lenalidomide is for PO (oral) administration only.
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10.2.3 storage conditions

Store lenalidomide at 25°C (77 °F) away from direct sunlight; excursions permitted to 15-30°C (59-86 °F).
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10.2.4 accountability

Bottles of lenalidomide will contain a sufficient number of capsules to last for one cycle of dosing.  
Sites will be required to record and document subject compliance regarding lenalidomide dosing.
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10.2.5 prescribing information

Lenalidomide will be provided in accordance with the Revlimid REMS® program of Celgene Corporation. Per standard Revlimid REMS® requirements, all physicians who prescribe lenalidomide for research subjects enrolled into this trial must be registered in must comply with all requirements of the Revlimid REMS® program. Prescriptions must be filled within 7 days. Only enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle. Unused Revlimid will be counted and documented by each site. Unused Revlimid will be returned to Celgene by the site using instructions provided by Celgene.
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10.2.6 special handling instructions

Females of child-bearing potential should not handle or administer lenalidomide unless they are wearing gloves.
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10.3.1 description

Dexamethasone, a synthetic adrenocortical steroid, is a white to practically white, odorless, crystalline powder. It is stable in air. It is practically insoluble in water.
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10.3.2 formulation

Dexamethasone is a commercially available PO drug, supplied as 2 and 4 mg tablets.
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10.3.3 storage conditions

Store dexamethasone at controlled room temperature 20 to 25ºC (68 to 77ºF)
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10.3.4 accountibility

Sites will be required to record and document subject compliance regarding dexamethasone dosing.
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11 regulatory obligations 11.1 informed

No Investigator may involve a human being as a subject in research unless the Investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An Investigator shall seek such consent only under circumstances that provide the prospective subject or the subject's legally authorized representative sufficient opportunity to consider whether or not to participate, and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in a language understandable to the subject or representative. The University of Chicago will provide the Treating Investigator with a sample consent form developed by the University of Chicago. Local and/or institutional requirements may require disclosure of additional information in the informed consent. Any changes to the consent form must be submitted to the University of Chicago for approval, prior to submission to the participating site IRB/IEC. The participating site IRB/IEC will review the consent form for approval. A copy of the IRB/IEC approval form must be submitted to the University of Chicago prior to initiation of the study at the participating site. Before implementing any study procedure, informed consent shall be documented by the use of a written consent form approved by the IRB/IEC and signed and dated by the subject or the subject's legally authorized representative at the time of consent. A copy of the signed informed consent will be given to the subject or subject's legally authorized representative. The original signed consent must be maintained by the Lead and Site Principal Investigator and available for inspection by the designated University of Chicago coordinator at any time.
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11.2 compliance with laws and

The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), the Declaration of Helsinki, Health Canada, any applicable local health authority, and Institutional Review Board (IRB) or Ethics Committee requirements. This study must have the approval of a properly constituted IRB or Ethics Committee. Before the investigational drug is shipped to the Lead or Site Principal Investigator, the Lead Investigator or designee will provide Onyx with a copy of the IRB or Ethics Committee approval letter stating that the study protocol and any subsequent amendments and informed consent form have been reviewed and approved. The Lead and Site Principal Investigator or designee will be responsible for obtaining annual IRB or Ethics Committee re-approval throughout the duration of the study. Copies of the Investigator's annual report to the IRB or Ethics Committee and copies of the IRB or Ethics Committee continuance of approval must be provided to Onyx as follows: Onyx Inc. Regulatory Department 2100 Powell St. Emeryville, CA 94608 The Lead and Site Principal Investigator is also responsible for notifying their IRB or Ethics Committee of any significant adverse events that are serious and/or unexpected. Onyx will provide study sites with any expedited safety reports generated from any ongoing studies with carfilzomib, changes to the Investigator's Brochure, and any other safety information which changes the risk/benefit profile of carfilzomib during the conduct of the study, to allow him/her to fulfill his/her obligation for timely reporting to the IRB/ECs and other Investigators participating in the study. Upon completion of the trial, the Lead Principal Investigator must provide the IRB or Ethics Committee and Onyx with a summary of the trial's outcome.
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11.3 pre-study documentation requirements

Before the start of the study, the following documents must be on file with the University of Chicago: - A U.S. Form FDA 1572 signed by the Principal Investigator - Current Curriculum Vitae (CV) for the Principal Investigator and all Sub-Investigators - Current IRB/IEC membership list and/or Department of Health and Human Services number - Copies of all appropriate laboratory certifications and laboratory normal ranges - IRB/IEC approval of the protocol - IRB/IEC approved informed consent and approval letter o The informed consent must also be reviewed and approved by the University of Chicago Cancer Clinical Trials Office
- IRB/IEC approval of any advertising materials to be used for study recruitment, if applicable
(also to be approved by the University of Chicago)
- CAP and CLIA Laboratory certification numbers and institution lab normal values - Investigational drug accountability standard operating procedures - Health Insurance Portability and Accountability Act forms, if required
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11.4 subject confidentiality

Subject medical information obtained as part of this study is confidential, and must not be disclosed to third parties, except as noted below. The subject may request in writing that medical information be given to his/her personal physician. The Investigator/Institution will permit direct access to source data and documents by Onyx, its designee, the FDA and/or other applicable regulatory authority. The access may consist of trialrelated monitoring, audits, IRB or Ethics Committee reviews, and FDA inspections. Release of research results should preserve the privacy of medical information and must be carried out in accordance with Department of Health and Human Services Standards for Privacy of Individually Identifiable Health Information, 45 CFR 164.508.
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12 administrative and legal obligations

All protocol amendments will be implemented by the University of Chicago and must receive IRB/IEC approval before implementation, except where necessary to eliminate an immediate hazard to subjects. Amendments should only be submitted to the IRB/IEC after consideration of Onyx. Only the Lead Investigator can authorize any modifications, amendments, or termination of the protocol. Once a protocol amendment has been approved by the University of Chicago IRB, the Regulatory Manager will send the amended protocol and consent form to the affiliate institutions electronically for submission to the affiliate institution's IRB. The Site Principal Investigator or designee must send a copy of the approval letter from the IRB for the amendment, along with the revised Informed Consent form (as applicable), to the University of Chicago. The University of Chicago version date and/or amendment number must appear on the affiliate consent form and on the affiliate IRB approval letter (the version date can be found on the footer of every page of the protocol and consent form, and the amendment number can be found on the University of Chicago IRB amendment approval letter sent with the amendment). The University of Chicago jointly with the study supporters and the Lead Principal Investigator reserves the right to terminate the study according to the study contract. The Site and Lead Principal Investigator or designee should notify jointly the IRB/IEC in writing of the study's completion or early termination and send a copy of the notification to the regulatory affairs manager at the University of Chicago Cancer Clinical Trials Office.
clinical study protocol
12.2 study documentation and archive

Source records are original documents, data, and records (e.g., medical records, raw data collection forms, pharmacy dispensing records, recorded data from automated instruments, laboratory data) that are relevant to the clinical trial. The Site and Lead Principal Investigators will prepare and maintain adequate and accurate source documents. These documents are designed to record all observations and other pertinent data for each subject enrolled in this clinical trial. Source records must be adequate to reconstruct all data transcribed onto the case report forms. 12.2.2 **CASE RERPORT FORM COMPLETION** All required data must be recorded in the Velos database in at the completion of each cycle. All case report forms must be completed by designated study personnel. Each screened (consented) patient is to be entered into Velos within 48 hours of enrollment approval. AEs are to be entered in real time. SAEs are to be entered in Velos on the SAE reporting form within 24 hours of the site's knowledge of the event. All other data to be entered within 30 days of source acquisition. 12.2.3 **ARCHIVAL OF RECORDS** According to 21 CFR 312.62I, the Site and Lead Principal Investigators shall retain records required to be maintained under this part for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated. If no application is to be filed or if the application is not approved for such indication, the Site and Lead Principal Investigator shall retain these records until 2 years after the investigation is discontinued and the FDA or applicable regulatory authorities are notified. The Site and Lead Principal Investigator must retain protocols, amendments, IRB/IEC approvals, copies of the Form FDA, signed and dated consent forms, medical records, case report forms, drug accountability records, all correspondence, and any other documents pertaining to the conduct of the study.
clinical study protocol
12.2.4 clinical monitoring procedures

Clinical studies coordinated by The University of Chicago must be conducted in accordance with the ethical principles that are consistent with Good Clinical Practices (GCP) and in compliance with other applicable regulatory requirements. This study will be remotely monitored by the designated University of Chicago Medicine Clinical Research Associate (CRA). Prior to subject recruitment, a participating site will undergo site initiation teleconference to be conducted by the designated University of Chicago Medicine CRA and Lead Principal Investigator. The site's principal investigator and his or her study staff should make every effort in attending the site initiation meeting. Study-related questions or issues identified during the site initiation meeting will be followed-up by the appropriate UCM personnel until they have been answered and resolved. Monitoring will be conducted to verify the following:
Adherence to the protocol  
Completeness and accuracy of study data and samples collected Compliance with regulations
Participating sites will also undergo a site close-out teleconference upon completion, termination or cancellation of a study to ensure fulfillment of study obligations during the conduct of the study, and that the Site Principal Investigator is aware of his/her ongoing responsibilities.
clinical study protocol
12.2.5 data safety and monitoring

The University of Chicago Medical Center is responsible for data and safety monitoring for this study, including reviewing and monitoring the study's scientific progress, accrual rate and any serious adverse events. This protocol will undergo weekly review at the University of Chicago multi-institutional data and safety monitoring teleconference as per procedures specified by the UCCCC NCI-approved Data and Safety Monitoring Plan. Each participating site is responsible for participating in Data Safety Monitoring (DSM), including participating in the teleconference. Prior to study start up, sites will be asked to submit their Data Safety Monitoring procedures for review by the University of Chicago. Drug accountability should be included in the monitoring plan. The study will conduct teleconferences at a rate determined by the Lead Principal Investigator to review the following:  
Enrollment rate relative to expectations, characteristics of participants Safety of study participants (Serious Adverse Event & Adverse Event reporting) Adherence to protocol (protocol deviations) Completeness, validity and integrity of study data Retention of study participants
Protocol deviations are to be documented within 7 calendar days of awareness of the event using the Protocol Deviation Form in Velos or using a Notice of Protocol Deviation form on paper that is sent to the UCM CRA or appropriate representative at the University of Chicago Medicine.
clinical study protocol
12.2.6 protocol deviations

Protocol deviations are to be documented using the Notice of Protocol Deviation Form in the Velos clinical trial management system. Deviations that are considered major because they impact subject safety or alter the risk/benefit ratio, compromise the integrity of the study data, and/or affect subjects' willingness to participate in the study must be reported into the Velos system within 7 days.
clinical study protocol
12.2.7 quality assurance and auditing

In addition to the clinical monitoring procedures, the University of Chicago Comprehensive Cancer Center will perform routine Quality Assurance Audits of investigator-initiated clinical trials as described in the NCI-approved UC CCC DSM Plan. Audits provide assurance that trials are conducted and study data are collected, documented and reported in compliance with the protocol. Further, quality assurance audits ensure that study data are collected, documented and reported in compliance with Good Clinical Practices (GCP) Guidelines and regulatory requirements. The audit will review subjects enrolled at the University of Chicago in accordance with audit procedures specified in the UC CCC Data and Safety Monitoring plan. For institutions who are forma members of the Personalized Cancer Care Consortium (PCCC), the UC CCC will conduct on site quality assurance audits on average every two years during the enrollment and treatment phase of the study. Auditing procedures for participating sites that are not full members of the PCCC must be specified and approved by the UC CCC Clinical Research Advisory Committee. In general, for sites that are not full members of the PCCC, auditing responsibility will be delegated to the participating center, with the annual audit report forwarded to the University of Chicago for review. A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its conduct or even after its completion. If an inspection has been requested by a regulatory authority, the site investigator must immediately inform the University of Chicago Cancer Clinical Trials Office and Regulatory Manager that such a request has been made.
clinical study protocol
13 references

1. Ries LAG, Melbert D, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2004, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975-2004/, based on November 2006 SEER data submission, posted to the SEER web site, 2007.  
2. Kumar et al. Improved Survival in Multiple Myeloma and the Impact of Novel Therapies. Blood. 2008 Mar 1;111(5):2516-20. Epub 2007 Nov 1.  
3. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357(21):21332142.  
4. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007; 357(21):2123-2132.  
5. Anderson KC, Jagannath S, Jakubowiak A. Phase II study of lenalidomide (Len),
bortezomib (Bz), and dexamethasone (Dex) in patients (pts) with relapsed or relapsed and refractory multiple myeloma (MM). J Clin Oncol 2008; 26 (suppl): abstract 8545.  
6. Richardson P, Jagannath S, Jakubowiak A. Lenalidomide, Bortezomib, and Dexamethasone in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Encouraging Response Rates and Tolerability with Correlation of Outcome and Adverse Cytogenetics in a Phase II Study. American Hematology Society Congress \#1742. San Francisco, CA. USA. Dec 6, 2008 7. Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005; 106(13): 4050-4053.  
8. Rajkumar SV, Jacobus S, Callander N, et al. Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2007; 25 (18S): Abstract LBA8025.  
9. Richardson P, Jagannath S, Raje N, et al. Lenalidomide, bortezomib, and dexamethasone (Rev/Vel/Dex) as front-line therapy for patients with multiple myeloma (MM): Preliminary results of a phase 1/2 study. Blood 2007; 110(11): abstract 187.  
10. Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE, Xie W, Ghoobrial IM, Scholssman RL, Mazumber A, Munshi N, Vesole DH, Joyce R, Kaufman JL, Doss D, Warren DL, Lunde LE, Kaster S, DeLaney C, Hideshima T, Mitsiades CS, Knight R, Esseltine D-L, Anderson KC. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010;116:679-86.  
12. Arastu-Kapur S, Shenk K, Parlati F and Bennett M. Non-Proteasomal Targets of Proteasome Inhibitors Bortezomib and Carfilzomib. Blood (ASH Annual Meeting Abstracts), Nov 2008; 112: 2657.  
13. Kirk CJ, Jiang J, Muchamuel T, Dajee M, Swinarski D, Aujay M, Bennett MK,
Yang J, Lewis E, Laidig G and Molineaux CJ. The Selective Proteasome Inhibitor Carfilzomib Is Well Tolerated in Experimental Animals with Dose Intensive Administration. Blood (ASH Annual Meeting Abstracts), Nov 2008; 112: 2765.  
14. Bortezomib Summary Basis of Approval
(www.fda.gov/cder/foi/nda/2003/21602_Velcade.htm)
15. Bross PF, Kane R, Farrell AT, Abraham S, Benson K, Brower ME, Bradley S,
Gobburu JV, Goheer A, Lee SL, Leighton J, Liang CY, Lostritto RT, McGuinn WD, Morse DE, Rahman A, Rosario LA, Verbois SL, Williams G, Wang YC, . Approval summary for bortezomib for injection in the treatment of multiple myeloma.Clin Cancer Res. 2004 10(12 Pt 1):3954-64.  
16. Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk, KD, Sun CM, Demo SD,
Bennett, SD, van Leeuwen, F, Chanan-Khan, A and Orlowski, RZ. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007 Nov 1;110(9):328190.  
17. Alsina M, Trudel S, Vallone M, Molineaux C, Kunkel L and Goy A. Phase 1 Single Agent Antitumor Activity of Twice Weekly Consecutive Day Dosing of the Proteasome Inhibitor Carfilzomib (PR-171) in Hematologic Malignancies. Blood (ASH Annual Meeting Abstracts), 2007; 110: 411.  
18. Jagannath S, Vij R, Stewart K, Somlo G, Jakubowiak A, Trudel S, Schwartz R,
Siegel D, Kunkel L, The Multiple Myeloma Research Consortium (MMRC). Final results of PX-171-003-A0, part 1 of an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). J ClinOncol. 2009 27:15s (suppl; abstr 8504).  
CONFIDENTIAL Page 99  5 OCT
2015 11. Demo SD, Kirk CJ, Aujay MA, et al. Anti-tumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007; 67(13):6383-91.  
19. Wang L, Siegel D, Kaufman JL, Stewart AK, Jakubowiak AJ, Alsina M, Kukreti V, Bahlis NJ, McDonagh KT, Belch A, Sebag M, Gabrail N, Le MH, Bennett MK, Kunkel L, Kauffman M, Orlowski RZ, Vij R, and The Multiple Myeloma Research Consortium (MMRC). Updated Results of Bortezomib-Naïve Patients in PX-171004, An Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory Myeloma (MM). Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 302.  
CONFIDENTIAL Page 100  **5 OCT**
2015 20. Siegel D, Wang L, Orlowski RZ, Kaufman JL, Stewart AK, Kukreti V, Alsina M,
Jakubowiak AJ, Jagannath D, McDonagh KT, Belch A, Bahlis NJ, Shustik C, Le MH, Kunkel L, Bennett MK, Kauffman M, Vij R, and The Multiple Myeloma Research Consortium (MMRC)PX-171-004, An Ongoing Open-Label, Phase II
Study of Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory Myeloma (MM); Updated Results From the Bortezomib-Treated Cohort.Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 303 21. Badros AZ, Vij R, Martin T, Zonder JA, Woo T, Wang, Lee S, Wong A, and Niesvizky R. Phase I Study of Carfilzomib in Patients (Pts) with Relapsed and Refractory Multiple Myeloma (MM) and Varying Degrees of Renal Insufficiency.Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 3877.  
22. Dredge K, Horsfall R, Robinson S, Zhang L-H, Lu L, et al. Orally administered lenalidomide (revlimid) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phophorylation in vitro. Microvascular Research 69 (2005) 5663.  
23. Corral LF, Haslett PAJ, Muller FW, Chen R, Wong LM, Ocampo CJ, Patterson RT,
Stirling DI, Kaplan G. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNFalpha. J Immunol. 1999; 163:380-386.  
24. Schafer PH, Gandhi AK, Loveland MA, Chen RS, Man H-W, et al. Enhancement of cytokine production and Ap-1 transcriptional activity in T cells by thalidomiderelated immunomodulatory drugs. J of Pharmacology and Exp Therapeutics, 305:1222-1232, 2003.  
25. Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K,
Gupta D, Chauhan D, Treon SP, Richarson PG, Schlossman RL, Morgan GJ, Muller GW, Stirling DI, Anderson KC. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98:210216.  
26. Niesvizky R, Wang L, Orlowski RZ, Bensinger W, Alsina M, Gabrail N, Gutierrez A, Lori Kunkel, Michael Kauffman, and The Multiple Myeloma Research Consortium (MMRC)Phase Ib Multicenter Dose Escalation Study of Carfilzomib Plus Lenalidomide and Low Dose Dexamethasone (CRd) in Relapsed and Refractory Multiple Myeloma (MM). Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 304.  
27. Jakubowiak, AJ et al. Carfilzomib, Lenalidomide, and Dexamethasone In Newly Diagnosed Multiple Myeloma: Initial Results of Phase I/II MMRC Trial. Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 862 28. Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D et at. A phase 1, 2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood Jun 2012.  
30. Jakubowiak AJ et al. ASCO 2012 and Blood 2012, June 4, EPub ahead of print CONFIDENTIAL Page 101  **5 OCT**
2015 29. Jakubowiak AJ et al. Final results of a frontline phase 1, 2 study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in Multiple Myeloma. ASH Annual Meeting Abstracts) 2011 Abstract 631 31. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortrezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2011 Nov 26;378(9806):1846  
| APPENDIX A. SCHEDULE OF TESTS AND OBSERVATIONS   |                 |                          |       |       |     |     |     |    |                  |
|--------------------------------------------------|-----------------|--------------------------|-------|-------|-----|-----|-----|----|------------------|
| PROCEDURES                                       | Screen          | CRd Induction Cycles 1-4 |       |       |     |     |     |    |                  |
| DAY                                              | -21 to - 1      | 1                        | 2     | 8     | 9   | 15  | 16  | 22 | End of  Cycle  4 |
| Informed Consent                                 | X               |                          |       |       |     |     |     |    |                  |
| Medical/Treatment History                        | X               |                          |       |       |     |     |     |    |                  |
| Skeletal Survey2                                 | X               |                          |       |       |     |     |     |    |                  |
| ECG3                                             | X               |                          |       |       |     |     |     |    |                  |
| Physical Exam5                                   | X               | X4                       |       |       |     |     |     |    |                  |
| Vital Signs6                                     | X               | X                        | X     | X     | X   | X   | X   | X  |                  |
| Height, Weight, BSA                              | X               | X                        |       |       |     |     |     |    |                  |
| 24-hour urine7                                   | X               | X4,7                     | X7    | X7    |     |     |     |    |                  |
| Urinalysis                                       | X               |                          |       |       |     |     |     |    |                  |
| Coagulation Tests8                               | X               |                          |       |       |     |     |     |    |                  |
| CRP                                              | X               |                          |       |       |     |     |     |    |                  |
| Hematology9                                      | X               | X                        | (X)10 | (X)10 |     |     |     |    |                  |
| Serum Chemistry                                  | X11             | X11                      | X12   | X11   | X12 | X11 | X12 |    |                  |
| Pregnancy Test13                                 | X               | X                        | X14   | X14   | X14 |     |     |    |                  |
| Disease Assessment                               | X15             |                          |       |       |     |     |     |    |                  |
| β2-microglobulin                                 | X               |                          |       |       |     |     |     |    |                  |
| SPEP, UPEP16                                     | X               | X4                       | X17   | X     |     |     |     |    |                  |
| Immunofixation - Serum and Urine                 | X               | X4                       | X17   | X     |     |     |     |    |                  |
| BM Aspirate/biopsy, cytogenetics, FISH18         | X               | X18                      |       |       |     |     |     |    |                  |
| Plasmacytoma Evaluation31                        | X               |                          |       |       |     |     |     |    |                  |
| Quantitative Igs                                 | X               | X4                       | X17   | X     |     |     |     |    |                  |
| CONFIDENTIAL                                     | Page 102 of 121 | 5 OCT                    |       |       |     |     |     |    |                  |  
CONFIDENTIAL Page 102  5 OCT  
2015  
| PROCEDURES                                                                 | Screen     | CRd Induction Cycles 1-4   |    |     |    |     |    |    |                  |
|----------------------------------------------------------------------------|------------|----------------------------|----|-----|----|-----|----|----|------------------|
| DAY                                                                        | -21 to - 1 | 1                          | 2  | 8   | 9  | 15  | 16 | 22 | End of  Cycle  4 |
| SFLC19                                                                     | X          | X19                        |    |     |    |     |    |    |                  |
| Neurological Assessment20                                                  | X          | X20                        |    |     |    |     |    |    |                  |
| Correlative Samples21                                                      | X          | X21                        |    |     |    |     |    |    |                  |
| Bone marrow aspirate sample for MRD  analysis32                            | X          | X                          |    |     |    |     |    |    |                  |
| CT-PET33                                                                   | X          | X                          |    |     |    |     |    |    |                  |
| Adverse Events22                                                           | Ongoing    |                            |    |     |    |     |    |    |                  |
| Concomitant Medications                                                    | Ongoing    |                            |    |     |    |     |    |    |                  |
| Register Patient into Revlimid REMS®  program and prescribe lenalidomide24 | X          |                            |    |     |    |     |    |    |                  |
| Carfilzomib25                                                              | X          | X                          | X  | X   | X  | X   |    |    |                  |
| Revlimid® (Lenalidomide)26                                                 | X          | X                          | X  | X   | X  | X   |    |    |                  |
| Dexamethasone27                                                            | X          | X27                        | X  | X27 | X  | X27 | X  |    |                  |  
*Following cycle 4, subjects will proceed to Stem Cell Collection and Autologous Stem Cell Transplant (section 6.4)  
| PROCEDURES                                         | CRd Consolidation Cycles 5-8   |             |       |    |    |    |    |                     |    |    |    |    |    |    |
|----------------------------------------------------|--------------------------------|-------------|-------|----|----|----|----|---------------------|----|----|----|----|----|----|
| (Following ASCT Days 70-90 but not  more than 120) | CRd Maintenance Cycles 9- 18   | End  of  Tx | LTF U |    |    |    |    |                     |    |    |    |    |    |    |
| DAY                                                | 1                              | 2           | 8     | 9  | 15 | 16 | 22 | End  of  Cycle  830 | 1  | 2  | 8  | 15 | 16 | 22 |
| Skeletal Survey                                    | X                              |             |       |    |    |    |    |                     |    |    |    |    |    |    |  
CONFIDENTIAL Page 103  5 OCT  
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| PROCEDURES                                         | CRd Consolidation Cycles 5-8   |             |       |     |     |    |    |                     |    |    |    |    |    |    |
|----------------------------------------------------|--------------------------------|-------------|-------|-----|-----|----|----|---------------------|----|----|----|----|----|----|
| (Following ASCT Days 70-90 but not  more than 120) | CRd Maintenance Cycles 9- 18   | End  of  Tx | LTF U |     |     |    |    |                     |    |    |    |    |    |    |
| DAY                                                | 1                              | 2           | 8     | 9   | 15  | 16 | 22 | End  of  Cycle  830 | 1  | 2  | 8  | 15 | 16 | 22 |
| ECG3                                               | X                              |             |       |     |     |    |    |                     |    |    |    |    |    |    |
| Physical Exam5                                     | X                              | X           | X     |     |     |    |    |                     |    |    |    |    |    |    |
| Vital Signs                                        | X                              | X           | X     | X   | X   | X  | X  | X                   | X  | X  | X  |    |    |    |
| Height, Weight, BSA                                | X                              | X           | X     |     |     |    |    |                     |    |    |    |    |    |    |
| 24-hour urine7                                     | X7                             | X7          | X7    |     |     |    |    |                     |    |    |    |    |    |    |
| Urinalysis Hematology9                             | X                              | X           | X     | X   |     |    |    |                     |    |    |    |    |    |    |
| Serum Chemistry                                    | X11                            | X11         | X11   | X11 | X11 | X  |    |                     |    |    |    |    |    |    |
| Pregnancy Test13                                   | X                              | X14         | X14   | X14 | X14 |    |    |                     |    |    |    |    |    |    |
| Disease Assessment                                 | X15                            | X1 5        | X23   |     |     |    |    |                     |    |    |    |    |    |    |
| β2-microglobulin                                   | X                              |             |       |     |     |    |    |                     |    |    |    |    |    |    |
| SPEP, UPEP16                                       | X                              | X           | X     | X   |     |    |    |                     |    |    |    |    |    |    |
| Immunofixation - Serum and Urine                   | X                              | X           | X     | X   |     |    |    |                     |    |    |    |    |    |    |
| BM Aspirate/biopsy, cytogenetics,  FISH18          | X18                            | X18         | X     |     |     |    |    |                     |    |    |    |    |    |    |
| Plasmacytoma Evaluation                            | X                              |             |       |     |     |    |    |                     |    |    |    |    |    |    |
| Quantitative Igs                                   | X                              | X           | X     | X   |     |    |    |                     |    |    |    |    |    |    |
| SFLC19                                             | X19                            | X19         |       |     |     |    |    |                     |    |    |    |    |    |    |
| Neurological Assessment20                          | X                              | X           | X     |     |     |    |    |                     |    |    |    |    |    |    |
| Correlative Samples21                              | X21                            |             |       |     |     |    |    |                     |    |    |    |    |    |    |  
| PROCEDURES                                                                                                                         | CRd Consolidation Cycles 5-8   |             |       |     |    |    |    |                     |    |    |    |    |     |    |
|------------------------------------------------------------------------------------------------------------------------------------|--------------------------------|-------------|-------|-----|----|----|----|---------------------|----|----|----|----|-----|----|
| (Following ASCT Days 70-90 but not  more than 120)                                                                                 | CRd Maintenance Cycles 9- 18   | End  of  Tx | LTF U |     |    |    |    |                     |    |    |    |    |     |    |
| DAY                                                                                                                                | 1                              | 2           | 8     | 9   | 15 | 16 | 22 | End  of  Cycle  830 | 1  | 2  | 8  | 15 | 16  | 22 |
| Bone marrow aspirate sample for  MRD analysis32                                                                                    | X                              | X           | X     | X32 |    |    |    |                     |    |    |    |    |     |    |
| CT-PET33                                                                                                                           | X                              | X           | X     | X33 |    |    |    |                     |    |    |    |    |     |    |
| Adverse Events22                                                                                                                   | Ongoing                        |             |       |     |    |    |    |                     |    |    |    |    |     |    |
| Concomitant Medications                                                                                                            | Ongoing                        |             |       |     |    |    |    |                     |    |    |    |    |     |    |
| Carfilzomib25                                                                                                                      | X                              | X           | X     | X   | X  | X  | X  | X                   | X  | X  |    |    |     |    |
| Revlimid® (Lenalidomide)26,28                                                                                                      | X                              | X           | X     | X   | X  | X  | X  | X                   | X  | X  | X  | X  | X28 |    |
| Dexamethasone27                                                                                                                    | X                              | X           | X     | X   | X  | X  | X  | X                   |    |    |    |    |     |    |
| Survival and New Cancer Evaluation 29                                                                                              | X                              |             |       |     |    |    |    |                     |    |    |    |    |     |    |
| * Variations of ± 3 days of the scheduled visit are permitted however doses of carfilzomib may only be rescheduled by up to 2 days |                                |             |       |     |    |    |    |                     |    |    |    |    |     |    |  
**The CRd consolidation cycles are cycle 5 - 8. Maintenance cycles are 5-18 for patients that do not proceed to ASCT.
clinical study protocol
footnotes for appendix a

+ Documented informed consent must be obtained within ≤ 30 days prior to initiation of therapy.  
1. Includes neuropathy history.  
2. May be within 30 days planned treatment start. Includes: lateral radiograph of the skull, anteroposterior and lateral views of the spine, and anteroposterior views of the pelvis, ribs, femora, and humeri. Skeletal surveys performed outside of the 30 day window may be considered for inclusion. Please contact the Lead Principal Investigator and/or/CRA on a case-by-case basis. End of treatment skeletal survey only if clinically indicated.  
3. 12-lead ECG, including QTc interval. End of treatment ECG only if clinically indicated. 4. For Day 1 of cycle 1, screening results may be used if within 7 days of treatment start.  
5. Complete physical exam (including vital signs [systolic and diastolic blood pressure, respiration, pulse, oral temperature], height, weight, calculation of body surface area [BSA]) and ECOG score) required at screening and Day 1 of each cycle. .  
6. Systolic and diastolic blood pressure, pulse, respiration, temperature approximately 1 hour before dosing.  
CONFIDENTIAL Page 106  5 OCT
2015 7. 24 hour urine total protein, urine protein electrophoresis (UPEP), and urine protein immunofixation. For subjects whose disease is being monitored through UPEP, additional post baseline 24-hour urine collections are required as indicated.  
8. Prothrombintime, activated partial thromboplastin time, and international normalized ratio. 9. Hemoglobin, hematocrit, WBC with complete differential, RBCs, platelet count. Results must be reviewed before dosing. 10. Cycles 1 and 2 only and subsequent cycles as clinically indicated or per institutional standard of care.  
11. Full serum chemistry panel at Screening, Days 1, 8, and 15 of Cycles 1-8, and Day 1 of Cycles 9+: sodium, potassium, chloride, bicarbonate, BUN,
creatinine, glucose, uric acid, total protein, albumin, calcium, phosphorus, magnesium, total bilirubin, alkaline phosphatase, ALT, AST, LDH. Results must be reviewed before dosing in Cycles 1 and 2.  
12. Abbreviated serum chemistry panel on Days 2, 9, and 16 of Cycles 1 and 2 only or as clinically indicated (e.g., risk factors for tumor lysis syndrome):
sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, uric acid.  
13. Pregnancy tests for females of childbearing potential. A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not had a hysterectomy or bilateral oophorectomy; or 2) has not been naturally post-menopausal for at least 24 consecutive months (i.e., menses within the preceding 24 months) See Appendix F of protocol for details.  
14. Pregnancy tests must occur within 10-14 days and again within 24 hours prior to prescribing lenalidomide (prescriptions must be filled within 7 days.  
FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on 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 therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.  
15. After 4 cycles, subjects are evaluated before receiving ASCT. It is anticipated that all patient will proceed to ASCT but if patient becomes not eligible, continuation of CRd treatment as per maintenance schedule can be granted by the Lead Principal Investigator..  
16. Serum protein electrophoresis and urine protein electrophoresis (the latter only for those whose disease is being followed by UPEP). Subjects with baseline urine protein greater than 200 mg/24 hours must have a UPEP to confirm VGPR or better. Obtain blood for M-protein levels measured by SPEP or quantitative immunoglobulins for those subjects in whom SPEP/UPEP are felt to be unreliable (IgA type multiple myeloma), depending upon which studies were positive at baseline.  
17. Disease assessments on Day 15 of Cycle 1 (only) are only for assessing onset of early response, not for definitive achievement of response.  
18. Bone marrow aspirate and biopsy - quantify % myeloma cell involvement; bone marrow sample for cytogenetics and fluorescent in situ hybridization
(FISH). Bone marrow aspirate and biopsy should be performed at screening, end of cycle 4 (pre-transplant), 3-months post-transplant, and the end of CRd consolidation (end of cycle 8). See sections 6.3-6.5. Repeat bone marrow biopsy/aspirate if CR is suspected (e.g., end of cycle 4) and as appropriate to confirm achievement of sCR, CR, or nCR (aspirate only—biopsy not required).If institution has established flow-based multi-color study for minimal residual disease (MRD), this evaluation should include MRD evaluation. Bone marrow biopsy/aspirate performed outside of the 30 day window may be considered for inclusion. Please contact the Lead Principal Investigator and/or the CRA on a case-by-case basis. (Cytogenetics is required at screening only. If cytogenetics is completed at a time point other than screening, the results should be captured in eCRF)
19. SFLC repeated only to confirm CR.  
20. Screening and Day 1 of every cycle. Includes neurologic exam (to detect peripheral neuropathy and/or changes in pre-existing neuropathy) and examination of clinical AEs indicative of neuropathy. Collect FACT/GOG neurotoxicity questionnaire at each time point above.  
21. Peripheral blood and bone marrow aspirate samples collected at screening, time of response (to confirm complete response), and/or end-of-treatment visit. Buccal mucosa swab will be collected at screening only.  
CONFIDENTIAL Page 107  5 OCT
2015 22. AEs will be collected from the time of signing informed consent. 30 days following the last dose of CRd, during ASCT period, patients will be considered to be off-study so no toxicities will be recorded for this period. AE tracking will re-commence at the initiation of Cycle 5. All concomitant medications must be recorded on the concomitant medications case report form from 21 days before Day 1 through 30 days following the last dose of study drugs.  
23. Assessment for disease progression in subjects who did not progress during treatment. At least every 3 months (+/- 30 days) for 5 years from safety follow-up visit (which must be 28days (+/- 3 days) post-last study treatment).  
24. Lenalidomide must be prescribed through and in compliance with the Revlimid REMS® program of Celgene Corporation. Prescriptions must be filled within 7 days. Consideration should be given to prescribing lenalidomide 5 to 7 days in advance of Day 1 of each cycle to allow time for required patient and prescriber surveys, and drug shipment to patient. Any unused Revlimid® (lenalidomide) should be returned to the patient for disposition in accordance with the Revlimid REMSt® program.  
25. Cycles 1-8: Days 1, 2, 8, 9, 15 & 16. Cycles 9-18 Days 1, 2, 15 & 16 26. Daily on Days 1-21 followed by a 7-day rest period every 28 days. On day coinciding with carfilzomib administration, lenalidomide should be taken at least 4 hours after the carfilzomib dose and may be self-administered at home by the subject. On days that carfilzomib is not administered, lenalidomide should be taken at approximately the same time each day.  
27. Days 1, 8, 15 and 22. Dexamethasone is given between 30 minutes and 4 hours before carfilzomib on days they coincide. Cycles 5-8 dexamethasone will be reduced down to 20 mg on days 1, 8, 15 and 22. Cycles 9-18 represent the CRd Maintenance Phase of therapy and the dose of dexamethasone will remain 20 mg on days 1, 8, 15 and 22. Subjects may be given 4 mg dexamethasone p.o. or IV on Days 2, 9 and 16 in Cycles 1 and 2 prior to carfilzomib infusion if signs of tumor flare are present. This will be prescribed at the Treating Investigator's discretion.  
28. Single-agent Lenalidomide maintenance therapy, is recommended using last tolerated dose of lenalidomide for 21 days in 28 day cycles after CRd protocol treatment (cycles 1-18) is completed.  
29. Patients will be followed for survival and development of any new cancers, at least every 3 months. Reports of any death should include date of death and specific cause (disease under study or specify other cause).  
30. Evaluations at the end Cycle 8 may be done on Day 1 of the next Cycle 9 31. Plasmacytoma evaluation is required at screening only and may be completed as physical exam or imaging if indicated and at the treating investigator's discretion. After screening, plasmacyotoma evaluation is required only for patients who have no other measurable disease and/or at investigator's discretion.  
32. Two bone marrow samples for central Minimal Residual Disease (MRD) analysis by flow at the University of Chicago and by NGS at Adaptive Biotechnologies will be collected from all subjects: 1) screening (sample is required for calibration of MRD by gene sequencing In the event that a superfluous bone marrow aspirate –BMA- sample from screening was not available, slides of BMA smear or clot from a time prior to enrollment can be used), 2) end of cycle 4, 3) post-transplant, 4) end of cycle 8, 5) end of cycle 18 (EOT), 6) 1, 2, 3, and 5 years after EOT for all subjects; 7) any time that a bone marrow is performed as SOC to assess CR response. For any bone marrow collected after Cycle 4, Cycle 8 or Cycle 18, the visit may be done on Day 22-28 of that cycle.  
33. A CT-PET will be performed to confirm MRD-negative disease per Standard of Care, at every time-point when MRD is checked. A bone marrow done as SOC a year after the EOT BM will be tested for MRD and a CT-PET done to confirm MRD-negative disease.
clinical study protocol
stage i

All of the following must be present:
- Hemoglobin > 10.5 g/dL or hematocrit >32%
- Serum calcium level normal (≤ 12mg/dL)
- Low serum myeloma protein production rates as evidenced by all of the following:
o IgG peak < 5g/dL o IgA peak < 3g/dL o Bence Jones protein < 4g/24 h
- No bone lesions
clinical study protocol
stage ii

All patients who do not meet criteria for Stage I or III are considered Stage II.
clinical study protocol
stage iii

One of the following abnormalities must be present:
- Hemoglobin < 8.5 g/dL, hematocrit < 25%
- Serum calcium >12 mg/dL
- Very high serum or urine myeloma protein production rates as evidenced by one or more of the following:
- IgG peak > 7g/dL
- IgA peak > 5g/dL
- Bence Jones protein > 12g/24 h
- > 3 lytic bone lesion on bone survey (bone scan not acceptable)
Sub-classification a: Serum creatinine < 2.0 mg/dL b: Serum creatinine >2.0 mg/dL
B. International Myeloma Working Group International Staging System (ISS)
1. Stage I: B2M < 3.5 plus serum albumin >3.5 (med S 62m) 2. Stage II: B2M < 3.5 but serum alb. < 3.5 OR B2M 3.5 - < 5.5 (med S 44m) 3. Stage III: B2M > 5.5 (med S 29m) 4. Subclassify stages 1+2 according to cr< or > 2 and stage 3 according to low platelets (< 130k) or high LDH
IMWG criteria for symptomatic myeloma:
All three criteria must be met:
1. Clonal bone marrow plasma cells and/or documented clonal plasmacytoma 2. Presence of serum and/or urinary monoclonal protein 3. Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
-Hypercalcemia: serumcalcium ≥ 11.5 mg/dl or -Renal insufficiency: serum creatinine >2 mg/dl or
-Anemia: hemoglobin at least 2 g/dl below the lower limit of normal or a hemoglobin <10 g/dl or
-Bone lesions: lytic lesions, osteopenia or pathologic fractures
clinical study protocol
appendix c. ecog performance scale

| Grade   | Description                                                                                                                                                                         |
|---------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0       | Normal activity, fully active, able to carry on all pre-disease  performance without restriction.                                                                                   |
| 1       | Symptoms, but fully ambulatory, restricted in physically  strenuous but ambulatory and able to carry out work of a light or  sedentary nature (e.g., light housework, office work). |
| 2       | Ambulatory and capable of all self-care but unable to carry out  any work activities. Up and about more than 50% of waking  hours.                                                  |
| 3       | Capable of only limited self-care, confined to bed or chair more  than 50% of waking hours.                                                                                         |
| 4       | Completely disabled. Cannot carry on any self-care. Totally  confined to bed or chair.                                                                                              |
| 5       | Dead                                                                                                                                                                                |
clinical study protocol
appendix d. nci ctcae version

Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) v4.0 Publish Date: September 15, 2009 http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_5x7.pdf  
| Table E1: IMWG Criteria Response IMWG criteria1,2 sCR CR as defined below plus:  - normal FLC ratio and  - absence of clonal cells in bone marrow by immunohistochemistry  or 2 - 4 color flow cytometry Stringent  Complete  Response CR - Negative immunofixation on the serum and urine and  - disappearance of any soft tissue plasmacytomas and  - < 5% plasma cells in bone marrow.  - In patients with only FLC disease, a normal FLC ratio of 0.26–1.65  is required. Complete  Response VGPR - Serum and urine M-protein detectable by immunofixation but not on  electrophoresis or - > 90% reduction in serum M-protein plus urine M-protein level <  100 mg/24 h.  - In patients with only FLC disease, >90% decrease in the difference  between involved and uninvolved FLC levels is required. Very Good  Partial  Response PR - 50% reduction of serum M-protein and reduction in 24 hours urinary  M-protein by >90% or to < 200 mg/24 h - If the serum and urine M-protein are unmeasurable,3 a > 50%  decrease in the difference between involved and uninvolved FLC  levels is required in place of the M-protein criteria - If serum and urine M-protein are not measurable, and serum free  light assay is also not measureable, > 50% reduction in plasma cells  is required in place of M-protein, provided baseline bone marrow  plasma cell percentage was > 30% - In addition to the above listed criteria, if present at baseline, a > 50%  reduction in the size of soft tissue plasmacytomas is also required Partial  Response Stable  - Not meeting criteria for CR, VGPR, PR or progressive diseaseDisease   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
clinical study protocol
appendix e. response criteria for

| Increase of > 25% from lowest response value in any one of the following: - Serum M-component (the absolute increase must be > 0.5 g/dL)4 and/or  - Urine M-component (the absolute increase must be > 200 mg/24  h)and/or  - Only in patients without measurable serum and urine M-protein, the  difference between involved and uninvolved FLC levels. The absolute  increase must be > 10 mg/dL - Only in patients without measurable serum and urine M-protein and  without measurable disease by FLC levels, bone marrow plasma cell  percentage (absolute % must be ≥ 10%)  - Definite development of new bone lesions or soft tissue plasmacytomas  or definite increase in the size of existing bone lesions or soft tissue  plasmacytomas - Development of hypercalcemia (corrected serum calcium >11.5 mg/dL)  that can be attributed solely to the plasma cell proliferative disorder   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
All relapse categories (CR, sCR, VGPR, and PD) require two consecutive assessments made at anytime before the institution of any new therapy; complete response and PR and SD categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. VGPR and CR categories require serum and urine studies regardless of whether disease at baseline was measurable in serum, urine both or either. Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be confirmed. For progressive disease, serum M-component increases of ≥ I gm/dl are sufficient to define response if starting M-component is ≥ 5 g/dl. IMWG clarification for coding PD:
- clarified that bone marrow criteria for PD are to be used only in patients without measurable disease by M protein and by FLC levels.  
- clarified that 25% increase refers to M protein, FLC, and bone marrow results and does not refer to bone lesions, soft tissue plasmacytomas or hypercalcemia. Note the lowest response value does not need to be a confirmed value.
clinical study protocol
table e2additional response criteria for

≥ 25% but < 49% reduction of serum M protein and reduction in 24 hour urine M protein by 50 - 89%, which still exceeds 200 mg/24hrs.  
| Minor response in patients with relapsed and  refractory myeloma adapted from the EMBT  criteria3   |
|-----------------------------------------------------------------------------------------------------|  
| In addition to above; if present at baseline, 25- 49% reduction in the size of soft tissue  plasmacytomas is also required   |
|------------------------------------------------------------------------------------------------------------------------------|  
No increase in size or number of lytic bone lesions (development of compression fractures does not exclude response)  
Near Complete Response nCR The absence of myeloma protein on  
electrophoresis, with positive immunofixation, stable bone disease, and a normal serum calcium concentration  
Immunophenotypic CR Stringent CR plus  
Absence of phenotypic abarrent PC (clonal) in bone marrow with a minimum of one million of total BM cells analyzed by multiparametric flow cytometry (with ≥4 colors)  
Molecular CR Stringent CR plus negative ASO-PCR (sensitivity  
10-5)  
1. Durie et al. International uniform response criteria for multiple myeloma. Leukemia  
2006;20:1467-73  
2. S. Vincent Rajkumar, Jean-Luc Harousseau, Brian Durie, Kenneth C. Anderson,  
Meletios Dimopoulos, Robert Kyle, Joan Blade, Paul Richardson, Robert Orlowski, David Siegel, Sundar Jagannath, Thierry Facon, Hervé Avet-Loiseau, Sagar Lonial, Antonio Palumbo, Jeffrey Zonder, Heinz Ludwig, David Vesole, Orhan Sezer, Nikhil C. Munshi, and Jesus San Miguel. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1 . Blood First Edition Paper, prepublished online February 3, 2011;DOI 10.1182/blood-2010-10-299487  
3. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar  
SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A Phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609, June 2, 2003.  
4. Richardson et al. Bortezomib or High-Dose Dexamethasone for Relapsed Multiple  
Myeloma. N Eng J Med. 352:2487-98, 2005
clinical study protocol
appendix f. risks of fetal

The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has the effect of the lenalidomide on human eggs and sperm. Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. An embryofetal development study in animals indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy. The teratogenic effect of lenalidomide in humans cannot be ruled out. Therefore, a risk minimization plan to prevent pregnancy must be observed.  
All study participants must be registered into the mandatory Revlimid REMS® program and be willing and able to comply with the requirements of Revlimid REMS®.  
Females of childbearing potential (FCBP) must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study:  
- for at least 28 days before starting lenalidomide; - while participating in the study - for at least 28 days after discontinuation from the study.
The 2 reliable methods of contraception must include 1 highly effective method—intrauterine device, hormonal (birth control pills, injections, or implants), tubal ligation, or partner's vasectomy—and 1 additional effective barrier method—latex condom, diaphragm, or cervical cap. FCBP must be referred to a qualified provider of contraceptive methods if needed. Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception the patient should switch to one of the effective method listed above. The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment with dexamethasone. Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia.
clinical study protocol
before starting lenalidomide female subjects

- FCBP must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating lenalidomide. The first pregnancy test must be performed within 10-14 days before, and the second pregnancy test must be performed within 24 hours beforeprescribing lenalidomide (prescriptions must be filled within 7 days).  
- The subject may not receive lenalidomide until the investigator has verified that the results of these pregnancy tests are negative.
clinical study protocol
male subjects

- Must agree to use a latex condom during sexual contact with FCBP while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy.
clinical study protocol
during study participation and for

- If pregnancy or a positive pregnancy test occurs in a study subject or in the partner of a male study subject during study participation, lenalidomide must be immediately discontinued.
clinical study protocol
female subjects

- FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 28 days while on study, at study discontinuation, and at day 28 following discontinuation from the study. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study discontinuation, and 14 and 28 days after discontinuation from the study.  
- In addition to the required pregnancy testing, the investigator must confirm with FCBP that she is continuing to use 2 reliable methods of birth control at each visit.  
- Pregnancy testing and counseling must be performed if a subject misses her period or if her pregnancy test or her menstrual bleeding is abnormal. Lenalidomide treatment must be discontinued during this evaluation.
clinical study protocol
male subjects

- Must agree to use a latex condom during sexual contact with FCBP while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy.
clinical study protocol
appendix g cockroft-gault estimation of

Cockroft-Gault estimation of creatinine clearance (CrCl): (Cockroft 1976; Luke 1990) CrCl (mL/min) for males: (140-age) x (weight, kg)
72 x (serum creatinine, mg/dL)
CrCl (mL/min) for males: (140-age) x (weight, kg) x 0.85 72 x (serum creatinine, mg/dL)
*Measured creatinine clearance on 24 hour urine collection can be used and is acceptable. If measured CrCl is different than calculated, measured CrCl should be used for eligibility assessment and/or dose modifications.
appendix h fact/gog-neurotoxicity questionnaire version
4.0

By circling one (1) number per line, please indicate how true each statement has been for you during the past 7 days.  
| Not                                                                                 | A      | little   |    |    |    |
|-------------------------------------------------------------------------------------|--------|----------|----|----|----|
| ADDITIONAL CONCERNS                                                                 | at all | bit      |    |    |    |
| I have numbness or tingling in my hands………                                          | 0      | 1        | 2  | 3  | 4  |
| I have numbness or tingling in my feet…………                                          | 0      | 1        | 2  | 3  | 4  |
| I feel discomfort in my hands………………….                                               | 0      | 1        | 2  | 3  | 4  |
| I feel discomfort in my feet……………………                                                | 0      | 1        | 2  | 3  | 4  |
| I have joint pain or muscle cramps……………                                             | 0      | 1        | 2  | 3  | 4  |
| I feel weak all over……………………………                                                     | 0      | 1        | 2  | 3  | 4  |
| I have trouble hearing…………………………                                                    | 0      | 1        | 2  | 3  | 4  |
| I get a ringing or buzzing in my ears…………                                           | 0      | 1        | 2  | 3  | 4  |
| I have trouble buttoning buttons………………                                              | 0      | 1        | 2  | 3  | 4  |
| I have trouble feeling the shape of small objects when they are in my hand……………………… | 0      | 1        | 2  | 3  | 4  |
| I have trouble walking…………………………                                                    | 0      | 1        | 2  | 3  | 4  |  
Sources: Cella DF, Tulsky DS, Gray G, Sarafian B, Lloyd S, Linn E, et al. The functional assessment of cancer therapy (FACT) scale: development and validation of the general measure. *J ClinOncol* 1993;11(3):570-79.  
| APPENDIX I:                                                 | IMWG CRITERIA FOR THE DIAGNOSIS OF MYELOMA Diagnosis Diagnostic Criteria: All Three  Required - Monoclonal plasma cells in  the bone marrow >/=10%  and/or presence of a biopsyproven plasmacytoma  - Monoclonal protein present  in the serum and/or urineb - Myeloma-related organ  dysfunction (>/=1)c  [C] Calcium  elevation in  the blood  (serum  calcium  >10.5 mg/l  or upper  limit of  normal [R] Renal  insufficiency  (serum  creatinine  >2mg per  100 ml) [A] Anemia  (hemoglobin  <10 g per  100 ml or 2  g <normal) [B] Lytic  bone lesions  or  osteoporosisd                                                                                    |                                |
|-------------------------------------------------------------|------------------------------------------------------------------------------------|--------------------------------|
| Symptomatic multiple myelomaa                               | -                                                                                  | Serum monoclonal protein  lowe |
| -                                                           | Monoclonal bone marrow  plasma cells <10%                                          |                                |
| -                                                           | No evidence of end-organ  damage attributable to the  clonal plasma cell disorder: |                                |
| Monoclonal gammopathy of  undetermined significance  (MGUS) |                                                                                    |                                |  
| o                               | Normal serum  calcium,  hemoglobin level  and serum creatinine                                                                                                                                                                                                                                                                       |               |
|---------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|
| o                               | No bone lesions on  full skeletal X-ray  survey and/or other  imaging if  performed                                                                                                                                                                                                                                                  |               |
| o                               | No clinical or  laboratory features  of amyloidosis or  light chain  deposition disease                                                                                                                                                                                                                                              |               |
| -                               | Monoclonal protein present  in the serum 3 g per 100 ml  or higher or                                                                                                                                                                                                                                                                |               |
| -                               | Monoclonal plasma cells  10% or greater present in  the bone marrow and/or a  tissue biopsy                                                                                                                                                                                                                                          |               |
| -                               | No evidence of end-organ  damage attributable to the  clonal plasma cell disorder: o Normal serum  calcium,  haemoglobin level  and serum creatinine o No bone lesions on  full skeletal X-ray  survey and/or other  imaging if  performed o No clinical or  laboratory features  of amyloidosis or  light chain  deposition disease |               |
| Smoldering or indolent myelomaf | -                                                                                                                                                                                                                                                                                                                                    | Biopsy-proven |
| Solitary plasmacytoma of bone   | plasmacytoma of bone in a  single site only. X-rays and                                                                                                                                                                                                                                                                              |               |  
| magnetic resonance  imaging and/or   |                                                                                  |
|--------------------------------------|----------------------------------------------------------------------------------|
| -                                    | FDG PET imaging (if  performed) must be  negative outside the  primary site.     |
| -                                    | The primary lesion may be  associated with a low serum  and/or urine M-component |
| -                                    | The bone marrow contains  no monoclonal plasma cells                             |
| -                                    | No other myeloma-related  organ dysfunction                                      |  
Adapted with permission from Kyle and Rajkumar, Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma..*Leukemia* 2009; 23: 3–9. aThese criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage. Stage IA
becomes smoldering or indolent myeloma.  
bIf no monoclonal protein is detected (non-secretory disease), then >/= 30% monoclonal bone marrow plasma cells and/or a biopsy-proven plasmacytoma required. cA variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma related.  
dIf a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) is the sole defining criteria, then >/= 30% plasma cells are required in the bone marrow.  
eLow is defined as serum M protein <3.0 g per 100 ml.  
fThese criteria identify Stage IA myeloma by Durie/Salmon stage.