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10.2.5 adverse events associated with

For complete information on safety, please refer to the latest version of the prescribing information for carfilzomib, which can be found at www.kyprolis.com. The safety of carfilzomib in combination with lenalidomide and dexamethasone (KRd) was evaluated in an open-label randomized study in patients with relapsed multiple myeloma. Adverse Reactions that occurred at a rate of ≥10% in the KRd arm (n=392) during the first 12 cycles of therapy are in the table below.  
| KRd Arm n (%)    |           |           |
|------------------|-----------|-----------|
| Adverse Reaction | Any Grade | ≥ Grade 3 |
| Anemia           | 138 (35)  | 53 (14)   |
| Asthenia         | 54 (14)   | 11 (3)    |  
| Back Pain                               | 41 (11)   | 4 (1)    |
|-----------------------------------------|-----------|----------|
| Bronchitis                              | 55 (14)   | 5 (1)    |
| Constipation                            | 68 (17)   | 0        |
| Cough                                   | 93 (24)   | 2 (1)    |
| Diarrhea                                | 119 (30)  | 8 (2)    |
| Dyspnea                                 | 71 (18)   | 8 (2)    |
| Fatigue                                 | 113 (29)  | 23 (6)   |
| Hyperglycemia                           | 43 (11)   | 18 (5)   |
| Hypertension                            | 41 (11)   | 12 (3)   |
| Hypocalcemia                            | 55 (14)   | 10 (3)   |
| Hypokalemia                             | 78 (20)   | 22 (6)   |
| Insomnia                                | 64 (16)   | 6 (2)    |
| Muscle spasms                           | 92 (24)   | 3 (1)    |
| Nausea                                  | 63 (16)   | 1 (0)    |
| Neutropenia                             | 124 (32)  | 104 (27) |
| Peripheral edema                        | 59 (15)   | 3 (1)    |
| Peripheral neuropathies                 | 43 (11)   | 7 (2)    |
| Pneumonia                               | 54 (14)   | 35 (9)   |
| Pyrexia                                 | 93 (24)   | 5 (1)    |
| Rash                                    | 45 (12)   | 5 (1)    |
| Thrombocytopenia                        | 100 (26)  | 58 (15)  |
| Upper Respiratory Tract Infection       | 87 (22)   | 7 (2)    |
| Venous Embolic and Thrombotic Events    | 49 (13)   | 16 (4)   |
| Viral upper respiratory tract infection | 55 (14)   | 0        |  
Laboratory abnormalities ≥ Grade 3 reported at a rate of ≥ 10% in the KRd arm included decreases in the following (% of patients): lymphocytes (46%), ANC (39%), phosphorus (31%), platelets (26%), total WBC (25%), hemoglobin (15%) and potassium (11%). Increased glucose (14%) was also reported. The following warnings are associated with the use of carfilzomib (from the August 2020 prescribing information):
- **Cardiac Toxicities:** New onset or worsening of pre-existing cardiac failure (e.g.,
congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of carfilzomib. Some events occurred in patients with normal baseline ventricular function. In clinical studies with carfilzomib, these events occurred throughout the course of carfilzomib therapy. Death due to cardiac arrest has occurred within one day of carfilzomib administration. In randomized, open-label, multicenter trials for combination therapies, the incidence of cardiac failure events was 8% and that of arrythmias was 8% (majority of which were atrial fibrillation and sinus tachycardia). In patients ≥ 75 years of age, the risk of cardiac failure is increased compared to younger patients.  
- **Acute Renal Failure:** Cases of acute renal failure have occurred in patients receiving carfilzomib. Some of these events have been fatal. Renal insufficiency adverse events (including renal failure) have occurred in approximately 9% of patients treated with carfilzomib. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received carfilzomib monotherapy. This risk was greater in patients with a baseline reduced estimated creatinine clearance (calculated using Cockcroft and Gault equation).  
- **Tumor Lysis Syndrome:** Cases of TLS, including fatal outcomes, have been reported in patients who received carfilzomib. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS.  
- **Pulmonary Toxicity:** Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in approximately 2% of patients receiving carfilzomib. Some events have been fatal.  
- **Pulmonary Hypertension:** Pulmonary arterial hypertension was reported in approximately 2% of patients treated with carfilzomib and was ≥Grade 3 in less than 1% of patients.  
- **Dyspnea:** Dyspnea was reported in 25% of patients treated with carfilzomib and was
≥Grade 3 in 4% of patients. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes.  
- **Hypertension:** Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with carfilzomib. In a randomized, open-label, multicenter trial evaluating carfilzomib in combination with KRd *versus* Rd, the incidence of hypertension events was 17% in the KRd arm *versus* 9% in the Rd arm. In a randomized, open-label, multicenter trial of Kd *versus* Vd, the incidence of hypertension events was 34% in the Kd arm *versus* 11% in the Vd arm. Some of these events have been fatal. Monitor blood pressure regularly in all patients.  
- **Venous Thrombosis:** Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with carfilzomib. In a randomized, open-label, multicenter trial evaluating KRd *versus* Rd (with thromboprophylaxis used in both arms), the incidence of venous thromboembolic events in the first 12 cycles was 13% in the KRd arm *versus* 6% in the Rd arm. In a randomized, open-label, multicenter trial of Kd *versus* Vd, the incidence of venous thromboembolic events in months 1–6 was 9% in the Kd arm *versus* 2% in the Vd arm. With carfilzomib monotherapy, the incidence of venous thromboembolic events was 2%.  
- **Infusion Reactions:** Infusion reactions including life-threatening reactions, have occurred in patients receiving carfilzomib. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of carfilzomib.  
- **Hemorrhage:** Fatal or serious cases of hemorrhage have been reported in patients treated with carfilzomib. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. The bleeding can be spontaneous, and intracranial hemorrhage has occurred without trauma. Hemorrhage has been reported in patients having either low or normal platelet counts. Hemorrhage has also been reported in patients who were not on antiplatelet therapy or anticoagulation.  
- **Thrombocytopenia:** Carfilzomib causes thrombocytopenia with platelet nadirs observed between Day 8 and Day 15 of each 28-day cycle, with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in approximately 32% of patients in clinical trials with carfilzomib.  
- **Hepatic Toxicity and Hepatic Failure:** Cases of hepatic failure, including fatal cases, have been reported (2%) during treatment with carfilzomib. Carfilzomib can cause increased serum transaminases.  
- **Thrombotic Microangiopathy:** Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received carfilzomib. Some of these events have been fatal. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop carfilzomib and evaluate. If the diagnosis of TTP/HUS is excluded, carfilzomib may be restarted. The safety of reinitiating carfilzomib therapy in patients previously experiencing TTP/HUS is not known
- **Posterior Reversible Encephalopathy Syndrome:** Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving carfilzomib. PRES, formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is a neurological disorder which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis is confirmed by neuro-radiological imaging (MRI). Discontinue carfilzomib if PRES is suspected and evaluate. The safety of reinitiating carfilzomib therapy in patients previously experiencing PRES is not known.  
- **Progressive Multifocal Leukoencephalopathy (PML):** Progressive multifocal leukoencephalopathy (PML), which can be fatal, has been reported with Kyprolis. In addition to Kyprolis, other possible contributary factors include prior or concurrent immunosuppressive therapy that may cause immunosuppression. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue Kyprolis and initiate evaluation for PML including neurology consultation.  
- **HBV Reactivation:** Cases of HBV reactivation have been reported in the clinical trial and post-marketing setting in patients receiving treatment with carfilzomib. Subjects should be tested for HBV infection before initiating treatment with carfilzomib. Subjects who are currently receiving treatment with carfilzomib and with unknown HBV status should be also be tested for HBV infection. For subjects who are carriers of HBV, prophylaxis with antivirals should be considered. Carriers of HBV who require treatment with carfilzomib should be closely monitored for signs and symptoms of active HBV infection throughout and following the end of treatment with carfilzomib. Consider consulting a specialist for subjects who test positive for HBV prior to or during treatment with carfilzomib. For subjects with active HBV reactivation, carfilzomib should be withheld until infection is adequately controlled. The safety of resuming carfilzomib after HBV reactivation is adequately controlled is not known. Therefore, investigators should weigh the risks and benefits when considering resumption of therapy in this situation.  
- Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients: In a clinical trial of 955 transplant-ineligible patients with newly diagnosed multiple myeloma randomized to carfilzomib (20/36 mg/m2 by 30-minute infusion twice weekly for four of each six-week cycle), melphalan and prednisone (KMP) or bortezomib, melphalan and prednisone (VMP), a higher incidence of fatal adverse reactions (7% versus 4%) and serious adverse reactions (50% versus 42%) were observed in the KMP arm compared to patients in the VMP arm, respectively. Patients in the KMP arm were observed to have a higher incidence of any grade adverse reactions involving cardiac failure (11% versus 4%), hypertension (25% versus 8%), acute renal failure (14% versus 6%), and dyspnea (18% versus 9%). This study did not meet its primary outcome measure of superiority in progression-free survival for the KMP arm. Carfilzomib in combination with melphalan and prednisone is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma
- **Embryo-fetal Toxicity**: Carfilzomib can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Carfilzomib administered intravenously to pregnant rabbits during organogenesis at a dose approximately 40% of the clinical dose of 27 mg/m2based on body surface area caused post-implantation loss and a decrease in fetal weight. Females of reproductive potential should avoid becoming pregnant while being treated with carfilzomib and must use contraception during treatment and for 6 months following the final dose. Males with female sexual partners of reproductive potential must use contraception during treatment with carfilzomib and for 3 months following the final dose.
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10.3 lenalidomide

For complete information, please refer to the latest version of the prescribing information for lenalidomide, which can be found at www.revlimid.com. Lenalidomide is a thalidomide analogue approved by the FDA in combination with dexamethasone for the treatment of patients with MM, and for use as maintenance therapy post ASCT.
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10.3.1 supplier/how supplied

Commercial supplies of lenalidomide will be used and charged to the subject and or their insurance provider. However, subjects in the U.S. must be enrolled into the REVLIMID Risk Evaluation and Mitigation Strategy (REMS)™ program for the procurement of lenalidomide. Lenalidomide is formulated in hard capsules containing 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg active drug for PO administration only.
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10.3.3 handling

Lenalidomide should be handled using standard precautions for the safe handling of antineoplastic agents. Latex gloves are recommended. Lenalidomide capsules should not be opened or broken.
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10.3.4 adverse events associated with

For complete information on safety, please refer to the latest version of the prescribing information for lenalidomide, which can be found at www.revlimid.com. The most common adverse reactions (≥20%) when lenalidomide is used in MM include diarrhea, fatigue, anemia, constipation, neutropenia, leukopenia, peripheral edema, insomnia, muscle cramp/spasms, abdominal pain, back pain, nausea, asthenia, pyrexia, upper respiratory tract infection, bronchitis, nasopharyngitis, gastroenteritis, cough, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia and tremor. The following warnings are associated with the use of lenalidomide **in MM**:
- **BLACK BOX WARNING: Embryo-fetal Toxicity**: Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. Because of this, lenalidomide is only available through a restricted distribution program called the REVLIMID REMS™ program.  
- **BLACK BOX WARNING: Hematologic Toxicity:** Lenalidomide can cause significant neutropenia and thrombocytopenia.  
- **BLACK BOX WARNING: Venous and Arterial Thromboembolism:** There is a significantly increased risk of venous thromboembolic events (deep vein thrombosis and pulmonary embolism), as well as risk of arterial thromboembolic events (ATE, myocardial infarction and stroke) in patients with MM receiving lenalidomide in combination with dexamethasone. Anti-thrombotic prophylaxis is recommended.  
- **Second Primary Malignancies:** In clinical trials in patients with MM receiving lenalidomide an increase of invasive second primary malignancies notably AML and MDS have been observed. The increase of cases of AML and MDS occurred predominantly in NDMM patients receiving lenalidomide in combination with oral melphalan (frequency of 5.3%) or immediately following high dose intravenous melphalan and ASCT (frequency of 7.5%).  
- Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone: In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.  
- **Hepatotoxicity:** Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with MM and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Preexisting viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors.  
- **Severe Cutaneous Reactions Including Hypersensitivity Reactions**: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS), toxic
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10.4 dexamethasone

Dexamethasone is a synthetic adrenoglucocorticoid. It is commercially available as a generic in tablet form for oral administration. It is indicated for a variety of medical conditions, including cancer. Commercial supplies of dexamethasone will be used for this study and charged to study subjects or their insurance company.
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10.4.1 storage

Dexamethasone is to be stored at controlled room temperature 20 to 25°C (68 to 77°F). Consult the package insert of the respective product for additional storage and usage instructions.
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10.4.2 summary of adverse events

See Reference [25] for a more complete summary. Also see Section 6.6.2, Table 14. The side effects from systemic glucocorticoids are usually dose and duration dependent, and can impact virtually all body systems. Common side effects include thinning of the skin, purpura, Cushingoid appearance, weight gain, sleep disturbance and mood changes.  
Hyperglycemia is common if these agents are used in patients with pre-existing diabetes or those at risk of diabetes for other reasons. Cataracts are also common with prolonged (>1 year) of glucocorticoids. Other risks of concern with glucocorticoids include an increased risk of cardiovascular disease and hypertension (particularly when glucocorticoids are prescribed in patients with pre-existing cardiac or renal disease), increased risk of peptic ulcer disease and gastritis (especially when patients are also taking nonsteroidal anti-inflammatory agents), osteoporosis, increased fracture risk, osteonecrosis, myopathy, edema, and immunosuppression with an increased risk of infection. With the exception of cataracts and some of the cardiac and bone toxicities, adverse effects from glucocorticoids are at least partially reversible upon discontinuation. epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal.  
- **Tumor Lysis Syndrome:** Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment.  
- **Impaired Stem Cell mobilization**: A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with lenalidomide has been reported.  
- **Thyroid Disorders**: Both hypothyroidism and hyperthyroidism have been reported. - **Hypersensitivity**: Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to lenalidomide has been reported.
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11. data and safety monitoring

This protocol will be monitored according to the processes in effect for all LCI investigator-initiated studies and the protocol-specific monitoring plan, and will abide by standard operating procedures (SOPs) set forth by both AH Office of Clinical and Translational Research and the LCI Clinical Trials Office. It is the responsibility of the Sponsor-Investigator to monitor the safety data for this study. The Sponsor-Investigator, Statistician, and other team members as needed will meet regularly to monitor subject consents, enrollment and retention, safety data for all subjects (including AEs for all grades and attributions, SAEs), study drug administration, and validity/integrity of the data.  
Documentation of these meetings will be kept with study records. The SponsorInvestigator will submit data to the LCI Data and Safety Monitoring Committee according to the protocol-specific Data and Safety Monitoring Plan. The Sponsor-Investigator will monitor the study accrual data regularly.
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11.2 data monitoring

This study will be organized, performed, and reported in compliance with the study protocol, SOPs of the LCI and AH Office of Clinical and Translational Research (and/or other participating institutional SOPs), the FDA, and other applicable regulations and guidelines (e.g. GCP). Subjects will be monitored by LCI Research /Data Monitors per the study-specific monitoring plan and LCI/AH SOPs for data quality. This monitoring will be done by comparing source documentation to the electronic case report forms (eCRFs). Any variation between the two data sets will be discussed with the investigator, SponsorInvestigator and/or other study team members as appropriate.  
The study database will be reviewed and checked for omissions, apparent errors, and values requiring further clarification using computerized and manual procedures. Data queries requiring clarification will be generated and addressed by the appropriate study team member. Only authorized personnel will make corrections to the study database and all corrections will be documented in an electronic audit trail. The trial site may also be subject to quality assurance audit by BMS or its designee as well as inspection by appropriate regulatory agencies. It is important for all investigators and their relevant personnel to be available during the monitoring visits and possible audits and for sufficient time to be devoted to the process.
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12. safety data collection recording

An adverse event is any untoward medical occurrence in a study subject who is administered any drug that does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Pre-existing conditions that increase in frequency or severity or change in nature during or as a consequence of use of a drug in human clinical trials are also considered adverse events. Adverse events may also include pre- or post-treatment complications that occur as a result of protocol mandated procedures (e.g., invasive procedures such as biopsies). An increase in grade to a pre-existing CTCAE toxicity grade present at the time of study treatment initiation will be recorded as an AE. Changes in vital signs, ECG, physical examination and laboratory test results will be recorded as an AE if they are judged clinically significant by the investigator and/or require a medical intervention or dose modification. Any continuing medical condition or clinically significant laboratory abnormality with an onset date before the first date of study treatment administration should be considered pre-existing and should be documented.
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an ae does not include

- relapse or progression of the underlying malignant disease; - medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion);
NOTE: the condition that leads to the procedure may be an adverse event;
- situations where an untoward medical occurrence has not occurred (e.g., hospitalization for elective surgery, social and/or convenience admissions);
The severity of adverse events should be classified and recorded according to the CTCAE version 4.03.
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12.1.2 suspected adverse reaction (sar)

A suspected adverse reaction (SAR) is any AE for which there is a *reasonable possibility* that the drug is the cause. *Reasonable possibility* means that there is evidence to suggest a causal relationship between the drug and the AE. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug. Causality assessment to a study drug is a medical judgment made in consideration of the following factors: temporal relationship of the AE to study drug exposure, known mechanism of action or side effect profile of study treatment, other recent or concomitant drug exposures, normal clinical course of the disease under investigation, and any other underlying or concurrent medical conditions. Other factors to consider in considering drug as the cause of the AE:
- Single occurrence of an uncommon event known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome)
- One or more occurrences of an event not commonly associated with drug exposure, but otherwise uncommon in the population (e.g., tendon rupture); often more than once occurrence from one or multiple studies would be needed before the Sponsor-Investigator could determine that there is *reasonable possibility* that the drug caused the event.  
- An aggregate analysis of specific events observed in a clinical trial that indicates the events occur more frequently in the drug treatment group than in a concurrent or historical control group
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12.1.3 adverse reaction

An adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions where there is reason to conclude that the drug caused the event.
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12.1.4 serious ae or sar

An AE or SAR is to be considered serious if the investigator deems it as such and the event results in any of the following outcomes:
- Death (fatal); - Life-threatening situation (subject is at immediate risk of death); - Persistent or significant disability/incapacity;
- Requires or prolongs inpatient hospitalization1;
- A congenital anomaly/birth defect in the offspring of a subject who received study drug;
- Based upon appropriate medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent one of the afore listed outcomes from occurring (e.g. intensive treatment in an emergency room without hospitalization, blood dyscrasias or convulsions that do not result in hospitalization, development of drug dependency or drug abuse). **NOTE:** Potential drug induced liver injury (DILI2) is also considered an important medical event.  
- Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study drug is an SAE.  
- Although pregnancy3, overdose4, and cancer are not always serious by regulatory definition, these events must be handled as SAEs.  
1Hospitalizations for study drug administration, protocol-related procedures, palliative or hospice care, or placement of an indwelling catheter, unless associated with other serious events, will not be recorded as SAEs. Other hospitalizations planned at the beginning of the trial also do not need to be reported as an SAE.
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2potential drug induced liver injury

Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur prior to the reporting of a potential DILI event. All occurrences of potential  
DILIs, meeting the defined criteria below must be reported as SAEs. Potential DILI is defined as 1. ALT or AST elevation > 3 X ULN AND 2. Total bilirubin > 2 X ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase) AND
3. No other immediately apparent possible causes of AST/ALT elevation and hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the administration of other drug(s) known to be hepatotoxic.
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3pregnancy

If, following initiation of study treatment, it is subsequently discovered that a study subject is pregnant or may have been pregnant at the time of study treatment exposure, including during at least 5 half-lives after product administration, the pregnancy must be reported as an SAE.
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4overdose

An overdose is defined as the accidental or intentional administration of any dose of a product that is considered both excessive and medically important. All occurrences of overdose must be reported as an SAE.
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12.1.5 unexpected ae (ae or

An AE or SAR (whether serious or not) is considered unexpected if the specificity or severity of it is not consistent with the applicable product information (e.g., IB for an unapproved investigational product or package insert/summary of product characteristics for an approved product). Unexpected also refers to AEs or SARs that are mentioned in the IB as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.
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12.1.6 other safety considerations

Any significant worsening noted during interim or final physical examinations, electrocardiograms, x-rays, and any other potential safety assessments, whether or not these procedures are required by the protocol, should also be recorded as a non-serious or serious AE, as appropriate, and reported accordingly.
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12.1.7 unanticipated problem (uap)

An UAP is any incidence, experience or outcome that is unexpected, given the information provided in research-related documentation (e.g., IB, informed consent) and the study population characteristics that is related or possibly related to participation in the research study and places the participant at an increased risk. By this definition, any event that meets the criteria defined in Section 12.1.5 would meet the criteria for a UAP. However other events may also meet the criteria for a UAP, e.g., a lost or stolen laptop computer that contains sensitive study information.
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12.2 attribution

The relationship to study treatment should be assessed using the following definitions:  
| Definite   | The AE is clearly related to the drug(s) under investigation     |
|------------|------------------------------------------------------------------|
| Probable   | The AE is likely related to the drug(s) under investigation      |
| Possible   | The AE possibly related to the drug(s) under investigation       |
| Unlikely   | The AE is doubtfully related to the drug(s) under investigation  |
| Unrelated  | The AE is clearly not related to the drug(s) under investigation |  
The investigator is responsible for verifying and providing source documentation for all AEs and assigning the attribution for each event for all subjects enrolled on the trial.
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12.3 timing and reporting 12.3.1

All AEs, (including event name, grade, start/stop date and attribution) will be documented. AEs will be collected from the time of D1 of treatment until 90 days after last dose of study treatment. If the subject initiates subsequent anti-cancer therapy prior to 90 days after cessation of study treatment, the reporting period is through 30 days following cessation of study treatment or until the start of the subsequent anti-cancer therapy, whichever is later.
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12.3.2 pregnancy

All initial reports of pregnancy must be reported as an SAE to BMS Worldwide Safety (see Section 12.3.3.2) by the Sponsor-Investigator or designee within 24 hours of becoming aware of the event using the BMS Pregnancy Surveillance Form (provided as a document separate from this protocol). Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomaly, ectopic pregnancy) are considered SAEs and must be reported as such. Any subject who becomes pregnant during the study must be discontinued promptly from all protocol mandated treatment and followed up per protocol. Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, where applicable, offspring information must be reported on the Pregnancy Surveillance Form [provided upon request from BMS]. Any pregnancy that occurs in a female partner of a male study participant should be reported to BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
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12.3.3 saes

All SAEs, whether related to study treatment or not, including those thought to be associated with protocol-specified procedures, will be collected. SAEs will be reported after informed consent and continuing through 90 days after the discontinuation of all protocol mandated therapy. If the subject initiates subsequent anti-cancer therapy prior to 90 days after cessation of study treatment, the reporting period is through 60 days following cessation of study treatment or until the start of the subsequent anti-cancer therapy, whichever is later. Any SAE occurring after these time periods that is believed to be related to study drug(s) or protocol-specified procedure should also be reported. It is the responsibility of the Sponsor-Investigator, investigators and the protocol team to ensure SAEs are reported according to the Code of Federal Regulations (CFR), GCP, the protocol guidelines, IRB, and FDA policy. SAEs will be followed until clinical recovery is complete and laboratory tests have returned to baseline, until progression has been stabilized, or until there has been acceptable resolution of the event. This may at times cause the follow-up period for SAEs to be greater than 90 days. Similarly, the Sponsor-Investigator is responsible for following the subject during the required follow-up period even if the subject lives elsewhere or has been released from his or her care and is being treated under another service at LCI.
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12.3.3.1 reporting to sponsor-investigator

All SAEs (whether considered related or not, expected or not) and pregnancies must be reported to the Sponsor-Investigator within 1 business day of awareness. When new significant information becomes available, a follow-up report must be reported to the Sponsor-Investigator within 1 business day of awareness.  
In the event of an unanticipated problem (UAP) as defined in Section 12.1.7 or lifethreatening complication the Sponsor-Investigator must be notified via email immediately after awareness.
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12.3.3.2 reporting to bms worldwide

All SAEs whether considered related or not, expected or not, and pregnancies must be reported to BMS within 24 hours of Sponsor-Investigator awareness. SAEs are reportable to BMS from informed consent through 60 days after last dose of study treatment. SAEs must be recorded on a BMS approved form; pregnancies must be reported on a Pregnancy Surveillance Form.  
SAE Email Address: Worldwide.Safety@BMS.com SAE **Facsimile Number:** 609-818-3804 If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE reports should include the same investigator term(s) initially reported.) If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or designee) using the same procedure used for transmitting the initial SAE report. NOTE: if a report is submitted to the FDA (see Section 12.3.5), a simultaneous copy should be submitted to BMS.
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12.3.4 reporting to the irb

All events occurring during the conduct of a protocol and meeting the definition of an SAE or UAP will be reported to the IRB per IRB reporting requirements.
protocol signature page phase ii
12.3.5 reporting to the fda

According to CFR 312.32, the Sponsor-Investigator, or designee, will be responsible for notifying the FDA (via Form FDA 3500 (MedWatch Form)) and all participating investigators of any **unexpected fatal or life-threatening events** possibly related with the use of the study drug (drugs) as soon as possible, but in no case later than 7 calendar days after the Sponsor's initial receipt of the information. For all other serious and unexpected safety events, the Sponsor-Investigator, or designee, will notify the FDA within 15 calendar days. It is the responsibility of the Sponsor-Investigator, investigators, and the Protocol Team to ensure SAEs are reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, Institutional Review Board, and FDA policy.
protocol signature page phase ii
13. disease evaluation 13.1 imwg

Abbreviations: NGF=next-generation flow. NGS=next-generation sequencing. FLC=free light chain. M-protein=myeloma protein. SPD=sum of the products of the maximal perpendicular diameters of measured lesions. CRAB features=calcium elevation, renal failure, anemia, lytic bone lesions. FCM=flow cytometry. SUVmax=maximum standardised uptake value.  
MFC=multiparameter flow cytometry. ⁸F-FDG PET=⁸F-fluorodeoxyglucose PET. ASCT=autologous stem cell transplantation.
protocol signature page phase ii
imwg mrd criteria (requires a

| Sustained MRDnegative   | MRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined below,  confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify  the duration of negativity (e.g., MRD-negative at 5 years)†   |
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| Flow MRD-negative                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Absence of phenotypically aberrant clonal plasma cells by NGF‡ on bone marrow aspirates  using the EuroFlow standard operation procedure for MRD detection in MM (or validated  equivalent method) with a minimum sensitivity of 1 in 10⁵ nucleated cells or higher                                                                          |
| Sequencing MRDnegative                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a  clone is defined as less than two identical sequencing reads obtained after DNA sequencing  of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent  method) with a minimum sensitivity of 1 in 10⁵ nucleated cells§or higher |
| Imaging-positive                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | MRD negativity as defined by NGF or NGS plus disappearance of every area of increased                                                                                                                                                                                                                                                        |
| MRD-negative                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | tracer uptake found at baseline or a preceding PET/CT or decrease to less mediastinal blood  pool SUV or decrease to less than that of surrounding normal tissue¶                                                                                                                                                                            |
| Standard IMWG Response Criteria||; NOTE: see [22, 30 & 31] for additional details Stringent Complete  Response (sCR) CR as defined below plus:  - normal FLC ratio** and  - absence of clonal cells in bone marrow by immunohistochemistry(κ/λ ratio ≤4:1 or  ≥1:2 for κ and λ patients, respectively, after counting ≥100 plasma cells)†† Complete Response - Negative immunofixation on the serum and urine ‡‡ and (CR) - disappearance of any soft tissue plasmacytomas and  - < 5% plasma cells in bone marrow aspirates.  Very Good Partial  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.  Partial Response - ≥ 50% reduction of serum M-protein plus reduction in 24 hour urinary M-protein  (PR) by > 90% or to < 200 mg/24 h - If the serum and urine M-protein are unmeasurable, 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 measurable, > 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 (SPD) §§of soft tissue plasmacytomas is also required Minimal Response - ≥25% but ≤49% reduction of serum M-protein and  - reduction in 24-h urine M-protein by 50–89%.  In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size  (SPD)§§ of soft tissue plasmacytomas is also required Stable Disease (SD) - Not meeting criteria for CR, VGPR, PR, minimal response, or PD Progressive disease Any one or more of the following criteria: (PD)¶¶,|||| - Increase of 25% from lowest confirmed response value in one or more of the  following criteria: |                                                                                                                                                                                                                                                                                                                                              |  
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| o                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Serum M-protein (absolute increase must be > 0.5 g/dL)                                                                                                                                                             |
| o                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Serum M-protein increase ≥ 1 g/dL, if the lowest M component was ≥ 5 g/dL;                                                                                                                                         |
| o                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Urine M-protein ( absolute increase must be > 200 mg/24 h);                                                                                                                                                        |
| o                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | In patients without measurable serum and urine M-protein levels, the difference  between involved and uninvolved FLC levels. (absolute increase must be > 10  mg/dL);                                              |
| o                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | In patients without measurable serum and urine M-protein levels and without  measurable involved FLC levels, bone marrow plasma-cell percentage  irrespective of baseline status (absolute increase must be ≥ 10%) |
| o                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Appearance of a new lesion(s), ≥50% increase from nadir in SPD§§ of >1 lesion,  or ≥50% increase in the longest diameter of a previous lesion >1 cm in short  axis;                                                |
| o                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | ≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if this  is the only measure of disease=                                                                                                   |
| Clinical Relapse                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Clinical relapse requires one or more of the following criteria: - Direct indicators of increasing disease and/or end organ dysfunction (CRAB  features) related to the underlying clonal plasma-cell proliferative disorder. It is not  used in calculation of TTP or PFS but is listed as something that can be reported  optionally or for use in clinical practice - Development of new soft tissue plasmacytomas or bone lesions (osteoporotic  fractures do not constitute progression) - Definite increase in the size of existing plasmacytomas or bone lesions. A definite  increase is defined as a 50% (and ≥1 cm) increase as measured serially by the SPD§§ of the measurable lesion - Hypercalcaemia (>11 mg/dL) - Decrease in hemoglobin of ≥2 g/dL not related to therapy or other non-myelomarelated conditions - Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and  attributable to myeloma; - Hyperviscosity related to serum paraprotein                                                                                                                                                                                                                    |
| For MRD assessment, the first bone marrow aspirate should be sent to MRD (not for morphology) and this sample  should be taken in one draw with a volume of minimally 2 mL (to obtain sufficient cells), but maximally 4–5 mL to avoid hemodilution. *All response categories require two consecutive assessments made at any time before the institution of any new  therapy; for MRD there is no need for two consecutive assessments, but information on MRD after each treatment  stage is recommended (e.g. after induction, high-dose therapy/ASCT, consolidation, maintenance). MRD tests should  be initiated only at the time of suspected complete response. All categories of response and MRD require no known  evidence of progressive or new bone lesions or extra medullary plasmacytomas if radiographic studies were  performed. However, radiographic studies are not required to satisfy these response requirements except for the  requirement of FDG PET if imaging MRD-negative status is reported.  †Sustained MRD negativity when reported should also annotate the method used (e.g. sustained flow MRD-negative,  sustained sequencing MRD-negative).  ‡Bone marrow MFC should follow NGF guidelines26 . The reference NGF method is an eight-colour two-tube  approach, which has been extensively validated. The two-tube approach improves reliability, consistency, and  sensitivity because of the acquisition of a greater number of cells. The eight-colour technology is widely available |                                                                                                                                                                                                                    |  
globally and the NGF method has already been adopted in many flow laboratories worldwide. The complete eightcolour method is most efficient using a lyophilised mixture of antibodies which reduces errors, time, and costs. 5 million cells should be assessed. The FCM method employed should have a sensitivity of detection of at least 1 in 10⁵
plasma cells.  
§DNA sequencing assay on bone marrow aspirate should use a validated assay such as LymphoSIGHT (Sequenta).  
¶Criteria used by Zamagni and colleagues27 and expert panel (IMPetUs; Italian Myeloma criteria for PET Use)28,29.  
Baseline positive lesions were identified by presence of focal areas of increased uptake within bones, with or without any underlying lesion identified by CT and present on at least two consecutive slices. Alternatively, an SUVmax=2.5 within osteolytic CT areas >1 cm in size, or SUVmax=1.5 within osteolytic CT areas ≤1 cm in size were considered positive. Imaging should be performed once MRD negativity is determined by MFC or NGS.  
||Derived from international uniform response criteria for multiple myeloma. 30Minor response definition and clarifications derived from Rajkumar and colleagues31. When the only method to measure disease is by serum FLC
levels: complete response can be defined as a normal FLC ratio of 0.26 to 1.65 in addition to the complete response criteria listed previously. Very good partial response in such patients requires a ≥90% decrease in the difference between involved and uninvolved FLC levels. All response categories require two consecutive assessments made at any time before the institution of any new therapy; all categories also require no known evidence of progressive or new bone lesions or extramedullary plasmacytomas if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments do not need to be confirmed. Each category, except for stable disease, will be considered unconfirmed until the confirmatory test is performed. The date of the initial test is considered as the date of response for evaluation of time dependent outcomes such as duration of response. **All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based on results obtained with the validated Freelite test (Binding Site, Birmingham, UK). ††Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ/L ratio. An abnormal κ/λ ratio by immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is κ/λ of >4:1 or <1:2. ‡‡Special attention should be given to the emergence of a different monoclonal protein following treatment, especially in the setting of patients having achieved a conventional complete response, often related to oligoclonal reconstitution of the immune system. These bands typically disappear over time and in some studies have been associated with a better outcome. Also, appearance of monoclonal IgG κ in patients receiving monoclonal antibodies should be differentiated from the therapeutic antibody. §§Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or dedicated CT scans where applicable. For patients with only skin involvement, skin lesions should be measured with a ruler.  
Measurement of tumor size will be determined by the SPD. ¶¶Positive immunofixation alone in a patient previously classified as achieving a complete response will not be considered progression. For purposes of calculating time to progression and progression-free survival, patients who have achieved a complete response and are MRD-negative should be evaluated using criteria listed for progressive disease. Criteria for relapse from a complete response or relapse from MRD should be used only when calculating disease-free survival.  
||||In the case where a value is felt to be a spurious result per physician discretion (e.g. a possible laboratory error), that value will not be considered when determining the lowest value.
14. statistical considerations
14.1.2 enrollment (on study) date

The date of initiation of study treatment on Cycle 1, Day 1.
14. statistical considerations
14.1.3 treatment discontinuation date

The date the investigator makes the decision to discontinue elotuzumab. See Section 9 for criteria for discontinuation of treatment.
14. statistical considerations
14.2 sample size determination

The primary objective of this study is to evaluate the very good partial response or better (VGPR+) rate in subjects treated with elotuzumab in addition to the combination of carfilzomib, lenalidomde, and dexamethasone (KRd) in relapsed or refractory multiple myeloma subjects. This will be evaluated in terms of the percent of subjects who achieve a VGPR+ to induction therapy. Wang [6] reported a VGPR+ rate of approximately 40% in this patient population treated with KRd. See Section 1.4 for the rationale for using this as the historical control. This study will be used to test the null hypothesis that the VGPR+ rate in subjects treated with elotuzumab+KRd is less than or equal to 40%. Forty (40) response evaluable subjects will be enrolled, and if at least 21 of 40 subjects achieve a VGPR+, the null hypothesis will be rejected. The design will provide 90% power with a 1-sided alpha = 0.10 significance level, assuming the true VGPR+ rate is 60%. An improvement from 40% to 60% in the VGPR+ rate is considered clinically relevant.
14. statistical considerations
14.3 endpoint definitions 14.3.1 very

VGPR+ will be determined for each subject as a binary variable indicating whether or not the subject achieved a VGPR or better to induction, as determined by the IMWG 2016 response criteria (see Section 13.1).
14. statistical considerations
14.3.2 objective response

Objective response will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of PR or better as determined by the IMWG 2016 response criteria.
14. statistical considerations
14.3.3 overall survival

Overall survival (OS) is defined as the duration from enrollment to the study (treatment start date) to the date of death from any cause. Subjects who are alive or lost to followup at the time of the analysis will be censored at the last known date they were alive.
14. statistical considerations
14.3.4 progression free survival

Progression free survival (PFS) is defined as the duration of time from enrollment to the study (treatment start date) to first occurrence of either PD or death. Disease progression must be objectively determined per IMWG 2016 criteria (see Section 13.1), where the date of progression is the date of the last assessment that identified PD. If the subject died without documented disease progression, the date of progression will be the date of death. For surviving subjects who do not have documented disease progression, PFS will be censored at the date of last disease assessment. For subjects who receive subsequent anti-cancer therapy prior to documented disease progression, PFS will be censored at the date of last disease assessment prior to the commencement of subsequent therapy. Subjects who have an initial PFS event immediately following 2 or more consecutive missed disease assessments will be censored at the date of the last assessment prior to those missed assessments. For participants with only one missed assessment, the documented PD status and assessment date will be used.
14. statistical considerations
14.3.5 time to disease progression

Time to disease progression (TTP) will be calculated in the same fashion as described for PFS with the exception that for subjects who die for causes other than disease progression, TTP will be censored at the date of the other cause mortality. Otherwise, the censoring mechanism for TTP will be the same as previously described for PFS.
14. statistical considerations
14.3.6 duration of response

Duration of response (DoR) will be calculated for each subject with response for the VGPR+ and overall response endpoints. The DoR intervals will be calculated from the time of the first assessment that identified response until disease progression or death. The censoring mechanism for DoR will be the same as described for PFS.
14. statistical considerations
14.3.7 time to next treatment

Time to next treatment (TTNT) will be calculated from the time of treatment start until the start of the first subsequent anti-cancer therapy after all protocol directed therapy is completed. For surviving subjects who do not receive subsequent therapy, TTNT will be censored at the last contact date. For subjects who die before beginning subsequent anticancer therapy, TTNT will be censored at the date of death.
14. statistical considerations
14.3.8 safety endpoints

Safety endpoints will include treatment administration (cumulative dose, dose intensity, and relative dose intensity—dose intensity as a percent of intended dose intensity), AEs, SAEs, and deaths while on study therapy.
14. statistical considerations
14.4 analysis populations

Analyses of response endpoints (response evaluable population) will be conducted on the population of subjects who initiate treatment with elotuzumab and who have measurable disease at baseline. Analyses of other efficacy and safety endpoints will be conducted on the population of subjects who initiate treatment with elotuzumab. Exploratory analyses will be conducted on the population of subjects who initiate treatment with elotuzumab treatment and who have available biomarker data.
14. statistical considerations
14.5 analysis methods 14.5.1 timing

The primary analysis will occur after VGPR+ status (yes or no) has been determined for all subjects. Secondary endpoints will also be assessed at the time of the primary analyses. Updated analyses will be conducted after the PFS censoring rate reaches 20% or when all surviving subjects who are not lost to follow up or have not been withdrawn from the study have been on study for at least 3 years, whichever occurs first. A final analysis will be conducted after the overall survival censoring rate reaches 20% or after all surviving subjects who are not lost to follow up or have not been withdrawn from the study have been on study for at least 5 years, whichever occurs first.
14. statistical considerations
14.5.2 subject disposition

A disposition summary of all consenting subjects will be provided. This will include a summary of subjects who consented, were treated, discontinued treatment, died, and were lost to follow-up or withdrew consent.
14. statistical considerations
14.5.3 baseline subject and disease

A summary of subject demographics and disease-related characteristics will be summarized and evaluated. These results will be qualitatively compared to patient and disease characteristics in the same patient population that have been previously reported.
14. statistical considerations
14.5.4 primary analysis

The frequency and proportion of subjects experiencing a VGPR+ will be calculated. A corresponding 95% confidence interval will be estimated using the Clopper-Pearson method. A one-sided test for binomial proportions using the rejection region described in the sample size section (Section 14.2) will be carried out, testing the null hypothesis that the VGPR+ rate is less than or equal to 40%. Based on the design and corresponding sample size calculations described in Section 14.2, if at least 21 subjects experience a VGPR+, the null hypothesis can be rejected.  
Logistic regression techniques will be used to correlate VGRR+ rate with baseline subject and disease characteristics, and results from biomarker studies as previously described. This will include univariate and multivariable regression model techniques to identify individual and independent prognostic factors.
14. statistical considerations
14.5.5 secondary analysis

The frequencies and proportions of overall response will be calculated. Corresponding 95% confidence intervals will be estimated using the Clopper-Pearson method. OS, PFS, TTP, TTNT, and DoR endpoints will be analyzed using Kaplan Meier techniques. Selected landmarks will be estimated and reported. Logistic regression models and Cox proportional hazards models will be used to analyze the treatment response endpoints as functions of baseline subject and disease characteristics, and results from biomarker studies as previously described. The percent of subjects achieving MRD negative status will be summarized. Subgroup analyses will be conducted for selected efficacy endpoints on the subset of MRD negative subjects (i.e. time to event endpoints).
14. statistical considerations
14.5.6 safety analysis

Incident rates for treatment-emergent adverse events, adverse events leading to study drug discontinuation, SAEs and deaths while on study therapy will be summarized. Treatment-emergent adverse events are defined as follows:
- An adverse event that occurs after treatment start that was not present at the time of treatment start; OR
- An adverse event that increases in severity after treatment start if the event was present at the time of treatment start.  
Cumulative doses will be calculated for each subject (for elotuzumab, carfilzomib and lenalidomide) in both absolute terms and as a percent of expected cumulative dose (relative dose intensity). Cumulative dose and relative dose intensity will then be summarized for the study arm.
14. statistical considerations
15. study completion or termination

The study will be considered complete when one or more of the following conditions is met:
- All subjects have died and/or are withdrawn from the study
- All subjects have discontinued from the study - The IRB, FDA, LCI DSMC, or Sponsor-Investigator discontinues the study because of safety considerations
- The Sponsor-Investigator defines an administrative or clinical cut-off date
14. statistical considerations
15.2 termination

The study will be terminated when one or more of the following conditions occur:
- If risk-benefit ratio becomes unacceptable owing to, for example, o Safety findings from this study (e.g. SAEs)
o Results of any interim analysis o Results of parallel clinical studies o Results of parallel animal studies (e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).  
o If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol compliance) does not suggest a proper completion of the trial within a reasonable time frame.  
- The Sponsor-Investigator has decided to close the trial at any site and at any time For any of the above closures, the following applies:
- Closures should occur only after consultation between involved parties.  
- All affected institutions must be informed as applicable according to local law.  
- In case of a partial study closure, ongoing subjects, including those in follow- up, must be taken care of in an ethical manner.
14. statistical considerations
16. study management 16.1 irb

The final study protocol and the final version of the informed consent form(s) must be approved in writing by the Sponsor IRB. The Sponsor-Investigator is responsible for informing the Sponsor IRB of any amendment to the protocol in accordance with local requirements. The protocol must be re-approved by the IRB annually, as local regulations require.
14. statistical considerations
16.2 informed consent

Before recruitment and enrollment onto this study, the subject will be given a full explanation of the study and will be given the opportunity to review the consent form. Prior to a subject's participation in the trial, the written informed consent form should be signed and personally dated by the subject and by the person who conducted the informed consent discussion.
14. statistical considerations
16.3 protocol adherence

Except for an emergency situation in which proper care for the protection, safety, and wellbeing of the study subject requires alternative treatment, the study shall be conducted exactly as described in the approved protocol.
14. statistical considerations
16.4 changes to the protocol

If it is necessary for the study protocol to be amended and/or the informed consent revised, the amendment or a new version of the study protocol (amended protocol) and/or the revised informed consent must be approved by the Sponsor-Investigator, funding company(ies) (if required by the contract(s), the FDA and the Sponsor IRB.
14. statistical considerations
16.4.2 emergency modification

The Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial subjects without prior approval from applicable agencies. As soon as possible, the implemented deviation or change, the reasons for it and if appropriate the proposed protocol amendment should be submitted to the appropriate agencies. Any deviations from the protocol must be explained and documented by the investigator.
14. statistical considerations
16.5 other protocol deviations

If a deviation occurs, the event should be reported to the Sponsor-Investigator via entry in the CTMS no later than 10 business days after awareness. Protocol deviations that, in the Investigator's judgment, potentially caused harm to participants or others or indicates that the participants or others are at an increased risk of harm, or has adversely impacted data integrity will be reported promptly to the SponsorInvestigator and IRB per IRB reporting requirements.  
NOTE: Planned protocol deviations will be submitted to the FDA for prior approval only if the deviation affects the scientific validity of the study and/or the rights, safety, or welfare of subjects.
14. statistical considerations
16.6 retention of records

Essential documentation (e.g. AEs, records of study drug receipt and dispensation), including all IRB correspondence, will be retained for at least 2 years after the investigation is completed. Documentation will be readily available upon request.
14. statistical considerations
16.7 ethical and legal conduct

The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation of this study, are designed to ensure that the Investigator abide by GCP guidelines. The study will also be carried out in full conformity with Regulations for the Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and/or the ICH E6 and in keeping with applicable local law(s) and regulation(s). Documented approval from appropriate agencies (e.g. DSMC, IRB, FDA) will be obtained for all participating centers before the start of the study, according to GCP, local laws, regulations and organizations. Strict adherence to all specifications laid down in this protocol is required for all aspects of study conduct; the investigators may not modify or alter the procedures described in this protocol. The Sponsor-Investigator is responsible for the conduct of the clinical trial at the sites in accordance with Title 21 of the CFR and/or the Declaration of Helsinki. The SponsorInvestigator is responsible for overseeing the treatment of all study subjects. The SponsorInvestigator must assure that all study site personnel, including sub-investigators and other study staff members, adhere to the study protocol and all applicable regulations and guidelines regarding clinical trials both during and after study completion. The Sponsor-Investigator will be responsible for assuring that all the required data will be collected and properly documented.
14. statistical considerations
16.8 confidentiality of records

All records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available.
14. statistical considerations
16.9 compliance with clinicaltrials.gov

The Sponsor-Investigator is solely responsible for determining whether the trial and its results are subject to the requirements for submission to ClinicalTrials.gov (http://www.clinicaltrials.gov).  
67
14. statistical considerations
17. references

1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Multiple Myeloma.  
Version 3.2017.  
2. 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.  
3. Arastu-Kapur S, Shenk K, Parlati F et al. Non-proteasomal targets of proteasome inhibitors bortezomib and carfilzomib. Blood (ASH Annual Meeting Abstracts), Nov 2008; 112: abstract \#2657.  
4. Shaughnessy J, Qu P, Usmani S, et al. Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with Total Therapy 3. Blood 2011;118(13):3512-24.  
5. Niesvizky R, Martin TG 3rd, Bensinger WI, et al. Phase Ib dose-escalation study (PX-171006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Clin Cancer Res. 2013;19(8):2248-2256.  
6. Wang M, Martin T, Bensinger W et al. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood. 2013;122(18):3122-3128.  
7. Stewart AK, Rajkumar SV, Dimopoulos MA et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152.  
8. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 14:2775–2784, 2008 9. Elotuzumab: From mechanism to meaningful results in multiple myeloma. Bristol-Myers Squibb Company. Princeton, NJ. June 2015. Document Control No. 930089832.  
10. Tai YT, Dillon M, Song W, et. al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008;112:1329-1337.  
11. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzomab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621-631.  
12. Jakubowiak AJ, Benson DM, Bensinger W et al. Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/ refractory multiple myeloma. J Clin Oncol. 2012;30:1960-1965.  
13. Jakubowiak A, Offidani M, Pegourie B et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood 2016;127:2833-2840.  
14. Landgren O, Hultcrantz M, Lesokhin AM, et al: Weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy provides unprecedented MRD negativity rates in newly diagnosed multiple myeloma: A clinical and correlative phase 2 study. 2019 ASH Annual Meeting & Exposition. Abstract 862. Presented December 9, 2019.  
15. Costa LJ, Chhabra S et al: Daratumumab, carfilzomib, lenalidomide and dexamethasone
(Dara-KrdD) Induction, Autologous Transplantation and Post-Transplant, ResponseAdapted, Measurable Residual Disease (MRD)-Based Dara-Krd Consolidation in Patients with Newly Diagnosed Multiple Myeloma. 2019 ASH Annual Meeting & Exposition.  
Abstract 860. Presented December 9, 2019.  
16. Yang G, Gao M, Zhang Y et al. Carfilzomib enhances natural killer cell-mediated lysis of myeloma linked with decreasing expression of HLA class I. Oncotarget 2015:6(29):2698226994.  
17. Braga WMT, Atanackovic D, Colleoni GWB. The role of regulatory T cells and TH17 cells in multiple myeloma. Clin Dev Immunol 2012; 1-4.  
18. Hsu AK, Quach H, Tai T et al. The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy. Blood 2011;117(5):1605-1613.  
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expression during T cell activation: an insight into the optimum application of glucocorticoids in anti-cancer therapy. BMC Immunology 2015:16:39, 1-9.  
20. Guo H, Cruz-Munoz ME, Wu N et al. Immune cell inhibition by SLAMF7 is mediated by a mechanism requiring SRC kinases, CD45, and SHIP-1 that is defective in multiple myeloma cells. Mol Cell Biol. 2015; 35(1):41-51.  
21. Balasa B, Yun R, Belmar NA et al. Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-α pathways. Cancer Immunol Immunother. 2015;64(1):61-73.  
22. Kumar S, Paiva B, Anderson KC et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016 Aug;17(8):e328-46.  
23. Mahnke, Y. D., Beddall, M. H., Roederer, M. OMIP-017: Human CD4+helper T-cell subsets including follicular helper cells. Cytometry 2013; 83A: 439–440.  
24. Eller, M. A., Currier, J. R. OMIP-007: Phenotypic analysis of human natural killer cells.  
Cytometry 2012;81A: 447–449.  
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26. Sarasquete ME, Garcia-Sanz R, Gonzalez D, et al. Minimal residual disease monitoring in multiple myeloma: a comparison between allelic-specific oligonucleotide real-time quantitative polymerase chain reaction and flow cytometry. *Haematologica* 2005; 90: 136572 27. Zamagni E, Nanni C, Mancuso K, et al. PET/CT improves the definition of complete response and allows to detect otherwise unidentifiable skeletal progression in multiple myeloma. *Clin Cancer Res* 2015; 21: 4384–90.  
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14. statistical considerations
18. appendices 18.1 appendix a

| Grade                                                                                                                                                       | Description                                                                                                                                                                             |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0                                                                                                                                                           | Normal activity. Fully active, able to carry on all pre-disease  performance without restriction.                                                                                       |
| 1                                                                                                                                                           | Symptoms, but ambulatory. Restricted in physically strenuous  activity, but ambulatory and able to carry out work of a light or  sedentary nature (e.g., light housework, office work). |
| 2                                                                                                                                                           | In bed <50% of the time. Capable of only limited self-care,  confined to bed or chair more than 50% of waking hours.                                                                    |
| 3                                                                                                                                                           | In bed >50% of the time. Capable of only limited self-care,  confined to bed or chair more than 50% of waking hours.                                                                    |
| 4                                                                                                                                                           | 100% bedridden. Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.                                                                                                                                                                                         |
| 5                                                                                                                                                           | Dead.                                                                                                                                                                                   |
| Reference: Oken MM, Creech RH, Hormey RH et al. Toxicity and Response Criteria of the  Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5:649-655. |                                                                                                                                                                                         |  
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14. statistical considerations
18.2 appendix b cockcroft-gault equation

Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL
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14. statistical considerations
18.3 appendix c nyha classification

| Class                                                                         | Description                                                                                                                                                                                                                                                           |
|-------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| I                                                                             | Subjects with cardiac disease but without resulting limitations of  physical activity. Ordinary physical activity does not cause undue  fatigue, palpitation, dyspnea, or anginal pain.                                                                               |
| II                                                                            | Subjects with cardiac disease resulting in slight limitation of physical  activity. They are comfortable at rest. Ordinary physical activity  results in fatigue, palpitation, dyspnea, or anginal pain.                                                              |
| III                                                                           | Subjects with cardiac disease resulting in marked limitation of  physical activity. They are comfortable at rest. Less than ordinary  physical activity causes fatigue, palpitation, dyspnea, or anginal pain.                                                        |
| IV                                                                            | Subjects with cardiac disease resulting in inability to carry on  physical activity without discomfort. Symptoms of cardiac  insufficiency or of the anginal syndrome may be present event at rest.  If any physical activity is undertaken, discomfort is increased. |
| Excerpt from Oxford Textbook of Medicine. Vol. 2, p.2228. Oxford Press. 1997. |                                                                                                                                                                                                                                                                       |  
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