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8.2.8 ordering

Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their participation in this trial at no charge to them or their insurance providers. Lenalidomide will be provided in accordance with the Celgene Corporation's Revlimid REMS® program. Per standard Revlimid REMS® program requirements, all physicians who prescribe lenalidomide for research subjects enrolled into this trial, and all research subjects enrolled into this trial, must be registered in, and must comply with, all requirements of the Revlimid REMS® program. Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site. Only enough lenalidomide for one cycle of therapy will be supplied to the patient each **cycle**. Lenalidomide will be shipped directly to the clinic site. Bottles will contain a sufficient number of capsules for one cycle of dosing. A study specific order form will be provided by the lead site.
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8.2.9 accountability

The Investigator or designee is responsible for taking an inventory of each shipment of study drug received, and comparing it with the accompanying study drug accountability form.
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8.2.10 destruction and return

If study drugs (those supplied by the sponsor or sourced by the investigator) are to be destroyed on site, it is the investigator's responsibility to ensure that arrangements have been made for the disposal, procedures for proper disposal have been established according to applicable regulations, guidelines and institutional procedures, and appropriate records of the disposal have been documented. The unused study drugs should be destroyed per institutional policies after the drug returns have been reconciled by the monitor, or when the lead site instructs the site to do so. If any study drug is lost or damaged, its disposition should be documented in the source documents. Patients will be instructed to return empty bottles or unused capsules to the clinic site.
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8.3 dexamethasone 8.3.1 description

Dexamethasone is a synthetic adrenocortical steroid. Corticosteroids are naturally occurring chemicals produced by the adrenal glands located above the kidneys. Corticosteroids affect the function of many cells within the body and suppress the immune system. Corticosteroids also block inflammation and are used in a wide variety of inflammatory diseases affecting many organs.  
The molecular weight for dexamethasone is 392.47. It is designated chemically as 9- fluoro11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione. Dexamethasone is stable in air and almost insoluble in water.
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8.3.2 form

Dexamethasone is a white to practically white, odorless, crystalline powder. It is available in 2 or 4 mg tablets (commercially) for oral administration. Each tablet contains dexamethasone as the active ingredient, and the following inactive ingredients: calcium phosphate, lactose, magnesium stearate, and starch. The tablet shell may contain the following: D&C Yellow 10, FD&C Yellow 6, and/or FD&C Blue 1.
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8.3.3 storage and stability

At the study site, all investigational study drugs will be stored in a locked, safe area to prevent unauthorized access. Dexamethasone should be stored at controlled room temperature, 68-77◦F (20-25◦C) and not frozen, and according to label requirements.
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8.3.4 handling

Dexamethasone should be handled by trained pharmacy staff. The use of gloves and other appropriate protective clothing is recommended as necessary.  
8.3.5 Availability Dexamethasone supply will be obtained through commercial supply.  
8.3.6 Preparation Dexamethasone is an oral drug, and does not require specific preparation details.  
8.3.7 Administration
, Participants will receive dexamethasone Days 1, 8 15 and 22 during cycles 1-2 and then days 1, 8, 15 on cycles 3-8 and on day 1 of cycles 9-24 of maintenance .
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8.3.8 ordering

The investigator or designee will order drug supply from commercial supply.  
CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.  
55 8.3.9 Accountability As drug is from commercial supply, sites should keep records per their institutional policies.  
8.3.10 Destruction and Return At the end of the study, unused supplies of dexamethasone should be destroyed and documented according to institutional policies.
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9. biomarker correlative and special

This trial will provide samples high-risk SMM patients treated with elotuzumab and lenalidomide to comprehensively characterize the MM genome and immune cells function and define molecular events driving development and progression of MM. We will attempt to obtain samples on all patients at the following time points: before therapy, at the end of cycle 8, at the time of response determination (CR) , at disease relapse, and at several more time points over the course of the study. It is anticipated that approximately 90% of samples collected will be adequate for sequencing studies proposed. The tumor cells will be collected as described below. From these samples, high quality DNA (for tumor cells) and RNA (for tumor cells and immune cells) for both exome sequencing and RNA sequencing will be obtained. Germline DNA will be also obtained from a buccal swab from all patients at any time point of the study. Peripheral blood and bone marrow derived mononuclear cells will undergo immunologic assessments to assess the impact of therapy on general measures of cellular immunity, MM reactive T cells, and antigen specific immunity. The percentage of circulating and bone marrow derived regulatory T cells, NK cells and MDSCs will be determined. The percent of PD-1 and other checkpoint regulators on immune cells will also be measured. Levels of naïve, effector and central memory cells will be quantified. T cell proliferative response to tetanus toxoid and PHA
mitogen will be determined. NK cell mediated cytotoxicity will be measured. We will also determine the level of SLAMF7 on these cells. In addition, we will examine the level of soluble SLAMF7 pre-treatment and monthly on Day 1 of each cycle. Peripheral blood and bone marrow samples will be collected at the screening time and for analysis in order to confirm response as well as at C9D1. The collection kits and shipping supplies will be provided to the sites by Sequenta. These samples will be packaged whole, and shipped to Sequenta, Inc. in South San Francisco, CA same day priority overnight.. Using Sequenta's LymphoSIGHT platform, rearranged immunoreceptor loci from genomic DNA will be extracted, amplified, and sequenced using V and J segment primers for each immunoreceptor gene. Tumor-specific clonotypes will be identified for each patient based on their high prevalence in peripheral blood. Sequences will be analyzed using standardized algorithms for clonotype determination. Sequenta MRD levels will be quantified using spiked-in reference sequences.
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9.1 bone marrow aspirate samples

Collection of bone marrow aspirate specimens for exploratory analysis will be requested for this trial. Collections that are requested will be obtained at screening, C9D1, confirmation of CR and at end of study treatment. At any time a bone marrow aspirate procedure is performed, an additional sample for exploratory analysis is requested. This will not require extra access for participants. Specimens will be shipped (via traceable carrier) to and subsequently processed, analyzed, and stored at Dana-Farber Cancer Institute. Specimens Requested: 2 Purple Top Tubes (K2EDTA), 10mL each. Specimens must be collected on Mondays to Thursdays for same-day shipment. Processing Information: There is no required processing for bone marrow samples at each participating site prior to shipment. Shipping Information for Bone Marrow Aspirate Specimens: Label all specimens with the following: Subject Initials, Subject study number (will include protocol number), Visit at which sample was drawn (screening, response or relapse/progression), Date sample drawn (mm/dd/yyyy), Time sample drawn (24 hour clock)
9.1.1 Shipping Instructions:
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shipments must be sent on

1. An inventory sheet including a complete list of samples shipped (patient number, timepoint, study \#) must accompany each shipment. Please sign and date the requisition form.  
2. An electronic copy (Word or Excel) of the sample list must also be sent via email. The listing must also include a contact name, address and phone number of the person who is responsible for the shipment.  
3. Please email the lead site contact to notify of an incoming shipment. 4. Please ship **ONLY** Monday to Thursday as shipments cannot be received on weekends and/or on holidays.
5. Once drawn, samples may be shipped via overnight air to:
Dana Farber Cancer Institute Ghobrial Lab 360 Longwood Avenue LC8116 Boston, MA 02215 Email: GhobrialLab@dfci.harvard.edu Please retain a copy for site record maintenance. Please see Appendix C and D **for** Collection Schedule and Requisition Form
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9.2 peripheral blood samples

Collection of peripheral blood specimens (including serum and plasma) for exploratory analysis are requested for this trial. Purple top tube collections should be obtained at the same timepoints as bone marrow samples for correlative studies (see Section 10 for list of required timepoints, and Appendix C for specific instructions). These collections will be taken at the time of routine blood collection timepoints required for this study. Specimens will be processed on site according to instructions below and shipped (via traceable carrier) to Dana-Farber Cancer Institute. Once the shipment is received, samples will be subsequently processed, analyzed, and stored at Dana-Farber.  
9.2.1 Specimens Required: 2 x 10ml Purple Top Tubes (K2EDTA), and 1x 6ml Red Top (no additive) tube, must be collected Mondays to Thursdays for same-day shipment.  
9.2.2 Shipping Information: Label all specimens with the following:  
- Subject Initials - Subject study number (will include protocol number) - Visit at which sample was drawn (screening, response or relapse/progression) - Date sample drawn (mm/dd/yyyy) - Time sample drawn (24 hour clock)
9.2.3 Processing Information: Once collected, the vacutainers will be refrigerated and stored according to instructions below. There is no required processing for purple top tubes at each participating site prior to shipment.  
9.2.4 Shipping Instructions: Shipments must be sent on the day of collection and cannot be batched.  
Processing Information: Invert each tube 5 times at blood collection to ensure adequate mixing of anticoagulant with blood immediately after the blood collection. Package tubes at room temperature and wrap in a liberal amount of paper towel around the tubes to ensure adequate insulation of the specimen(s) and absorption in the event of a breakage. Place wrapped specimen in a biohazard labeled Ziploc bag with a fridge pack and zip close. Wrap bubble wrap around the bag and place in a cardboard box. If space remains in the box, stuff with extra paper towel to reduce shifting of samples. Complete the shipping requisition form using the address listed below. Prepare the package for shipping, applying packing tape as needed. Ship the package using FedEx or UPS next day or overnight delivery the same day the sample was collected. Please only ship Monday-Thursday, as the lab is only able to accept Saturday shipments with 1 week advance notice. With each shipment, please include the following:
1. An inventory sheet including a complete list of samples shipped (patient number, timepoint, study \#) must accompany each shipment. Please sign and date the form, and retain a copy for site record maintenance. **See Appendix D for Sample Requisition** Form  
2. An electronic copy (Word or Excel) of the sample list must also be sent via email and include the tracking number of the package. The listing must also include a contact name, address and phone number of the person who is responsible for the shipment.  
3. Please email the Dana-Farber/lead site contact to notify of an incoming shipment.
4. Please ship Monday to Thursday as shipments cannot be received on weekends and/or on holidays.  
5. Once drawn, samples may be shipped via overnight air to:
Dana Farber Cancer Institute Ghobrial Lab 360 Longwood Avenue LC8116 Boston, MA 02215 Email: GhobrialLab@dfci.harvard.edu For Sequenta samples, use the packing supplies provided in each individual kit and follow the directions below:  
1. Label each tube with date of collection, patient's study specific number, initials, and date of birth
2. Store collected tubes at room temperature until same day shipment.  
3. On the ClonoSEQtest requisition form, fill out requisition with patient first and last name, date of birth, and gender. Ordering physician should be listed as Irene Ghobrial, MD. Please ensure that the sample tubes are labeled, and reference patient specific study number, the treating site, and the treating physician name at the top of the requisition form.  
4. Under ICD-10, Other: Multiple Myeloma C90.00 should be entered 5. Under specimen information, enter collection date under fresh specimens, and mark which samples have been provide ( blood and bone marrow )
6. For baseline samples, ClonoSIGHT ID Test should be checked. For confirmation of response time point, ClonoSIGHT MRD Test should be checked.  
7. Under billing, please provide insurance information for the patient 8. Complete pathology, physician signature, and billing information sections 9. Please make a copy of the requisition to retain for your records along with the Fed-Ex tracking number in the event that the package is lost.  
10. Follow the sample packing instructions included in the kit, and send out same day.  
Shipping on Friday is ok for Saturday processing for these samples.  
11. An electronic notification must be sent via email and include the tracking number of the package, and all relevant sample information and patient identifiers to the study team The listing must also include a contact name, address and phone number of the person who is responsible for the shipment.  
a) Please email the lead site contact to notify of an incoming shipment.
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10. study calendar

Screening evaluations are to be conducted within 28 days prior to initiation of registration. Protocol therapy should start as soon after registration as feasible. Baseline assessments are to be conducted on C1D1 of initial therapy and should be considered separate from screening evaluations. Evaluations need not be repeated for C1D1 if screening evaluations are performed within 7 days of registration. Scans and bone marrow assessments do not need to be repeated if performed within 6 weeks of registration. All assessments must be performed prior to administration of any study medication.. See below for detailed scheduled of assessments. Study medications will be administered according to the schedule and guidelines outlined in Section 5.  
| medications will be administered according to the schedule and guidelines outlined in Section 5. Pre-registration Cycles 1-24 (28 days) 3 Follow Up11 Days 8, 15 and 22 of Cycle 9  cycles 1 & 2 Day 1/ Or  to confirm  CR9 Every 3 or 6 Months Days 1 &15  (+/- 28 from cycle  days) 3-8   |                        |                                   |                        |            |     |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|-----------------------------------|------------------------|------------|-----|
| History and exam, height,  weight. Performance Status                                                                                                                                                                                                                                       | X                      | X                                 | X                      | (X)        |     |
| Toxicity Notation                                                                                                                                                                                                                                                                           | X                      | X                                 |                        |            |     |
| Hematology group (WBC  w/ diff, PLT, Hgb, ANC)                                                                                                                                                                                                                                              | X                      | X                                 | X                      | X          | X   |
| Chemistry4                                                                                                                                                                                                                                                                                  | X                      | X                                 | X                      | X          | X   |
| Direct & total bilirubin2                                                                                                                                                                                                                                                                   | X                      | X                                 | X                      |            |     |
| Free light chain assay                                                                                                                                                                                                                                                                      | X                      | X                                 | X                      | X          |     |
| Serum and Urine  Immunofixation (SPEP and  UPEP) with quantitative  immunoglobulins10                                                                                                                                                                                                       | ≤ 28 days              |                                   |                        |            |     |
| Tests and procedures                                                                                                                                                                                                                                                                        | prior to  registration | ≤ 21 days  prior to  registration | Day 1  of all  cycles1 | End of  Tx |     |
| X                                                                                                                                                                                                                                                                                           | X                      | X                                 | X                      |            |     |
| 2M, CRP, LDH                                                                                                                                                                                                                                                                               | X                      | X                                 |                        |            |     |
| Metastatic Bone Survey/  Spine MRI or PET/CT12                                                                                                                                                                                                                                              | X                      | X                                 | (X)                    |            |     |
| EKG                                                                                                                                                                                                                                                                                         | X                      | X                                 |                        |            |     |
| Serum pregnancy test                                                                                                                                                                                                                                                                        | X                      |                                   |                        |            |     |
| Unilateral bone marrow  aspirate and biopsy5                                                                                                                                                                                                                                                | X                      | X                                 | X                      | (X)        |     |
| Research bone marrow  aspirate6                                                                                                                                                                                                                                                             | X5                     | X6                                | X6                     | (X)        |     |
| Research Blood7                                                                                                                                                                                                                                                                             | X8                     | X                                 | X                      | X          | (X) |
| 1- Cycle 1, Day 1 laboratory values need to meet eligibility criteria 2- Direct bilirubin to be obtained if total bilirubin is abnormal.                                                                                                                                                    |                        |                                   |                        |            |     |  
2M, CRP, LDH X X  
Metastatic Bone Survey/  
Spine MRI or PET/CT12 X X (X)  
EKG X X Serum pregnancy test X  
Unilateral bone marrow  
aspirate and biopsy5 X X X (X)  
Research bone marrow  
aspirate6 X5 X6 X6(X)  
Research Blood7 X8 X X X (X)  
1- Cycle 1, Day 1 laboratory values need to meet eligibility criteria 2- Direct bilirubin to be obtained if total bilirubin is abnormal. 3- Scheduling allows for +/- 3 days cycles 1-2 and +/- 7 days for cycle 3 and beyond.  
4- Chemistry includes sodium, potassium, chloride, bicarbonate, bun, creatinine, calcium, glucose, albumin, ALT (SGPT), total protein, AST (SGOT), total bilirubin, magnesium, and phosphorus.  
5- These procedures should also be done at any time during the course of the study to confirm CR. 6- Research bone marrow aspirate and biopsy at the same time of clinically indicated bone marrow biopsy and to confirm response. 7- Peripheral blood samples for correlative studies including serum SLAMF7 levels. 8- Oragene kit for germline DNA will be acquired once at any time point from patients enrolled on this study. 9-If C9D1 or confirmation of response BM biopsy was performed within 3 weeks of subsequent time point listed; do not need to repeat BM biopsy.  
10- Patients who are not followed for disease response in their urine per IMWG criteria need only bring urine every third cycle and at end of treatment after baseline 11- Follow up will occur approximately every 3 to 6 months (+/- 28days) for up to 3 years after discontinuation of therapy (EOT). Participants unable to participate in follow up every 3 months may follow up every 6 months at PI discretion in accordance with standard of care follow-up frequency and COVID precautions. Physical exams and correlative blood draws that are not done due to virtual visits will not be considered violations. Local myeloma labs must be provided to the participating site for data entry purposes. Bone marrow biopsy and scans are strongly recommended yearly after EOT but are required when there is suspicion of clinical progression. These assessments can be waived due to extenuating circumstances or for insurance coverage reasons. Scans and bone marrow biopsy and research samples are required at time of suspected disease progression if one is performed as part of standard of care procedures. 12- A CD of scans at screening and end of treatment is requested to be sent to the lead site for central review. Screening scans should be sent with the eligibility packet to the lead site (X)- Indicates this assessment may not be required Note: Research blood and bone marrow studies are voluntary and do not exclude patients from participating
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11. measurement of effect 11.1

In this study, the final endpoint is development of symptomatic MM that requires therapy. This is defined as one of the following criteria (CRAB* and Myeloma defining events< MDE):
- Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the upper limit of normal or >.275 mmol/dL);
- Renal insufficiency (attributable to myeloma);
- Anemia (Hgb 2g/dL below the lower limit of normal or <10g/dL);
- Bone lesions (lytic lesions or generalized osteoporosis with compression fractures)
- Or any MYELOMA DEFINING EVENTS (MDE) as follows:
o Clonal bone marrow plasma cell percentage*> 60%2 o An abnormal FLC-ratio ≥100 (involved kappa) or ≤0.01 (involved lambda)52 o 2 or more focal lesions on MRI or PET-CT studies53,54
* Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible
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for measurement of response

In this study, patients must have measurable disease. The disease response will be assessed using criteria based on the International Working Group Uniform Response Criteria in Section 11.2.4. If the only measurable parameter is serum immunoglobulins free light chain (FLC), the participant will be followed by FreeLite™ Disease Response Criteria provided in Section 11.2.5. Disease response by the Modified EBMT Response Criteria in Section 11.2.6.2 will also be collected on participants as a secondary measure. The same method of assessment and technique should be used for disease **measurement** at baseline and during follow-up. Disease response should be confirmed by two consecutive CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.  
62
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11.2 antitumor effect

11.2.1 Disease Parameters Measurable disease: Measurable disease is disease that can be measured either by serum or urinary evaluation of the monoclonal component or by serum assay of FLC and is defined by at least one of the following three measurements:
- Serum M-protein > 0.5 g/dl - Urine M-protein > 200 mg/24 h  
- Serum FLC assay: Involved FLC level > 10 mg/dl (> 100 mg/l) provided serum FLC ratio is abnormal.
If a patient has measurable disease, but not by IMWG standards listed above, the patient may be eligible after discussion with the Overall Principal Investigator. 11.2.2 Methods for Evaluation of Measurable Disease All baseline evaluationsshould be performed on Cycle 1, Day 1 of initial therapy. Response will be assessed by M-protein quantification, protein electrophoresis and immunofixation from serum and a 24-hour urine collection. A serum sample for FreeLiteTM testing will be obtained.  
In addition, bone marrow aspiration and biopsy, as well as skeletal survey will be performed to determine overall response or confirm response. The same method of assessment and technique should be used for disease measurement at baseline and during follow-up.  
11.2.3 Response Criteria A confirmation measurement for disease response assessments is required in this protocol.  
11.2.4 International Myeloma Working Group Response Criteria Response criteria for all categories and subcategories of response except CR are applicable only to patients who have 'measurable' disease, as defined in Section 11.2 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 if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements. Stringent CR: CR as defined below plus normal free light chain ratio and absence of clonal cells in bone marrow*by immunohistochemistry or immunofluorescence.**
*Confirmation with repeat bone marrow biopsy is not needed. **Presence/absence of clonal cells is based upon the k/λ ratio. An abnormal k/ λ ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is k/λ of > 4:1 or < 1:2. CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. *Confirmation with repeat bone marrow biopsy is not needed. VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24 hours. PR: > 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by > 90% or to < 200mg per 24 hours. If the serum and urine M-protein are unmeasurable, a > 50% decrease in the difference between involved and uninvolved free light chain levels is required in place of the M-protein criteria (definition of measurable disease in Section 10.2.3). If serum and urine Mprotein are unmeasurable, and serum free light assay is also unmeasurable, >
50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was > 30%. In addition to the above listed criteria, if present at baseline, a > 50% reduction in the size of soft tissue plasmacytomas is also required. SD: Not meeting criteria for CR, VGPR, PR or progressive disease. This is not recommended as an indicator of response; stability of disease is best described by providing the time to progression estimates. PD: > 25% increase of serum M-protein (which must also be an absolute increase of > 0.5 g/dL) and/or urine M-protein (which must also be an absolute increase of > 200 mg/24hr). If serum and urine M-protein are unmeasurable, there must be an absolute increase of > 10 mg/dL between involved and uninvolved FLC levels. PD is also measured by an absolute increase in bone marrow plasma cells > 10%. In addition to the above listed criteria, progression may also be measured by a definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas or development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.  
11.2.5 FreeLite™ Disease Response Criteria Complete **Response**: For those patients being followed by serum free light chain (and NO measurable serum or urine M-spike), which were immunofixation negative at enrollment, normalization of serum free light chain ratio.  
- Normalization is defined as the serum free light chain ratio being within the normal range.  
If the serum free light chain ratio is not within the normal range, but the individual kappa and lambda light chain values are within normal range, this may be considered CR. Partial **Response**: If only measurable parameter is serum immunoglobulinsfree light chain (FLC), EITHER of the following changes qualify as partial response: - A 50% decrease in the difference between involved and uninvolved FLC levels; OR - A 50% decrease in the level of involved FLC AND a 50% decrease (or normalization) in the ratio of involved/uninvolved FLC Progressive **Disease**: If only measurable parameter is serum immunoglobulins free light (FLC), either of the following qualify as progression: - 50% increase in the difference between involved and uninvolved FLC levels from the lowest response level, which must also be an absolute increase of at least 10 mg/dL; OR - 50% increase in the level of involved FLC AND a 50% increase in the ratio of involved/uninvolved FLC from the lowest response level.  
11.2.6 Criteria for Molecular CR and Minimal Residual Disease (MRD) measurement We will measure MRD in patients who achieve CR to determine the number of patients who are MRD negative vs MRD positive.
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11.2.6.1 mrd by lymphosight

MRD will be carried out according to the LymphoSIGHTTM method (Sequenta, Inc., San Francisco, CA)55. Prior studies have compared this technique to the traditional MRD immunofluorescence technique, as previously reported 60 and showed that MRD by LymphoSight is a sensitive method that can be used in future clinical practice. For MM diagnostic samples, genomic DNA will be amplified using locus-specific primer sets for the immunoglobulin heavy-chain locus (IGH) complete (IGH-VDJH), IGH incomplete (IGHDJH), and immunoglobulin κ locus (IGK). The amplified product will be subjected to sequencing, and the sequences and frequencies of the different clonotypes in the sample will be obtained. Myeloma gene rearrangements will be identified. Patients in whom a high-frequency myeloma clone (>5%) is not identified will be excluded from the MRD analysis. MRD will be assessed in patients with a high-frequency myeloma clone using the IGH-VDJH and IGK or IGH-VDJH, IGH-DJH, and IGK assays. Once the absolute amount of total cancer-derived molecules present in a sample will be determined, a final MRD measurement will be calculated, providing the number of cancer-derived molecules per 1 million cell equivalents. In cases in which 2 or more tumor clones existed, the clone with the highest MRD value will be reported. Molecular CR will be defined according to the International Myeloma Working Group (IMWG)
consensus recommendations.56  
| Response                                                                                                                                                                                                                                                                                          | Criteria for Responsea                                                                                                                                                                                                                                            |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Requires all of the following: Disappearance of the original monoclonal protein from the blood and  urine on at least two determinations for a minimum of six weeks by  immunofixation studies. <5% plasma cells in the bone marrow on at least two  determinations for a minimum of six weeks. b |                                                                                                                                                                                                                                                                   |
| Complete response  (CR)                                                                                                                                                                                                                                                                           | No increase in the size or number of lytic bone lesions  (development of a compression fracture does not exclude  response).c Disappearance of soft tissue plasmacytomas for at least six weeks. Requires the following:                                          |
| Near Complete  Response  (nCR)                                                                                                                                                                                                                                                                    | Same as CR, but immunofixation studies continue to show presence  of the monoclonal protein Requires the following: > 90% reduction in serum M-protein plus urine M-protein level <100mg  per 24 hours on at least two determinations for a minimum of six weeks. |
| Very Good Partial  Response (VGPR)                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                   |  
| PR includes participants in whom some, but not all, criteria for CR are  fulfilled providing the remaining criteria satisfy the requirements for PR.  Required all of the following: 50% reduction in the level of serum monoclonal protein for at  least two determinations six weeks apart.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Partial response  (PR)                                                                                                                                                                                                                                                                           | If present, reduction in 24-hour urinary light chain excretion by either 90% or to <200 mg for at least two determinations six weeks apart. 50% reduction in the size of soft tissue plasmacytomas (by  clinical or radiographic examination) for at least six weeks. No increase in size or number of lytic bone lesions (development of  compression fracture does not exclude response).c MR included participants in whom some, but not all, criteria for PR  were fulfilled, providing the remaining criteria satisfied the  requirements for MR. Required all of the following: 25% to  49% reduction in the level of serum monoclonal protein for  at least two determinations six weeks apart. If present, a 50 to 89% reduction in 24-hour light chain excretion,  which still exceeds 200 mg/24 h, for at least two determinations six  weeks apart. |
| Minimal response  (MR)                                                                                                                                                                                                                                                                           | 25-49% reduction in the size of plasmacytomas (by clinical or  radiographic examination) for at least six weeks. No increase in size or number of lytic bone lesions (development of  compression fracture does not exclude response).c                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| No change (NC)                                                                                                                                                                                                                                                                                   | Not meeting the criteria for MR or PD.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |  
| Response                                                                                                                                                                                                                                                                                                                                                                     | Criteria for Responsea                                                                                                                                                                                                                                                                                                                                                                                                                                           |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Requires one or more of the following: >25% increased in the level of serum monoclonal paraprotein, which  must also be an absolute increase of at least 5 g/L and confirmed on a  repeat investigation. >25% increased in 24-hour urinary light chain excretion, which must  also be an absolute increase of at least 200 mg/24 h and confirmed on a  repeat investigation. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| Progressive  disease (PD) (for  participants not  in CR)                                                                                                                                                                                                                                                                                                                     | >25% increased in plasma cells in a bone marrow aspirate or on trephine  biopsy, which must also be an absolute increase of at least 10%. Definite increase in the size of existing lytic bone lesions or soft  tissue plasmacytomas. Development of new bone lesions or soft tissue plasmacytomas (not  including compression fracture). Development of hypercalcemia (corrected serum calcium >11.5 mg/dL  or 2.8 mmol/L not attributable to any other cause). |  
| Required at least one of the following: Reappearance of serum or urinary paraprotein on immunofixation or  routine electrophoresis confirmed by at least one follow-up and  excluding oligoclonal immune reconstitution. 5% plasma cells in the bone marrow aspirate or biopsy.   |                                                                                                                                                                                                                                                                                              |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Relapse from CR                                                                                                                                                                                                                                                                    | Development of new lytic bone lesions or soft tissue plasmacytomas or  definite increase in the size of residual bone lesions (not including  compression fracture). Development of hypercalcemia (corrected serum calcium >11.5 mg/dL  or 2.8 mmol/L not attributable to any other cause).e |
| a                                                                                                                                                                                                                                                                                  | Based on the criteria reported by Blade et al., 1998.                                                                                                                                                                                                                                        |
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11.2.7 duration of response and

Duration of overall response: The duration of overall response is measured as the time from initiation of first response to first documentation of disease progression or death. Patients who have not progressed or died are censored at the date last known progression-free. Duration of overall complete response: The duration of overall CR is progression or death. Patients who have not progressed or died are censored at the date last known progression-free. Time to progression: Time to progression is defined as the time of randomization until progression. Patients who have died without evidence of progression are censored in the TTP analysis at the time of death and patients who are alive without progression are censored at the last disease assessment. Overallsurvival (OS): OS is defined as the time from randomization to death. Alive patients are censored at the date last known alive.
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11.2.8 progression-free survival

Progression-Free Survival (PFS): the primary endpoint in thisstudy. PFS is defined as the time from randomization to the disease progression or death from any cause. Patients who have not progressed or died are censored at the date last known progression-free.  
11.2.9 Response Review Central review of disease response assessments is not planned.
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12. data reporting / regulatory

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: List and Reporting Requirements).
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12.1 data reporting 12.1.1 method

The QACT will collect, manage, and perform quality checks on the data for this study.  
12.1.2 Responsibility for Data Submission Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data forms to the QACT according to the schedule set by the QACT. Data should be entered within 14 business days of the corresponding visit and within 14 business days of the end of a cycle for any forms to be completed per cycle.
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12.2 data safety monitoring

The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data from this study. The committee is composed of clinical specialists with experience in oncology and who have no direct relationship with the study. Information that raises any questions about participant safety will be addressed with the Overall PI and study team. The DSMC will review each protocol up to four times a year or more often if required to review toxicity and accrual data. Information to be provided to the committee may include: up-to-date participant accrual; current dose level information; DLT information; all grade 2 or higher unexpected adverse events that have been reported; summary of all deaths occurring with 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths while being treated and during active follow-up; any response information; audit results, and a summary provided by the study team. Other information (e.g. scans, laboratory values) will be provided upon request.
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13. statistical considerations 13.1 study

The primary endpoint of this phase II study is to determine the proportion of high risk smoldering multiple myeloma (SMM) patients who are progressive free at 2 years after receiving treatment (Elotuzumab + lenalidomide+ Dexamethasone). The secondary objectives include toxicities, objective response rate, time to progression, duration of response, and overall survival. In addition, we will examine the molecular evolution of the tumor cells, the role of circulating tumor cells and immune cells, and the role of NK cells and other immune cells present in the bone marrow in the progression of smoldering MM. The proportion of patients who achieve progression free at 2 years will be compared to the rate published for the high risk SMM. By the Mayo Clinic model for risk factors, the median time to progression for patients with high risk SMM was only 1.9 years. Therefore, we assume that for this study, a 2-years progression-free rate of 50% will not be considered promising and a true progression free rate of 70% or higher will be considered promising. A single-stage design will be employed with 39 eligible patients entered. If 24 or more of the 39 eligible patients are progression free at 2 years (observed rate of 62%), we will conclude that this treatment warrants further study. The probability of concluding that the treatment is effective if the true rate is 50% is 0.10 and is >0.9 if the true rate is 70%. Assuming an ineligibility rate of 5%, we will accrue 41 patients/per Arm to the trial in order to have 39 eligible patients. A total of 55 patients will be enrolled.
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13.1.1 analysis of primary endpoint

Time to progression (TTP) is defined as the time from protocol therapy initiation until documented progression, censored at date last known progression-free for those who have not progressed. At time of final analysis, the 2-year progression-free rate will be estimated using the Kaplan-Meier method with 90% confidence interval per Arm. All patients who have received one dose of study treatment will be included for the TTP analysis, including those who die or are lost to follow-up within 2 years. The percent of patients who undergo stem cell mobilization and the modality of mobilization will be noted in the study. These patients will not be censored.
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13.1.2 analysis of secondary endpoints

The objective response rate (partial response or better according to the modified IMWG criteria) and the proportion of patients with a MRD, CR, PR or MR will be reported by Arm with 90% exact binominal confidence interval (CI). The exact 90% CI around response rate will be no wider than 28% with 39 eligible patients. To estimate the duration of response (time from objective response to disease progression or death, or date last known progression-free and alive for those who have not progressed or died), progression-free survival (time from protocol therapy initiation to the disease progression or death from any cause, censored at date last known progression free for those who have not progressed or died), and overall survival (time from protocol therapy initiation to death or date last known alive), the Kaplan-Meier method will be used. The results will be reported separately for each Arm. Safety analysis will be conducted using the Safety Population defined as any patient receiving one dose of study treatment. For toxicity reporting, all adverse events and laboratory abnormalities will be graded and analyzed using CTCAE version 4 as appropriate.
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13.2 sample size accrual rate

A total of 55 patients will be enrolled. We expect 3.5 years of active accrual (approximately 2 patients per month) and 3 years of follow-up of patients. The final analyses of progression-based endpoints, such as estimating the 2-year progression-free rate and estimating the TTP distribution, will be conducted at the end of the study, which will occur after either all subjects have progressed or died or 2-years after the initiation of therapy of the last subject enrolled, whichever occurs first.
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13.3 stratification factors

The patients will be stratified based on age and cytogenetics.  
- Age 65 years or older
- High risk cytogenetics based on t(4:14), t(14:16), 17p deletion or p53 mutation,
+1q amplification (3 groups: high risk, low risk or Fish failure)
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13.4 interim monitoring plan

The study will be monitored by the DFCI Data Safety Monitoring Committee (DSMC). The DSMC will meet at least four times a year and more often if needed (e.g., for safety review). For each meeting, the study will be reviewed for safety and progress toward completion. When appropriate, the DSMC will also review interim analyses of the outcome data. Copies of the toxicity reports prepared by the DSMC meetings will be distributed to the Principal Investigator. The Principal Investigator will then distribute to sub-investigators. Any DSMC recommendations for changes to the study will be distributed to the Principal Investigator and then circulated to sub- investigators by the Principal Investigator.
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13.5 stopping rule for safety

All participants will be evaluable for treatment-related toxicity from the time of therapy initiation. The severe adverse event (SAE) is defined as any grade 3 adverse events that affect organ function (cardiac, hepatic, thromboembolic) or grade 4/5 non hematologic AEs. We anticipate that the rate of SAE is low in this study population. However, if 2 or more SAEs are observed at any time in the first 20 treated patients in any study cohort, further patient enrollment will be paused for that cohort. The following table provides the probabilities of observing 2 or more SAEs with 20 treated participants in each cohort. For example, with 20 participants, there is 0.82 probability of observing 2 or more SAEs if a true rate is 15% and the probability is 0.12 if a true rate is 3%.  
| True SAE Rate         | 1%    | 3%    | 5%    | 10%   | 15%   | 20%   | 30%   |
|-----------------------|-------|-------|-------|-------|-------|-------|-------|
| Probability (≥2 SAEs) | 0.017 | 0.120 | 0.264 | 0.608 | 0.824 | 0.931 | 0.992 |
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14. publication plan

The results should be made public within 24 months of reaching the end of the study. The end of the study is the time point at which the last data items are to be reported, or after the outcome data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. A full report of the outcomes should be made public no later than three (3) years after the end of the study. Data sets from other relevant studies such as 17-212, 16-313, or data sets from other collaborators may be used and/or analyzed for the purposes of the publication.
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15. references

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3. Rajkumar SV, Landgren O, Mateos MV. Smoldering Multiple Myeloma. Blood. 2015 Apr 2. pii: blood-2014-09-568899 4. Mateos, M.V., et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. *The New England journal of medicine* 369, 438-447 (2013).  
5. Lonial, S., Kaufman, J., Laubach, J. & Richardson, P. Elotuzumab: a novel anti-CS1 monoclonal antibody for the treatment of multiple myeloma. Expert Opin Biol *Ther* 13, 1731-1740 (2013).  
6. Collins, S.M., et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer immunology, immunotherapy : CII 62, 1841-1849 (2013).  
7. Kuroda, J., Nagoshi, H., Shimura, Y. & Taniwaki, M. Elotuzumab and daratumumab:
emerging new monoclonal antibodies for multiple myeloma. Expert Rev Anticancer *Ther* 13, 1081-1088 (2013).  
8. Lonial, S.*, et al.* Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30, 1953-1959 (2012).  
9. Kronke, J., et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. *Science* 343, 301-305 (2014).  
10. Lu, G., et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. *Science* 343, 305-309 (2014).  
11. Anderson, K.C. & Carrasco, R.D. Pathogenesis of myeloma. Annu Rev *Pathol* 6, 249-274
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16. Dispenzieri, A., et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. *Blood* 111, 785-789 (2008).  
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19. Weiss, B.M., Abadie, J., Verma, P., Howard, R.S. & Kuehl, W.M. A monoclonal gammopathy precedes multiple myeloma in most patients. *Blood* 113, 5418-5422 (2009).  
20. Lopez-Corral, L., et al. SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status. *Leukemia* (2012).  
21. Visone, R. & Croce, C.M. MiRNAs and cancer. Am J *Pathol* 174, 1131-1138 (2009). 22. Pichiorri, F., et al. MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. *Proc Natl Acad Sci U S A* 105, 12885-12890 (2008).  
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24. Chesi, M.*, et al.* AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. *Cancer* Cell 13, 167-180 (2008).  
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27. Egan, J.B.*, et al.* Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. *Blood* 120, 1060-1066 (2012).  
28. Keats, J.J., et al. Clonal competition with alternating dominance in multiple myeloma.  
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29. Walker, B.A.*, et al.* Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma. *Blood* 120, 1077-1086 (2012).  
30. Bahlis, N.J. Darwinian evolution and tiding clones in multiple myeloma. *Blood* 120, 927928 (2012).  
31. Greaves, M. & Maley, C.C. Clonal evolution in cancer. *Nature* 481, 306-313 (2012). 32. Rasillo, A., et al. Fluorescence in situ hybridization analysis of aneuploidization patterns in monoclonal gammopathy of undetermined significance versus multiple myeloma and plasma cell leukemia. *Cancer* 97, 601-609 (2003).  
33. Bergsagel, P.L. & Kuehl, W.M. Molecular pathogenesis and a consequent classification of multiple myeloma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23, 6333-6338 (2005).  
34. Tassi, I. & Colonna, M. The cytotoxicity receptor CRACC (CS-1) recruits EAT-2 and activates the PI3K and phospholipase Cgamma signaling pathways in human NK cells. J Immunol 175, 7996-8002 (2005).  
35. Boles, K.S. & Mathew, P.A. Molecular cloning of CS1, a novel human natural killer cell receptor belonging to the CD2 subset of the immunoglobulin superfamily. Immunogenetics 52, 302-307 (2001).  
36. Tai, Y.T., et al. CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells. Blood 113, 4309-4318 (2009).  
37. Hsi, E.D., et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clinical cancer research : an official journal of the American Association for Cancer Research 14, 2775-2784 (2008).  
38. Tai, Y.T., et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. *Blood* 112, 1329-1337 (2008).  
39. Ebert, B.L., et al. An erythroid differentiation signature predicts response to lenalidomide in myelodysplastic syndrome. *PLoS Med* 5, e35 (2008).  
40. Anderson, K., et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. *Nature* 469, 356-361 (2011).  
41. Barrett, M.T., et al. Evolution of neoplastic cell lineages in Barrett oesophagus. *Nat* Genet 22, 106-109 (1999).  
42. Morgan, G.J., Walker, B.A. & Davies, F.E. The genetic architecture of multiple myeloma. *Nat Rev Cancer* 12, 335-348 (2012).  
43. Walker, B.A., et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. *Leukemia* (2013).  
44. Chng, W.J.*, et al.* Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma. *Leukemia* 25, 10261035 (2011).  
45. Lopez-Corral, L., et al. SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status. *Leukemia* 26, 2521-2529 (2012).  
46. Quail, D.F. & Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. *Nature medicine* 19, 1423-1437 (2013).  
47. Swann, J.B. & Smyth, M.J. Immune surveillance of tumors. J Clin *Invest* 117, 1137-1146
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48. Dhodapkar, M.V. Immune response to premalignancy: insights from patients with monoclonal gammopathy. *Ann N Y Acad Sci* **1062**, 22-28 (2005).  
49. Beyer, M. & Schultze, J.L. Regulatory T cells in cancer. *Blood* 108, 804-811 (2006). 50. Feyler, S.*, et al.* CD4(+)CD25(+)FoxP3(+) regulatory T cells are increased whilst CD3(+)CD4(-)CD8(-)alphabetaTCR(+) Double Negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden. British journal of haematology 144, 686-695 (2009).  
51. Cruz-Munoz, M.E., Dong, Z., Shi, X., Zhang, S. & Veillette, A. Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function. Nat Immunol 10, 297-305 (2009).  
52. Larsen, J.T., et al. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. *Leukemia* 27, 941-946 (2013).  
53. Hillengass, J.*, et al.* Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin *Oncol* 28, 1606-1610 (2010).  
54. Hillengass, J. & Landgren, O. Challenges and opportunities of novel imaging techniques in monoclonal plasma cell disorders: imaging "early myeloma". Leuk *Lymphoma* (2013).  
55. Martinez-Lopez, J., et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. *Blood* 123, 3073-3079 (2014).  
56. Rajkumar, S.V., et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. *Blood* 117, 4691-4695 (2011).  
57. Durie, B.G., et al. International uniform response criteria for multiple myeloma.  
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58. Cavo, M.*, et al.* International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. *Blood* 117, 6063-6073 (2011).  
59. Ludwig, H., et al. International Myeloma Working Group recommendations for global myeloma care. *Leukemia* 28, 981-992 (2014).  
60. Paiva, B.*, et al.* High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. *Blood* 119, 687-691 (2012).  
61. Rajkumar, S.V., et, al. Clinical course of light chain smouldering multiple myeloma
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| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                   |                                                                           |                                                                        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|---------------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade                                                                                                                                                                                      | Descriptions                                                  | Percent                                                                   | Description                                                            |
| 100                                                                                                                                                                                        | Normal, no complaints, no evidence  of disease.               |                                                                           |                                                                        |
| Normal activity. Fully active, able                                                                                                                                                        |                                                               |                                                                           |                                                                        |
| 0                                                                                                                                                                                          | to carry on all pre-disease  performance without restriction. | 90                                                                        | Able to carry on normal activity;  minor signs or symptoms of disease. |
| 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). | 80                                                            | Normal activity with effort; some  signs or symptoms of disease.          |                                                                        |
| 1                                                                                                                                                                                          | 70                                                            | Cares for self, unable to carry on  normal activity or to do active work. |                                                                        |
| In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                             | Requires occasional assistance, but                           |                                                                           |                                                                        |
| 60                                                                                                                                                                                         | is able to care for most of his/her  needs.                   |                                                                           |                                                                        |
| 2                                                                                                                                                                                          | 50                                                            | Requires considerable assistance and  frequent medical care.              |                                                                        |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                                                     | 40                                                            | Disabled, requires special care and  assistance.                          |                                                                        |
| 3                                                                                                                                                                                          | 30                                                            | Severely disabled, hospitalization  indicated. Death not imminent.        |                                                                        |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                   | 20                                                            | Very sick, hospitalization indicated.  Death not imminent.                |                                                                        |
| 4                                                                                                                                                                                          | 10                                                            | Moribund, fatal processes  progressing rapidly.                           |                                                                        |
| 5                                                                                                                                                                                          | Dead.                                                         | 0                                                                         | Dead.                                                                  |
appendix b preparation and administration
15. references

Dose Preparation Instructions After dilution in normal saline, elotuzumab must be administered within 8 hours if kept at room temperature (25°C). If a delay is anticipated after the dose has been diluted in normal saline, the prepared dose (properly identified) may be refrigerated at 2°C to 8°C for up to 24 hours. If stored under refrigerated conditions, the study drug solution should be equilibrated to room temperature (takes about 2 to 2.5 hours), and the container must be gently inverted to thoroughly mix the contents before administration. If the storage time limit is exceeded, the prepared dose solution must be discarded and the reason documented by the pharmacist in the study drug accountability records. Elotuzumab will be administered to each subject as an IV infusion, using an automated infusion pump set at the appropriate rate according to the dose administration section (see Administration Instruction section below) discussed below. The dose of elotuzumab will be calculated using the subject's predose weight on Day 1 of each cycle or predose weight at each visit, whichever institutional policy is, and then added to 0.9% saline for infusion. Do not round up or down. Reconstitute elotuzumab lyophilized study drug, as described in Steps 1 to 5. Each 400 mg vial contains 10% overfill for a total of 440 mg of study drug but is intended to deliver 400 mg of elotuzumab. Standard aseptic technique should be utilized. Step 1: Remove the flip-top from elotuzumab and Sterile Water for Injection (SWFI) vials. Step 2: Withdraw 17 mL of SWFI using an 18-gauge or smaller needle. Place the elotuzumab vial upright on a flat surface and insert the syringe needle into the vial through the center of the rubber stopper. Slowly inject the SWFI along the side of the vial to help prevent bubbling or foaming. Slowly remove the syringe needle out of the vial. Step 3: DO NOT SHAKE. Avoid prolonged or vigorous agitation. Hold the vial upright and gently swirl the solution by rotating the vial to dissolve the lyophilized cake. Then gently invert the vial a few times in order to dissolve any powder that may be present on top of the vial or the stopper. Finally, hold the vial upright again and gently swirl the solution a few more times to dissolve any remaining particles. Step 4: After the remaining solids are completely dissolved, allow the reconstituted solution to stand for 5 to 10 minutes. The final volume of the reconstituted solution is approximately 17.6 mL, for an approximate concentration of 25 mg/mL. It is acceptable to have small bubbles and/or foam around the edge of the vial. The reconstituted preparation results in a colorless to slightly yellow, clear to slightly opalescent solution. Step 5: Once the reconstitution is completed and prior to IV administration, the reconstituted solution is further diluted with 230-340 ml of 0.9% sodium chloride injection (NS), USP, resulting in elotuzumab concentrations between 2 mg/mL and 6.6 mg/mL. The infusion is to be administered through a sterile, non-pyrogenic, low protein binding in-line filter. Additionally, care must be taken to ensure the sterility of the prepared solution, as the drug product does not contain anti-microbial preservatives or bacteriostatic agents. A sufficient excess of drug product is included in each vial to account for withdrawal losses.  
The first dose of elotuzumab will be administered following pre-medications to each subject as an IV infusion, using an automated infusion pump set at an initial rate of 0.5 mL per minute (30 mL/hour). If the subject does not have an infusion reaction within 30 minutes, escalate the infusion rate by 0.5 mL per minute. If the subject still does not have an infusion reaction within 30 minutes, escalate the infusion rate to a maximum of 2 mL per minute (120 mL/hour). If a subject experiences a Grade 2 infusion reaction, the infusion must be interrupted. The second dose of elotuzumab should be initiated at an infusion rate of 3 mL per minute if no infusion reactions were reported with the first elotuzumab infusion. If the subject does not experience an infusion reaction during the first 30 minutes of the second dose of elotuzumab, escalate the infusion rate by 1.0 mL per minute to a maximum infusion rate of 4 mL per minute. If no infusion reactions were observed during the first two doses cycle of elotuzumab, the third dose can commence at a rate of 5 mL per minute. If a patient experiences an infusion reaction of less than or equal to Grade 2, and the infusion reaction does not recur, the patient can resume elotuzumab administration at the rate at which the reaction occurred at the start of the next cycle at the investigator's discretion. If a subject experiences a Grade 2 infusion reaction, the infusion must be interrupted. Please refer to Section 6.4.2 for detailed information on the management of infusion reaction and reinitiation of infusion. If a subject experiences a Grade 3 elotuzumab infusion reaction that has resolved to Grade 1, subsequent infusion rate of elotuzumab should be escalated in a stepwise fashion (0.5 mL every 30 minutes).  
1) Administer through a low-protein-binding 0.22-micrometer in-line filter (placed as proximal to the subject as is practical). Prime the infusion line with study drug before starting the infusion. 2) Set the IV pump to deliver the infusion at the rate of 0.5mL per minute (including the drug in the line). The total time of infusion will vary depending upon the maximum tolerated mL/min infusion rate as discussed above. 3) Record every time the infusion is started and stopped and the reason why the start and stop occurred. 4) Monitor the IV setup and the subject's IV site frequently during infusion, checking for the correct infusion rate and IV site infiltration. 5) Ensure that the full volume of elotuzumab is infused.  
After elotuzumab has been infused from the line, discontinue the infusion, disconnect the IV tubing, and dispose of materials appropriately according to the facility's standard procedure. The elotuzumab infusion rate will be increased gradually to a maximum of 5 mL/min as presented in the table below. The schedule below will be permitted only if no infusion reactions are encountered. For guidance related to elotuzumab infusion reactions, refer to section 6.4.  
| Approximate  TotalInfusion  Time               |               |                        |                         |
|------------------------------------------------|---------------|------------------------|-------------------------|
| Cycle/Day                                      | Infusion Rate | Duration of  Infusion  |                         |
| 0.5 mL/min                                     | 30 minutes    |                        |                         |
| Cycle 1 Day 1 (10mg/kg)                        | 1 mL/min      | 30 minutes             | 2 hours and 50  minutes |
| 2mL/min                                        | 110 minutes   |                        |                         |
| 3 mL/min                                       | 30 minutes    | 1 hour and 13  minutes |                         |
| 4 mL/min                                       | 43 minutes    |                        |                         |
| Cycle 1 Day 8 (10mg/kg)                        |               |                        |                         |
| Cycle 1 Day 15 and 22  And Cycle 2-8 (10mg/kg) | 5mL/min       | 53 minutes             | 53 minutes              |
| Cycle 9-24 (20mg/kg)                           | 5mL/min       | 81 minutes             | 81 minutes              |
appendix b preparation and administration
appendix c 14-338 specimen collection

| Sample Time Point                                                                               | Recipient            | Sample Type                  | Shipping Method              | Container1,2                                                       |
|-------------------------------------------------------------------------------------------------|----------------------|------------------------------|------------------------------|--------------------------------------------------------------------|
| 3x 10mL Purple Top  1x6ml Red Top                                                               |                      |                              |                              |                                                                    |
| Peripheral Blood                                                                                | Fridge pack same day |                              |                              |                                                                    |
| DFCI                                                                                            | Bone Marrow Aspirate | 2x10mL Purple Top            |                              |                                                                    |
| Baseline                                                                                        | Buccal Swab2         | Ambient same day             | 1x Buccal Swab Kit           |                                                                    |
| Sequenta                                                                                        | Bone Marrow Aspirate | Same day - Use kit  provided | 1x3ml Purple                 |                                                                    |
| Cycle1 Day 1  (Pre Dose)                                                                        | DFCI                 | Peripheral Blood             | Fridge pack same day         | 2x10mL Purple Top  1x6ml Red Top                                   |
| Cycle 2-8 Day 1  (Predose)                                                                      | DFCI                 | Peripheral Blood             | Fridge pack same day         | 2x10mL Purple Top3 1x6ml Red Top 2x 10mL Purple Top3 1x6ml Red Top |
| Peripheral Blood                                                                                |                      |                              |                              |                                                                    |
| End of Cycle 8  (Cycle 9 Day 1)                                                                 | DFCI                 | Fridge pack same day         |                              |                                                                    |
| Bone Marrow Aspirate                                                                            | 2x10mL Purple Top3   |                              |                              |                                                                    |
| Cycle 10-24 Day 1  (Predose)                                                                    | DFCI                 | Peripheral Blood             | Fridge pack same day         | 2x10mL Purple Top  1x6ml Red Top 2x 10mL Purple Top  1x6ml Red Top |
| Peripheral Blood                                                                                |                      |                              |                              |                                                                    |
| DFCI                                                                                            | Fridge pack same day |                              |                              |                                                                    |
| Bone Marrow Aspirate                                                                            | 2x10mL Purple Top    |                              |                              |                                                                    |
| Confirm Complete  Response 4                                                                    | Sequenta             | Bone Marrow Aspirate         | Same day - Use kit  provided | 1x3ml Purple Top 2x 10mL Purple Top  1x6ml Red Top                 |
| End of Treatment                                                                                | Peripheral Blood     |                              |                              |                                                                    |
| and/or Disease                                                                                  | DFCI                 | Fridge pack same day         |                              |                                                                    |
| Progression                                                                                     | Bone Marrow Aspirate | 2x10mL Purple Top            |                              |                                                                    |
| Clinically Indicated/  and/or Yearly Bone  Marrow  Biopsy/Aspirate                              | Bone Marrow Aspirate |                              |                              |                                                                    |
| DFCI                                                                                            | Fridge pack same day | 2x10mL Purple Top3           |                              |                                                                    |
| Peripheral Blood                                                                                |                      |                              |                              |                                                                    |
| 1 Purple Top= K2EDTA Tube; Red Top= No Additive; Sequenta Tubes= Provided by Sequenta/Lead Site |                      |                              |                              |                                                                    |  
1 Purple Top= K2EDTA Tube; Red Top= No Additive; Sequenta Tubes= Provided by Sequenta/Lead Site 2 Buccal Swabs will be provided by the lead site, and can be sent at any time point during the trial 3 Samples at these time points are voluntary, and do not exclude patients from treatment 4 For definition of Complete Response, please refer to section 11.2.3.  
Protocol \#: 14-338
Version Date: 4.9.2021
appendix b preparation and administration
appendix d 14-338 specimen requisition

Complete this form and include with the specimen shipment. Label all materials with DFCI participant study ID, collection time point and collection date and time. Email GhobrialLab@dfci.harvard.edu to alert study team of shipment and include tracking number.  
Ship specimen(s) to:
Dana Farber Cancer Institute Ghobrial Lab 360 Longwood Avenue LC8116 Boston, MA 02215
appendix b preparation and administration
specimen information

DFCI Participant Study ID Number: Date specimen(s) shipped:  
| Correlative Sample Time Points                   | Sample Type         | Quantity of Tubes   | Collection Date    | Collection Time    |
|--------------------------------------------------|---------------------|---------------------|--------------------|--------------------|
| (indicate inclusion in shipment by checking box) | (6ml or 10ml)       |                     |                    |                    |
| Pre-treatment/Baseline                           | Blood               | Aspirate            | Red Top            |                    |
| Swabs                                            | Purple Top          |                     |                    |                    |
| Cycle 1-24 Day 1                                 | Specify Cycle       | Blood               | Red Top Purple Top |                    |
| Confirm Response                                 | Blood               | Aspirate            | Red Top Purple Top |                    |
| Cycle 9 Day 1 (end of Cycle 8)                   | Blood               | Aspirate            | Red Top Purple Top |                    |
| End of Treatment                                 | Disease Progression | Blood               | Aspirate           | Red Top Purple Top |
| Clinical Necessity/ Standard of Care             | Aspirate            | Purple Top          |                    |                    |
appendix b preparation and administration
responsible contact email site

Phone number:
Note: All samples are to be shipped with a fridge pack Fed-Ex priority overnight- Please retain a copy of the waybill, and reference the tracking number in the email and paper correspondence. Ship only Monday- *Thursday*, as shipments cannot be received over the weekend
table of contents
responsible contact email site

| SCHEMA .                                                |                                                                                                                                                            |
|---------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| SYNOPSIS .                                              |                                                                                                                                                            |
| 1.                                                      | OBJECTIVES ..............................................................................................................................................9 |
| 1.1                                                     | Study Design .                                                                                                                                             |
| 1.2                                                     | Primary Objectives                                                                                                                                         |
| 1.3                                                     | Secondary Objectives ..................................................................................................................10                  |
| 2.                                                      | BACKGROUND                                                                                                                                                 |
| 2.1                                                     | MMultiple Myeloma                                                                                                                                          |
| 2.2                                                     | MGUS and SMM consistently precedes multiple myeloma ...........................................11                                                          |
| 2.3                                                     | Molecular studies in MGUS and SMM......................................................................................11                                  |
| 2.4                                                     | Definition of SMM......................................................................................................................13                  |
| 2.5                                                     | Definitions of high-risk SMM................................................................................................14                             |
| 2.6                                                     | Treatment of high risk SMM...................................................................................................14                            |
| 2.7                                                     | E Elotuzumab                                                                                                                                               |
| 2.8                                                     | Rationale for Elotuzumab in SMM ....................................................................................15                                     |
| 2.9                                                     | Rationale for dose and schedule of Elotuzumab .............................................................16                                              |
| 2.10                                                    | T Trial Rationale                                                                                                                                          |
| 2.11                                                    | Correlative Studies Background....................................................................................................22                       |
| 3.                                                      | PARTICIPANT SELECTION ......................................................................................................................23             |
| 3.1                                                     | Eligibility Criteria .........................................................................................................................23           |
| 3.2                                                     | Exclusion Criteria                                                                                                                                         |
| 3.3                                                     | Inclusion of Women and Minorities                                                                                                                          |
| 4.                                                      | REGISTRATION PROCEDURES                                                                                                                                    |
| 4.1                                                     | General Guidelines for DF/HCC and DF/PCC Institutions                                                                                                      |
| Registration Process for DF/HCC and DF/PCC Institutions |                                                                                                                                                            |
| 4.2                                                     |                                                                                                                                                            |
| 4.3                                                     | General Guidelines for Other Investigative Sites ..........................................................27                                              |
| 4.4                                                     | Registration Process for Other Investigative Sites ........................................................27                                              |
| 5.                                                      | TREATMENT PLAN .                                                                                                                                           |
| T Treatment Regimen                                     |                                                                                                                                                            |
| 5.1                                                     |                                                                                                                                                            |
| 5.2                                                     | Pre-Treatment Criteria                                                                                                                                     |
| 5.3                                                     | Agent Administration ...............................................................................................................31                     |
| 5.4                                                     | General Concomitant Medication and Supportive Care Guidelines ......................33                                                                     |
| 5.5                                                     | Criteria for Taking a Participant Off Protocol Therapy .............................................34                                                     |
| 5.6                                                     | D Duration of Follow Up                                                                                                                                    |
| 5.7                                                     | Criteria for Taking a Participant Off Study                                                                                                                |
| 6.                                                      | DOSING DELAYS/DOSE MODIFICATIONS ......................................................................36                                                  |
| 6.1                                                     | E Elotuzumab                                                                                                                                               |  
| Version Date: 4.9.2021                                                                                                                   |                                                                                                                                                   |                                                                                                                                  |
|------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------|
| 6.2                                                                                                                                      | Lenalidomide                                                                                                                                      |                                                                                                                                  |
| DEXAMETHASONE ..................................................................................................................40       |                                                                                                                                                   |                                                                                                                                  |
| 6.3                                                                                                                                      |                                                                                                                                                   |                                                                                                                                  |
| 6.4                                                                                                                                      | Guidelines for Elotuzumab Infusion in Subjects with Infusion Reactions.............42                                                             |                                                                                                                                  |
| 7.                                                                                                                                       | ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .................................44                                                              |                                                                                                                                  |
| 7.1                                                                                                                                      | Expected Toxicities .............................................................................................................44               |                                                                                                                                  |
| 7.2                                                                                                                                      | Adverse Event Characteristics                                                                                                                     |                                                                                                                                  |
| 7.3                                                                                                                                      | Expedited Adverse Event Reporting ............................................................................46                                  |                                                                                                                                  |
| 7.4                                                                                                                                      | DF/HCC Expedited Reporting Guidelines .....................................................................46                                     |                                                                                                                                  |
| OVerdose of Lenalidomide .............................................................................................................49 |                                                                                                                                                   |                                                                                                                                  |
| 7.5                                                                                                                                      | Expedited Reporting to the Food and Drug Administration (FDA)........................49                                                           |                                                                                                                                  |
| 7.6                                                                                                                                      | Expedited Reporting to Bristol-Myers Squibb (BMS)                                                                                                 |                                                                                                                                  |
| 7.7                                                                                                                                      | Expedited Reporting to Celgene ...................................................................................49                              |                                                                                                                                  |
| 7.8                                                                                                                                      | Expedited Reporting to Hospital Risk Management                                                                                                   |                                                                                                                                  |
| 7.9                                                                                                                                      | Routine Adverse Event Reporting                                                                                                                   |                                                                                                                                  |
| 8.                                                                                                                                       | PHARMACEUTICAL INFORMATION ..............................................................................................50                       |                                                                                                                                  |
| Elotuzumab                                                                                                                               |                                                                                                                                                   |                                                                                                                                  |
| 8.1                                                                                                                                      |                                                                                                                                                   |                                                                                                                                  |
| 8.2                                                                                                                                      | Lenalidomide                                                                                                                                      |                                                                                                                                  |
| 8.3                                                                                                                                      | DEXAMETHASONE                                                                                                                                     |                                                                                                                                  |
| BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ................................................56                                           |                                                                                                                                                   |                                                                                                                                  |
| 9.                                                                                                                                       | 9.1                                                                                                                                               | Bone Marrow Aspirate Samples .................................................................................................57 |
| 9.2                                                                                                                                      | Peripheral Blood Samples ...................................................................................................................58    |                                                                                                                                  |
| 10.                                                                                                                                      | STUDY CALENDAR.................................................................................................................................61 |                                                                                                                                  |
| 11.                                                                                                                                      | MEASUREMENT OF EFFECT ...................................................................................................................62       |                                                                                                                                  |
| 11.1                                                                                                                                     | Development of symptomatic disease ................................................................................62                             |                                                                                                                                  |
| 11.2                                                                                                                                     | Antitumor Effect ......................................................................................................................63         |                                                                                                                                  |
| 12.                                                                                                                                      | DATA REPORTING / REGULATORY REQUIREMENTS .................................................70                                                      |                                                                                                                                  |
| 12.1                                                                                                                                     | DATA Reporting ...............................................................................................................................70  |                                                                                                                                  |
| 12.2                                                                                                                                     | DATA SAFETY Monitoring                                                                                                                            |                                                                                                                                  |
| 13.                                                                                                                                      | STATISTICAL CONSIDERATIONS. ...........................................................................................70                         |                                                                                                                                  |
| 13.1                                                                                                                                     | Study Design/Endpoints ...........................................................................................................70              |                                                                                                                                  |
| Sample Size, Accrual Rate and Study Duration ...............................................................72                           |                                                                                                                                                   |                                                                                                                                  |
| 13.2                                                                                                                                     |                                                                                                                                                   |                                                                                                                                  |
| 13.3                                                                                                                                     | Stratification Factors .....................................................................................................................72    |                                                                                                                                  |
| 13.4                                                                                                                                     | Interim Monitoring Plan .                                                                                                                         |                                                                                                                                  |
| 13.5                                                                                                                                     | Stopping Rule for Safety ...........................................................................................................72            |                                                                                                                                  |
| 14.                                                                                                                                      | PUBLICATION PLAN                                                                                                                                  |                                                                                                                                  |
| 15.                                                                                                                                      | REFERENCES                                                                                                                                        |                                                                                                                                  |
| APPENDIX A: PERFORMANCE STATUS CRITERIA ..................................................................78                             |                                                                                                                                                   |                                                                                                                                  |  
APPENDIX B: PREPARATION AND ADMINISTRATION OF ELOTUZUMAB...................79 APPENDIX C: 14-338 SPECIMEN COLLECTION SCHEDULE ..............................................82 APPENDIX D: 14-338 SPECIMEN REQUISITION....................................................................84 APPENDIX E: DF/HCC MULTI-CENTER DATA AND SAFETY MONITORING PLAN......85  
| 1.   | INTRODUCTION 89 1.1 Purpose 89 1.2 Multi-Center Data and Safety Monitoring Plan Definitions 89                                                                                                                                                                                                                                                                                                                                                 |
|------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 2.   | GENERAL ROLES AND RESPONSIBILITIES 90 2.1 DF/HCC Sponsor 90 2.2 Coordinating Center 91 2.3 Participating Institution 91                                                                                                                                                                                                                                                                                                                        |
| 3.   | DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 92 3.1 Protocol Distribution 92 3.2 Protocol Revisions and Closures 92 3.3 Informed Consent Requirements 93 3.4 IRB Documentation 93 3.5 IRB Re-Approval 93 3.6 Participant Confidentiality and Authorization Statement 94 3.7 DF/HCC Multi-Center Protocol Registration Policy 94 3.8 DF/HCC Protocol Case Number 95 3.9 Safety Assessments and Toxicity Monitoring 96 3.10 Data Management 97 |
| 4.   | REQUISITIONING INVESTIGATIONAL DRUG 97                                                                                                                                                                                                                                                                                                                                                                                                         |
| 5.   | MONITORING: QUALITY CONTROL 98 5.1 Ongoing Monitoring of Protocol Compliance 98 5.2 Monitoring Reports 99 5.3 Accrual Monitoring 99                                                                                                                                                                                                                                                                                                            |
| 6.   | AUDITING: QUALITY ASSURANCE 99 6.1 Audit Plan: DF/HCC Sponsored Trials 99 6.2 Audit Notification 99 6.3 Audit Reports 100 6.4 Participating Institution Performance 100                                                                                                                                                                                                                                                                        |
table of contents
1. introduction

The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC
that will be participating in the research protocol.
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1.1 purpose

To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center MultiCenter protocol will comply with Federal Regulations, Health Insurance Portability and Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures.
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1.2 multi-center data and safety

DF/HCC Multi-Center Protocol: A research protocol in which one or more outside institutions are collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates.  
Lead Institution: One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center (BIDMC), Boston Children's Hospital (BCH), Brigham and Women's Hospital (BWH)) responsible for the coordination, development, submission, and approval of a protocol as well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines (CTEP, Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.). The Lead Institution is typically the home of the DF/HCC Sponsor. The Lead Institution also typically serves as the Coordinating Center for the DF/HCC Multi-Center Protocol. DF/HCC Sponsor: The person sponsoring the submitted Multi-Center protocol. Within DF/HCC, this person is the Overall Principal Investigator who takes responsibility for initiation, management and conduct of the protocol at all research locations. In applicable protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory agencies. The DF/HCC Sponsor has ultimate authority over the protocol and is responsible for the conduct of the study at DF/HCC and all Participating Institutions. In most cases the DF/HCC Sponsor is the same person as the DF/HCC Overall Principal Investigator; however, both roles can be filled by two different people. Participating Institution: An institution that is outside the DF/HCC and DF/PCC consortium that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator. The Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority and responsibility for the overall conduct of the study. Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research Organization (CRO), etc) that provides administrative support to the DF/HCC Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol document and DSMP, and as specified in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). In general, the Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol. Should the DF/HCC Sponsor decide to use a CRO,
the CRO will be deemed the Coordinating Center.  
DF/HCC Quality Assurance Office for Clinical Trials: A group within DF/HCC responsible for registering human subjects for trials, ensuring high-quality standards are used for data collection and the ongoing management of clinical trials, auditing, and data and safety monitoring. QACT also coordinates quality assurance efforts related to multicenter clinical research.
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2. general roles and responsibilities

For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the Participating Institutions are expected to adhere to the following general responsibilities:
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2.1 df/hcc sponsor

The DF/HCC Sponsor, **Irene Ghobrial, MD** will accept responsibility for all aspects of conducting a DF/HCC Multi-Center protocol which includes but is not limited to:
- Oversee the coordination, development, submission, and approval of the protocol as well as subsequent amendments.  
- Ensure that the investigators, study team members, and Participating Institutions are qualified and appropriately resourced to conduct the protocol.  
- Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol.  
- Ensure all Participating Institutions are using the correct version of the protocol. - Ensure that each participating investigator and study team member receives adequate protocol training and/or a Site Initiation Visit prior to enrolling participants and throughout trial's conduct as needed.  
- Ensure the protocol will be provided to each participating site in a language understandable to all applicable site personnel when English is not the primary language.  
- Monitor progress and overall conduct of the study at all Participating Institutions.  
- Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable reporting requirements are met.  
- Review data and maintain timely submission of data for study analysis.  
- Ensure compliance with all requirements as set forth in the Code of Federal Regulations, applicable DF/HCC requirements, HIPAA requirements, and the approved protocol.  
- Commit to the provision that the protocol will not be rewritten or modified by anyone other than the DF/HCC Sponsor.  
- Identify and qualify Participating Institutions and obtain accrual commitments prior to extending the protocol to that site.  
- Monitor accrual and address Participating Institutions that are not meeting their accrual requirements.
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2.2 coordinating center

The general responsibilities of the Coordinating Center may include but are not limited to:
- Assist in protocol development.  
- Review registration materials for eligibility and register participants from Participating Institutions with DF/HCC QACT.  
- Distribute protocol and informed consent document updates to Participating Institutions as needed.  
- Oversee the data collection process from Participating Institutions. - Maintain documentation of Serious Adverse Event (SAE) reports and deviations/violation submitted by Participating Institutions and provide to the DF/HCC Sponsor for timely review.  
- Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions.  
- Provide Participating Institutions with information regarding DF/HCC
requirements that they will be expected to comply with.  
- Carry out plan to monitor Participating Institutions either by on-site or remote monitoring.  
- Maintain Regulatory documents of all Participating Institutions which includes but is not limited to the following: local IRB approvals/notifications from all Participating Institutions, confirmation of Federalwide Assurances (FWAs) for all sites, all SAE submissions, Screening Logs for all sites, IRB approved consents for all sites
- Conduct regular communications with all Participating Institutions (conference calls, emails, etc) and maintain documentation all relevant communications.
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2.3 participating institution

Each Participating Institution is expected to comply with all applicable federal regulations and DF/HCC requirements, the protocol and HIPAA requirements. The general responsibilities for each Participating Institution may include but are not limited to:
- Document the delegation of research specific activities to study personnel. - Commit to the accrual of participants to the protocol.  
- Submit protocol and/or amendments to their local IRB.  
- Maintain regulatory files as per sponsor requirements.  
- Provide the Coordinating Center with regulatory documents or source documents as requested.  
- Participate in protocol training prior to enrolling participants and throughout the trial as required (i.e. teleconferences).  
- Update Coordinating Center with research staff changes on a timely basis. - Register participants through the Coordinating Center prior to beginning research related activities.  
- Submit Serious Adverse Event (SAE) reports to local IRB per local requirements and to the Coordinating Center, in accordance with DF/HCC requirements.  
- Submit protocol deviations and violations to local IRB per local requirements and to the DF/HCC Sponsor in accordance with DF/HCC requirements.  
- Order, store and dispense investigational agents and/or other protocol mandated drugs per federal guidelines and protocol requirements.  
- Have office space, office equipment, and internet access that meet HIPAA
standards.  
- Participate in any quality assurance activities and meet with monitors or auditors at the conclusion of a visit to review findings.  
- Promptly provide follow-up and/or corrective action plans for any monitoring queries or audit findings.
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3. df/hcc requirements for multi-center

The following section will clarify DF/HCC Requirements and further detail the expectations for participating in a DF/HCC Multi-Center protocol.
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3.1 protocol distribution

The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent amended protocols to all Participating Institutions.
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3.2 protocol revisions and closures

The Participating Institutions will receive notification of protocol revisions and closures from the Coordinating Center. It is the individual Participating Institution's responsibility to notify its IRB of these revisions.  
- **Non life-threatening revisions:** Participating Institutions will receive written notification of protocol revisions regarding non life-threatening events from the Coordinating Center. Non-life-threatening protocol revisions must be IRB approved and implemented within 90 days from receipt of the notification.  
- **Revisions for life-threatening causes:** Participating Institutions will receive immediate notification from the Coordinating Center concerning protocol revisions required to protect lives with follow-up by fax, mail, e-mail, etc. Life-threatening protocol revisions will be implemented immediately followed by IRB request for approval.  
- **Protocol closures and temporary holds:** Participating Institutions will receive notification of protocol closures and temporary holds from the Coordinating Center. Closures and holds will be effective immediately. In addition, the Coordinating Center, will update the Participating Institutions on an ongoing basis about protocol accrual data so that they will be aware of imminent protocol closures.
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3.3 informed consent requirements

The DF/HCC approved informed consent document will serve as a template for the informed consent for Participating Institutions. The Participating Institution consent form must follow the consent template as closely as possible and should adhere to specifications outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated Multi-Center Protocols. This document will be provided separately to each Participating Institution. Participating Institutions are to send their version of the informed consent document and HIPAA authorization, if a separate document, to the Coordinating Center for review and approval prior to submission to their local IRB. The approved consent form must also be submitted to the Coordinating Center after approval by the local IRB for all consent versions. The Principal Investigator (PI) at each Participating Institution will identify the physician members of the study team who will be obtaining consent and signing the consent form for therapeutic protocols. Participating institutions must follow the DF/HCC requirement that only attending physicians obtain informed consent and re-consent to interventional trials (i.e. drug and/or device trials).
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3.4 irb documentation

The following must be on file with the Coordinating Center:
- Initial approval letter of the Participating Institution's IRB.  
- Copy of the Informed Consent Form(s) approved by the Participating Institution's IRB.  
- Participating Institution's IRB approval for all amendments. - Annual approval letters by the Participating Institution's IRB.
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3.5 irb re-approval

Verification of IRB re-approval from the Participating Institutions is required in order to continue research activities. There is no grace period for continuing approvals. The Coordinating Center will not register participants if a re-approval letter is not received from the Participating Institution on or before the anniversary of the previous approval date.
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3.6 participant confidentiality and authorization

In 1996, congress passed the first federal law covering the privacy of health information known as the Health Insurance Portability and Accountability Act (HIPPA). Any information, related to the physical or mental health of an individual is called Protected Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be used or disclosed. In order for covered entities to use or disclose protected health information during the course of a study, the study participant must sign an authorization statement. This authorization statement may or may not be separate from the informed consent document. The Coordinating Center, with the approval from the DFCI IRB, will provide a consent template, with information regarding authorization for the disclosure of protected health information.  
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials. However, because of the nature of these trials, certain protected health information must be collected. DF/HCC has chosen to use authorizations, signed by the participant in the trial, rather than limited data sets with data use agreements.
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3.6.1 df/hcc multi-center protocol confidentiality

All documents, investigative reports, or information relating to the participant are strictly confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should be de-identified. It is recommended that the assigned DF/HCC QACT case number (as described below) be used for all participant specific documents. Participant initials may be included or retained for cross verification of identification.
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see sections 4.3 and 4.4

Participants must be registered with the DF/HCC QACT before receiving treatment. Treatment may not be initiated until the Participating Institution receives confirmation of the participant's registration from the Coordinating Center. The DF/HCC Sponsor and DFCI IRB must be notified of any violations to this policy.  
3.7.3 Eligibility Exceptions The DF/HCC QACT will make no exceptions to the eligibility requirements for a protocol without DFCI IRB approval. The DF/HCC QACT requires each institution to fully comply with this requirement.
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3.8 df/hcc protocol case number

At the time of registration, QACT requires the following identifiers for all subjects: initials, date of birth, gender, race and ethnicity. Once eligibility has been established and the participant successfully registered, the participant is assigned a unique protocol case number. Participating Institutions should submit all de-identified subsequent communication and documents to the Coordinating Center, using this case number to identify the subject.
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3.8.1 protocol deviations exceptions and

Federal Regulations require an IRB to review proposed changes in a research activity to ensure that researchers do not initiate changes in approved research without IRB review and approval, except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC requires all departures from the defined procedures set forth in the IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible for reporting to the DFCI IRB. For reporting purposes, DF/HCC uses the terms "violation", "deviation" and "exception" to describe departures from a protocol. All Participating Institutions must adhere to these requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy for reporting to their local IRB.
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3.8.2 definitions

Protocol Deviation: Any departure from the defined procedures set forth in the IRBapproved protocol which is *prospectively approved* prior to its implementation.  
Protocol Exception: Any protocol deviation that relates to the eligibility criteria, e.g. enrollment of a participant who does not meet all inclusion/exclusion criteria. Protocol Violation: Any protocol deviation that was not prospectively *approved* by the IRB prior to its initiation or implementation.
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3.8.3 reporting procedures

DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the medical record and/or regulatory documents to describe all protocol exceptions, deviations and violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol violations/deviations are promptly reported per DFCI IRB guidelines. Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. The Participating Institution must submit the deviation request to the Coordinating Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation is submitted to the Participating Institution IRB, per institutional policy. A copy of the Participating Institution's IRB report and determination will be forwarded to the Coordinating Center within 10 business days after the original submission. All protocol violations must be sent to the Coordinating Center in a timely manner. Coordinating Center: Upon receipt of the violation/deviation report from the Participating Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for review. Subsequently, the Participating Institution's IRB violation/deviation report will be submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will forward all violation reports to CTEP via an internal DF/HCC process, as applicable.
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3.9 safety assessments and toxicity

The study teams at all participating institutions are responsible for protecting the safety, rights and well-being of study participants. Recording and reporting of adverse events that occur during the course of a study help ensure the continuing safety of study participants. All participants receiving investigational agents and/or other protocol mandated treatment will be evaluated for safety. The safety parameters include all laboratory tests and hematological abnormalities, physical examination findings, and spontaneous reports of adverse events reported by participants. All toxicities encountered during the study will be evaluated according to the NCI criteria specified in the protocol. Life-threatening toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating Center. Additional safety assessments and toxicity monitoring will be outlined in the protocol.  
3.9.1 Guidelines for Reporting Serious Adverse Events Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed in **Section 7** of the protocol. Participating Institutions must report the SAEs to the DF/HCC Sponsor and the Coordinating Center following the DFCI IRB Adverse Event Reporting Policy. The Coordinating Center will maintain documentation of all Participating Institution Adverse Event reports and be responsible for communicating to all participating investigators, any observations reportable under the DFCI IRB Reporting Requirements. Participating Institutions will review and submit to their IRB according to their institutional policies and procedures 3.9.2 Guidelines for Processing IND Safety Reports The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety Reports are distributed to the Participating Institutions. Participating Institutions will review and submit to their IRB according to their institutional policies and procedures.
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3.10 data management

The DF/HCC QACT develops case report forms (CRF/eCRFs), for use with the protocol. These forms are designed to collect data for each study. The DF/HCC QACT provides a web based training for eCRF users.
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3.10.1 data forms review

Data submissions are monitored for timeliness and completeness of submission. Participating Institutions are notified of their data submission delinquencies in accordance with the following:
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incomplete or questionable data

If study forms are received with missing or questionable data, the submitting institution will receive a written or electronic query from the DF/HCC QACT Data Analyst, Coordinating Center or designee. Responses to all queries should be completed and submitted within 14 calendar days. Responses may be returned on the written query or on an amended paper case report form, or in the case of electronic queries, within the electronic data capture (eDC) system. In the case of a written query for data submitted on a paper case report form, the query must be attached to the specific data being resubmitted in response.
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missing forms

If study forms are not submitted on schedule, the Participating Institution will receive a Missing Form Report from the Coordinating Center noting the missing forms. These reports are compiled by the DF/HCC QACT and distributed on a monthly basis.
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4. requisitioning investigational drug

The ordering of investigational agent is specified in **Section 8** of the protocol.  
Participating Institutions should order their own agent regardless of the supplier. If the agent is commercially available, check with the local Director of Pharmacy and/or the Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure that the agent can be ordered once the protocol is approved by the local IRB. If the agent is investigational, ensure that the pharmacy will be able to receive and store the agent according to state and federal requirements. The local IRB should be kept informed of who will supply the agent so that any regulatory responsibilities can be met in a timely fashion.
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5. monitoring quality control

The quality control process for a clinical trial requires verification of protocol compliance and data accuracy. The Coordinating Center, with the aid of the QACT provides quality control oversight for the protocol.
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5.1 ongoing monitoring of protocol

The Participating Institutions will be required to submit subject source documents to the DF/HCC Lead Institution or designee for monitoring. Also, the Participating Institution may be subject to on-site monitoring conducted by the DF/HCC Lead Institution.  
The DF/HCC Lead Institution will implement on-site as well as virtual monitoring activities to ensure that Participating Institutions are complying with regulatory and protocol requirements, data quality, and subject safety. At a minimum, the DF/HCC Lead Institute, or designee, will monitor each participating site twice a year while patients are receiving treatment. Should a Participating Institution be monitored once and then not accrue any additional patients or participant visits, then a second monitoring visit may not be necessary. Monitoring practices may include but are not limited to; source verification, review and analysis of the following: eligibility requirements of all participants, informed consent procedures, adverse events and all associated documentation, study drug administration / treatment, regulatory records and site trial master files, protocol deviations, pharmacy records, response assessments, and data management. Additionally, regular and ongoing communication with Participating Institutions will be accomplished by holding all site teleconferences at least monthly. The Lead Institution will keep in close touch with the Participating Institutions via email and phone. Source documents from Participating Institutions, will be collected at specific data points that support the primary and or secondary endpoints. On-Site Monitoring: On-site monitoring will occur at least once per year. Participating Institutions will be required to provide access to participants' complete medical record and source documents for source documentation verification during the on-site visit. In addition, upon request from a monitor or auditor, Participating Institutions should provide access to regulatory documents, pharmacy records, local policies related to the conduct of research, and any other trial-related documentation maintained by the participating site. If there are concerns for protocol compliance, issues that impact subject safety or the integrity of the study are found, or trends identified based on areas of need, additional monitoring visits may be scheduled. On site monitoring visits can be supplemented with virtual monitoring assessments, provided that the minimum monitoring frequencies are adhered to. Virtual **Monitoring:** The Coordinating Center will request source documentation from Participating Institutions as needed to complete monitoring activities. Participating Institutions will be asked to forward de-identified copies of participants' medical record and source documents to the Coordinating Center to aid in source documentation verification.
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5.2 monitoring reports

The DF/HCC Sponsor will review all monitoring reports for on-site and remote monitoring of Participating Institutions to ensure protocol compliance. The DF/HCC Sponsor may increase the monitoring activities at Participating Institutions that are unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local regulations. Participating Institutions may also be subject to an audit as determined by the DF/HCC Sponsor.
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5.3 accrual monitoring

Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual requirements for each participating institution. Accrual will be monitored for each participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual expectations may be subject to termination. Due to the small patient population, the accrual minimum requirement is at least 1 patient every two years.
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6. auditing quality assurance

Auditing is a method of Quality Assurance. Its main focus is to measure whether standards and procedures were followed. Auditing is the systematic and independent examination of all trial related activities and documents. Audits determine if evaluated activities were appropriately conducted and whether data was generated, recorded and analyzed, and accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code of Federal Regulations (CFR).
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6.1 audit plan df/hcc sponsored

One on-site audit will be scheduled by the QACT, assuming at least three participants have been treated on protocol at the site, or at the discretion of the DF/HCC sponsor. Approximately 3-4 participants would be audited at the site over a 2 day period. If violations which impact participant safety or the integrity of the study are found, more participant records may be audited.
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6.2 audit notification

It is the Participating Institution's responsibility to notify the Coordinating Center of all scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve this protocol. All institutions will forward a copy of final audit and/or re-audit reports and corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after the audit date.
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6.3 audit reports

The DF/HCC Sponsor will review all final audit reports and corrective action plans if applicable. The Coordinating Center, must forward these reports to the DF/HCC QACT per DF/HCC policy for review by the DF/HCC Audit Committee. Based upon the audit assessments the DF/HCC Audit Committee could accept or conditionally accept the audit rating and final report. Conditional approval could require the DF/HCC Sponsor to implement recommendations or require further follow-up. For unacceptable audits, the DF/HCC Audit Committee would forward the final audit report and corrective action plan to the DFCI IRB as applicable.
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6.4 participating institution performance

The DF/HCC Sponsor and DFCI IRB is charged with considering the totality of an institution's performance in considering institutional participation in the protocol.
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6.4.1 corrective actions

Participating Institutions that fail to meet the performance goals of accrual, submission of timely and accurate data, adherence to protocol requirements, and compliance with state and federal regulations, may be recommended for a six-month probation period. Such institutions must respond with a corrective action plan and must demonstrate during the probation period that deficiencies have been corrected, as evidenced by the improved performance measures. Participating Institutions that fail to demonstrate significant improvement will be considered by the DF/HCC Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI IRB may terminate a site's participation if it is determined that a site is not fulfilling its responsibilities as described above.