irb fda etc.) must also
8.2.8 ordering

Commercial supply of lenalidomide (Revlimid®) will be ordered through the participant's insurance and will be filled through a retail pharmacy, and shipped on a per cycle basis to the patient's home or to the treating institution's outpatient pharmacy, whichever the study team prefers. Lenalidomide will be provided in accordance with the Celgene Corporation's Revlimid REMS® program. Per standard Revlimid REMS® program requirements (as listed in section 3.1.7), 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.
irb fda etc.) must also
8.2.9 accountability

As drug is from commercial supply, sites should keep records per their institutional policies.  
8.2.10 Destruction and Return Unused or returned supplies of lenalidomide should be destroyed and documented according to institutional policies.
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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.  
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 During induction therapy, participants will receive dexamethasone as a single oral daily dose of 40mg on Days 1, 8 and 15 of cycles 1-6.
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8.3.8 ordering

Dexamethasone will be ordered from retail pharmacy through commercial drug supply.  
8.3.9 Accountability As drug is from commercial supply, sites should keep records per their institutional policies.  
8.3.10 Destruction and Return Unused or returned supplies of dexamethasone should be destroyed and documented according to institutional policies.
irb fda etc.) must also
9. biomarker correlative mrd assessment

The mandatory correlative studies will consider several potential predictive biomarkers. As discussed in the appropriate sections of the protocol, mutations such as N-RAS, K-RAS, MYC up-regulation, and gain or loss of chromosome 1q or 1p are hypothesized to correlate with disease progression. The sample size of this phase-2 study, 41 patients, will allow exploratory analyses on TTP correlation with biomarkers. The number of biomarkers and the associated CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.  
61 multiplicities will only allow us to provide empirical point estimates and confidence intervals for TTP-biomarker concordance indexes. Please refer to Appendix B for a full sample collection table. This trial will provide samples from consenting SMM patients treated with Nivolumab, lenalidomide and dexamethasone 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 several time points during the study, including before therapy, at the end of cycle 6, at the time of response determination (CR),at disease relapse, and at the time of completion 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. Samples collected for the purpose of research at Dana Farber Cancer Institute will be banked and retained for research use indefinitely. 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 immune cells will be determined.
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9.1 minimal residual disease assessment

MRD will be assessed using Adaptive's LymphoSIGHT platform as part of normal clinical care. Bone marrow samples will be collected per the collection time described in the table of sample collection. The collection kits and shipping supplies will be provided to the sites by Adaptive Inc. These samples will be packaged whole, and shipped to Adaptive, Inc. the same day priority overnight. Using Adaptive'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. Adaptive MRD levels will be quantified using spiked-in reference sequences. Adaptive Inc. will hold samples for up to 6 months after they have been analyzed, and then will subsequently be destroyed. The processing of these samples will be billed to the patient's insurance, and therefore, all information requested on the online test ordering portal must be filled out completely, and not de-identified. For Adaptive Inc. samples, use the packing supplies provided in each individual kit and follow the directions below to establish your account and order the required testing:
1. Create an online ordering profile for your physician and any staff who may order this test for your patients using the Physician Registration Form provided to you by the lead site.  
a. Enter all information under the "Ordering Physician" as the site responsible PI for the trial at your site b. "Online Access" should be checked off to enable online portal ordering of tests c. The "Designated Point of Contact" should be one non-physician member of the team as the contact for any and all study/order related questions d. The "Designated Point of Contact" should be the person ( along with the physician) who will have access to the patient's results and be able to send them to the lead site e. Be sure to include your own practice as the Primary Institution f. Additional points of contact should list any other members of the study team who may place orders for the patients on the trial g. Submit the form to clinicalservices@adaptivebiotech.com to establish your site 2. Order kits for your site by placing an order to clinicalservices@adaptivebiotech.com ;
ensure that you identify yourself as being part of trial 16-242; Overall PI Irene Ghobrial, MD and provide the proper shipping address for the kits 3. To order a ClonoSEQ ID test(also known as the B-Cell Clonality Test required at baseline/screening) or a Follow up Test (MRD or Tracking Test) for a patient:
a. After logging into your account, click "New Order" b. Choose Ordering Physician associated with 16-242 c. Under Trial/Study Code, enter 16-242 d. Click Pick a Patient, and then Create New Patient ( for follow up/MRD
samples, select established patient- Their information will populate the form)
e. Enter patient complete demographics (new patients only)
f. Under Diagnosis (es)/Clinical Indication ICD Codes, Multiple Myeloma C90.00 not having achieved a remission should be selected.  
g. Under clonoSEQ Assay, choose B Cell Clonality Test (Diagnostic ID test)
if it is the baseline sample. For follow up samples, select Tracking Test ( Minimal Residual Disease "MRD" test)
h. Under Billing Information, select Insurance, and enter the patient's complete insurance information (new patients only)
i. Under patient status, select "outpatient" and enter your full institution name j. Enter any secondary insurance information for the patient if applicable
(new patients only)
k. Enter the patient's complete billing address (new patients only) l. Under Specimen Information, select " Shipping Specimen to Adaptive",
Specimen Type: fresh bone marrow and the collection date  
m. The unique specimen ID should be chosen by the site and able to be connected to the patient later on ( you may use either letters or numbers or a combination of the two)
n. Under special instructions, please enter Fed Ex tracking number of the package o. Print out a copy of the Test Requisition Form ( TRF) and have either the Point of Contact, Additional Contacts or the Physician listed on the Physician Registration Form sign the designated signature space, and include it in the shipment p. Retain retain a copy of the Fed Ex Waybill in the patient's research folder attached to the copy of the TRF and file in the patient's research chart q. Please email Patrick Henrick (Phenrick@dfci.harvard.edu) and Alexandra Savell (asavell@dfci.harvard.edu) to notify of an outgoing shipment.
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diagnostic portal log in https//diagnostics.adaptivebiotech.com/account/login

To order kits for your **site**: Please order via clinicalservices@adaptivebiotech.com and reference the study number, 16-242 , and include the address where the kits should be shipped Results: The results of these tests will be sent to the lead site in the form of a PDF/scanned document emailed to the study team listed abovein real time. The patient's PHI should be redacted appropriately with only the patient's date of birth, and study specific identifier (initials and assigned study number) visible.  
* External sites may choose to use an alternate method/source to bill for this test, if they so choose. This must first be discussed and approved by the lead site prior to ordering any test.
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9.2 bone marrow aspirate samples

Collection of bone marrow aspirate specimens for exploratory analysis are requested at the times of all standard of care bone marrow collections. Specimens will be shipped (via traceable carrier) to and subsequently processed, analyzed, and stored at Dana-Farber Cancer Institute.
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9.2.1 specimens requested

2 Purple Top Tubes (K2EDTA), 10mL each(3 tubes at baseline). Specimens must be collected on Mondays to Thursdays for same-day shipment. For complete sample collection table, please refer to Appendix B
9.2.2 Processing Information 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 First Priority Overnight delivery the same day the sample was collected. Please only ship Monday-Thursday. **Please see Appendix B and C for** Collection Schedule and Requisition Form
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9.2.3 shipping information for bone

Label all specimens with the following: Subject Initials, Subject study number (will include protocol number), Visit at which sample was drawn (screening, response, Cycle X, etc. or progression), Date sample drawn (mm/dd/yyyy), Time sample drawn (24 hour clock).
irb fda etc.) must also
shipping instructions shipments must be

1. Samples should be placed in a sealed biohazard bag and placed in a box with a fridge pack.  
2. 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.  
3. An electronic copy (Word or Excel) of the sample requisition form 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.  
4. Please email Patrick Henrick (Patrick_Henrick@dfci.harvard.edu) and Alexandra Savell
(AlexandraE_Savell@dfci.harvard.edu) to notify of an incoming shipment.  
5. Please ship **Monday to Thursday** as shipments cannot be received on weekends and/or on holidays.  
6. Once drawn, samples may be shipped via overnight **air** to:
Irene Ghobrial, MD, Dana-Farber Cancer Institute, 77 Avenue Louis Pasteur HIM Building room 240, MA551, Boston, MA 02215 Phone: (617) 582-9857 Fax: (617) 632-8535. Please retain a copy for site record maintenance. Please see Appendix B and C for Collection Schedule and Requisition Form
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9.3 peripheral blood samples

Collection of peripheral blood specimens (including serum and plasma) for exploratory analysis are requested for all patients on this trial. Purple top tube collections will be requested at the same timepoints as bone marrow samples for correlative studies (see Section 10 and Appendix B for specific time points and instructions). These specimens should be taken at the time of routine blood collection 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 indefinitely. Please see Appendix B and C for Collection Schedule and Requisition Form Specimens Required: 2 x 10mL purple top tubes (K2EDTA) and 1 x 10 mL Streck tube should be collected Mondays to Thursdays for same-day shipment.
irb fda etc.) must also
- label all specimens with

o Subject Initials, Subject study number (will include protocol number), Visit at which sample was drawn (screening, response, Cycle X, progression etc.), Date sample drawn (mm/dd/yyyy), Time sample drawn (24 hour clock)
9.3.1 Processing Information:
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 First Priority Overnight the same day the sample was collected. Only ship Monday-Thursday. With each shipment, please include the following:  
1. Samples should be placed in a sealed biohazard bag and placed in a box with a fridge pack.  
2. 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 C for Sample Requisition** Form 3. 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.
4. Please email the lead site Project Manager to notify of an incoming shipment. 5. Please ship Monday to Thursday as shipments cannot be received on weekends and/or on holidays.  
6. Once drawn, samples may be shipped via overnight **air to:**
Irene Ghobrial, MD, Dana-Farber Cancer Institute, 77 Avenue Louis Pasteur HIM Building room 240, MA551, Boston, MA 02215 Phone: (617) 582-9857 Fax: (617) 6328535. Please retain a copy for site record maintenance.
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9.4 buccal swab samples

9.4.1 Collection, Processing, and Shipping 1. Ideally have the patient rinse mouth out with water immediately prior to sample collection at least one hour after eating, drinking, or brushing teeth 2. Pull open the package from one end 3. Remove the swab from the tube, taking care not to touch the white swab head with your fingers 4. Insert the swab into your mouth and rub firmly against the inside of your cheek or underneath lower and upper lip. For standard DNA collection, rub for 1 minute and in all cases, for a minimum of 20 sections. Please use reasonable, firm, solid pressure 5. Slide the plastic cap over the swab handle with the flat side of the cap facing upwards and the swab facing downwards 6. Insert the swab into the clear plastic tube and push the cap into place- Next, hold the cap while pulling the swab handle outwards to release the swab material into the tube 7. Close the cap by pushing the stopper fully into the cap ensuring the stopper is flush with the cap- The tube is now completely sealed 8. Mail same day, ambient to the lead site for processing. The caps can be placed in an envelope or other container with the trial number, patient study number (if registered), date of birth, site name, collection date and time 9. Two swabs should be used for each patient to ensure adequate sample for analysis
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23 2018 10. study calendar

Screening evaluations are to be conducted within 28 days of registration. Imaging assessments that are completed within 6 weeks of registration need not be repeated at screening. If a patient had a bone marrow core biopsy done within 6 weeks of registration, a bone marrow aspirate sample need only be collected for baseline and research purposes. Baseline assessments are to be conducted on C1D1 of initial therapy and should be considered separate from screening evaluations. If screening assessments are performed within 7 days of C1D1, disease assessments (SPEP, UPEP, Immunofixation, Free light chain assay, quantitative immunoglobulins) do not need to be repeated. Lab values that are used to prove eligibility for patients with progressive (evolving) smoldering myeloma do not need to be within the 21 day window, but screening values will need to be established in window. 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.  
| schedule and guidelines outlined in Section 5. Pre-registration                                                                          | Cycles 1-12 (28 days) 3             | Follow-Up                           |    |       |    |
|------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|-------------------------------------|----|-------|----|
|  28 days  prior to  registrat  ion                                                                                                      |  21 days  prior to  registrat  ion | Cycle 7 Day 1  and to  confirm  CR8 |    |       |    |
| Day 1 of                                                                                                                                 | Day 1 of                            |                                     |    |       |    |
| cycles 1-                                                                                                                                | cycles 7-12                         |                                     |    |       |    |
| 6 1                                                                                                                                      | End of                              | Every 3                             |    |       |    |
| Treatment18                                                                                                                              | Months11                            |                                     |    |       |    |
| Tests and procedures History and exam, height,                                                                                           | weight.                             |                                     |    |       |    |
| Performance Status                                                                                                                       | X                                   | X                                   | X  | X     | X  |
| Response Assessment17                                                                                                                    | X                                   | X                                   | X  | X     |    |
| Toxicity Notation                                                                                                                        | X                                   | 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  | X     |    |
| Free light chain assay                                                                                                                   | X                                   | X                                   | X  | X     | X  |
| Serum and Urine Immunofixation  (SPEP and UPEP) with quantitative                                                                        | X                                   | X                                   | X  | X     | X  |
| immunoglobulins9 2M, CRP, LDH16                                                                                                         | X                                   | X                                   | X  | X     |    |
| TSH, Free T4, Free T3                                                                                                                    | X                                   | X                                   | X  | X     |    |
| Metastatic Bone Survey and                                                                                                               | Spine                               |                                     |    |       |    |
| MRI OR PET/CT only10                                                                                                                     | X                                   | X                                   |    |       |    |
| EKG15                                                                                                                                    | X                                   | X                                   |    |       |    |
| Serum pregnancy test12                                                                                                                   | X                                   |                                     |    |       |    |
| Unilateral bone marrow aspirate and  biopsy5                                                                                             | X                                   | X                                   | X  |       |    |
| Research bone marrow aspirate6                                                                                                           | X5                                  | X6                                  | X6 |       |    |
| Research Blood7                                                                                                                          | X7                                  | X7                                  | X7 | X7    | X7 |
| Buccal Swab13                                                                                                                            | X                                   |                                     |    |       |    |
| 1- Cycle 1, Day 1 laboratory values need to meet eligibility criteria 2- Direct bilirubin to be obtained if total bilirubin is abnormal. |                                     |                                     |    |       |    |  
23  2018 7- Peripheral blood samples for correlative studies may be done at any time pre-treatment, though baseline and C1D1 samples should be considered separate time points.  
8-If C7D1 or confirmation of response BM aspirate and core biopsy was performed within 3 weeks of either timepoint, the procedure need not be repeated. At minimum, an aspirate sample is required 9- Disease assessment/response assessment is required each Day 1 starting with C2-If the participant's disease response is not followed primarily via a UPEP (24 hour urine collection) and Urine immunofixation, these tests may be done only at screening, end of treatment, and every 3 months during treatment.  
10-A CD of scans at screening and end of treatment is required to be sent to the lead site for central review. Screening scans should be sent with the eligibility packet to the lead site- This requirement includes a full body skeletal survey in addition to spinal MRI OR the patient may have only a low dose PET CT
11- Follow-up should occur every 3 months (+/- 14 days) for up to 3 years after end of treatment. 12- Women of child-bearing potential must abide by revlimid REMS procedures and may require additional pregnancy testing as described in section 3.1.7. 13- Buccal swab may be collected at any time throughout the study but should be collected pre treatment on C1D1 14- Thyroid labs are required at screening, C3D1, C6D1 and every 3 cycles thereafter, at end of treatment, and at any time that it is clinically indicated 15- Alert Overall PI immediately if there is concern for cardiac toxicity (At minimum, the following should be performed: cardiology consult, EKG, echocardiogram, and labs CPK and troponin; refer to section 6.2.7 for more details 16- B2M, CRP, and LDH are required at screening, C3D1, C6D1 and every 3 cycles thereafter, at end of treatment, and at any time that it is clinically indicated 17- A disease response assessment will be required at every Day 1 starting with Cycle 2, end of treatment, and every follow up visit ( q3 months) until completion, withdrawal, disease progression, subsequent therapy or death 18- All end of treatment assessments will be performed within 14 days from the date that the decision to end treatment was made by the study team
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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 (≥1 CRAB Criterion and Myeloma Defining Events ≥1 MDE):
- Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the upper limit of normal or >2.75 mmol/dL) due to myeloma
- Renal insufficiency (attributable to myeloma);
- Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) due to myeloma - Bone lesions (lytic lesions or generalized osteoporosis with compression fractures)
- Myeloma Defining Events (MDE) as follows:
o Clonal bone marrow plasma cell percentage ≥ 60%7 o An abnormal FLC-ratio ≥100 (involved kappa) or <0.01 (involved lambda)8 o 2 or more focal lesions on MRI or PET-CT studies9,10
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for measurement of response

The disease response will be assessed using criteria based on the International Myeloma Working Group Uniform Response Criteria in Section 11.2.2.1 or FreeLite™ Disease Response Criteria in Section 11.2.2.2. Disease response by the Modified EBMT Response Criteria in Section 11.3.2.3 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 **assessments.**
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11.2 antitumor effect

11.2.1 Methods for Evaluation of Disease All baseline evaluationsshould be performed on Cycle 1, Day 1 of initial therapy. Response will be assessed  
23  2018 every cycle for the first 6 cycles and then every 3 months in the maintenance phase. 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
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baseline and during follow-up.

11.2.2 Response Criteria A confirmation measurement for disease response assessments is required in this protocol. 11.2.2.1 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 11.1.1 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.  
| Response                                                                                                                                                | Criteria for Response                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| CR as defined below plus normal free light chain ratio and absence of  * by immunohistochemistry or  clonal cells in bone marrow ** immunofluorescence. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| Stringent CR  (sCR)                                                                                                                                     | *Confirmation with repeat bone marrow biopsy is not needed. **Presence/absence of clonal cells is based upon the k/λ ratio. An abnormal  k/l 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. Negative immunofixation on the serum and urine and disappearance of  any soft tissue plasmacytomas and <5% plasma cells in bone marrow. |
| Complete  Response (CR)                                                                                                                                 | *Confirmation with repeat bone marrow biopsy is not needed. 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.                                                                                                                                                                                                                                           |
| Very Good Partial  Response (VGPR)                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |  
| > 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   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Local Protocol #: 16-242  Version Date: 23 January 2018   | 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 M-protein  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 plasmacytomasis also required. 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.            |
|-----------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Stable Disease  (SD)                                      | > 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. |
| Progressive  Disease (PD)                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |  
11.2.2.2 FreeLite™ Disease Response Criteria  
| Response               | Criteria for 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.   |
|------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Complete Response (CR) |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |  
Partial Response **(PR)** If only measurable parameter is serum  
immunoglobulinsfree light chain (FLC), EITHER  
| Local Protocol #: 16-242  Version Date: 23 January 2018   | of the following changes qualify as partial response: - ≥50% decrease 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% decrease in the level of involved FLC  AND a ≥50% decrease in the ratio of  involved/uninvolved FLC from the lowest  response level. 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.   |
|-----------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Progressive Disease (PD)                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |  
11.2.2.3 Modified EBMT Response Criteria Criteria for Response **Response** a  
| Local Protocol #: 16-242  Version Date: 23 January 2018                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | 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.                          |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Complete Response                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | <5% plasma cells in the bone marrow on at least two determinations for a  minimum of six weeks. b                                                                                                                       |
| (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. 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. Partial response (PR) ≥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 |                                                                                                                                                                                                                         |  
| Local Protocol #: 16-242  Version Date: 23 January 2018                                                                                                                                                                                                                                                                                                                    | 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.                                                                                                                                                        |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Minimal response (MR)                                                                                                                                                                                                                                                                                                                                                      | 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. ≥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.                                                                                                                                                                                                                                                                                                                                                                                                                           |
| 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). |  
| Relapse from CR   |
|-------------------|  
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.  
| electrophoresis confirmed by at least one follow-up and excluding oligoclonal  immune reconstitution. ≥5% plasma cells in the bone marrow aspirate or biopsy. 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 .   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
11.2.3 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.
irb fda etc.) must also
11.2.3.1 mrd by lymphosight (adaptive

MRD will be carried out according to the LymphoSIGHTTM method (Adaptive Inc, Seattle, WA) 61. Prior studies have compared this technique to the traditional MRD immunofluorescence technique, as previously reported 62 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 (IGH-DJH), 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 recommendations63.  
11.2.4 Duration of Response and Endpoint Definitions 11.2.4.1 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.  
11.2.4.2 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.  
11.2.4.3 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.  
11.2.5 Progression-Free Survival The secondary endpoint in thisstudy, PFS is defined asthe 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.  
11.2.6 Response Review Central review of disease response assessments is not planned.
irb fda etc.) must also
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).
irb fda etc.) must also
12.1 data reporting

12.1.1 Method The DFCI Office of Data Quality 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 Data Safety Monitoring Committee According to the schedule set by the Office of Data Quality. 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.
irb fda etc.) must also
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.
irb fda etc.) must also
13. statistical considerations 13.1 study

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, 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 a dropout rate of 5%, we will accrue 41 patients to the trial in order to have 39 eligible patients. The Type I and II error probabilities have been derived using exact binomial probabilities.
irb fda etc.) must also
13.1.1 analysis of primary endpoint

The primary endpoint will be the 2-year progression-free rate and will be analyzed using binomial probability and corresponding 90% confidence interval. 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.
irb fda etc.) must also
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 with 90% exact binominal confidence interval (CI). The exact 90% CI around response rate will be no wider than 28% with 39 eligible patients 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. 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  
23  2018 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. It is expected that approximately 20% of the patients will receive cyclophosphamide (CTX) for mobilization and this may influence the PFS. Therefore, in a secondary analysis the 2 year PFS rate will be evaluated among those patients who did not receive CTX. Assuming that among the 39 eligible patients between 5-20% of the patients receive CTX for mobilization, the treatment will be considered promising if the observed response rate is at least 62%. With this rule, there is at least 80% probability of concluding the treatment is effective, when the true rate is 70% and less than 10% if true rate is 50%. 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.
irb fda etc.) must also
13.2 sample size accrual rate

A total of 41 patients will be enrolled. We expect 1.5 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.
irb fda etc.) must also
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. Copies of the toxicity reports prepared by the DSMC
meetings will be distributed to the Principal Investigator. The Principal Investigator will then distribute to subinvestigators. 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. No interim analysis of the outcome data is planned.
irb fda etc.) must also
13.5 stopping rule for safety

All participants will be evaluable for treatment-related toxicity from the time of therapy initiation. The serious adverse event (SAE) for this purpose is defined as any grade 4 or higher unexpected, adverse event that is assessed as being related to the study intervention. The following table provides the probabilities of observing 3 or more SAEs after the 20th patient and before the 40th patient. For example, with 20 participants, there is 0.60 probability of observing 3 or more SAEs if a true rate is 15% and the probability is 0.021 if a true rate is 3%.  
| True SAE rate   | 1%    | 3%    | 5%    | 10%   | 15%   | 20%   | 30%   |
|-----------------|-------|-------|-------|-------|-------|-------|-------|
| Probability     | 0.001 | 0.021 | 0.075 | 0.32  | 0.60  | 0.79  | 0.96  |
| (≥SAEs)         |       |       |       |       |       |       |       |
irb fda etc.) must also
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. 1. Dispenzieri A, Stewart AK, Chanan-Khan A, et al: Smoldering multiple myeloma requiring treatment: time for a new definition? Blood 122:4172-81, 2013 2. Kyle RA, Greipp PR: Smoldering multiple myeloma. N Engl J Med 302:1347-9, 1980 3. Alexanian R: Localized and indolent myeloma. Blood 56:521-5, 1980 4. Durie BG, Salmon SE: A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 36:842-54, 1975 5. Kyle RA, Durie BG, Rajkumar SV, et al: Monoclonal gammopathy of undetermined significance (MGUS)
and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 24:1121-7, 2010 6. International Myeloma Working G: Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 121:749-57, 2003 7. Rajkumar SV, Larson D, Kyle RA: Diagnosis of smoldering multiple myeloma. N Engl J Med 365:474-5, 2011 8. Larsen JT, Kumar SK, Dispenzieri A, et al: Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia 27:941-6, 2013 9. Hillengass J, Fechtner K, Weber MA, et al: Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 28:1606-10, 2010 10. Hillengass J, Landgren O: Challenges and opportunities of novel imaging techniques in monoclonal plasma cell disorders: imaging "early myeloma". Leuk Lymphoma, 2013 11. Kyle RA, Remstein ED, Therneau TM, et al: Clinical course and prognosis of smoldering (asymptomatic)
multiple myeloma. N Engl J Med 356:2582-90, 2007 12. Dispenzieri A, Kyle RA, Katzmann JA, et al: Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood 111:785-9, 2008 13. Perez-Persona E, Vidriales MB, Mateo G, et al: New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 110:2586-92, 2007 14. Ghobrial IM: Revisiting treatment paradigms in high-risk smoldering multiple myeloma: out with the old, in with the new? Leuk Lymphoma 54:2328-30, 2013 15. Mateos MV, San Miguel JF: New approaches to smoldering myeloma. Curr Hematol Malig Rep 8:270-6,  
23  2018 2013 16. Cherry BM, Korde N, Kwok M, et al: Modeling progression risk for smoldering multiple myeloma: results from a prospective clinical study. Leuk Lymphoma 54:2215-8, 2013 17. Mateos MV, Hernandez MT, Giraldo P, et al: Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 369:438-47, 2013 18. Anderson KC, Carrasco RD: Pathogenesis of myeloma. Annu Rev Pathol 6:249-74, 2011 19. Kyle RA, Durie BG, Rajkumar SV, et al: Monoclonal gammopathy of undetermined significance (MGUS)
and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 24:1121-7, 2010 20. Kyle RA, Therneau TM, Rajkumar SV, et al: Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 354:1362-9, 2006 21. Dispenzieri A, Katzmann JA, Kyle RA, et al: Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study. Lancet 375:1721-8, 2010 22. Landgren O, Kyle RA, Pfeiffer RM, et al: Monoclonal gammopathy of undetermined significance (MGUS)
consistently precedes multiple myeloma: a prospective study. Blood 113:5412-7, 2009 23. Weiss BM, Abadie J, Verma P, et al: A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 113:5418-22, 2009 24. Lopez-Corral L, Sarasquete ME, Bea S, et al: SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status. Leukemia, 2012 25. Visone R, Croce CM: MiRNAs and cancer. Am J Pathol 174:1131-8, 2009 26. Pichiorri F, Suh SS, Ladetto M, et al: MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci U S A 105:12885-90, 2008 27. O'Donnell KA, Wentzel EA, Zeller KI, et al: c-Myc-regulated microRNAs modulate E2F1 expression.  
Nature 435:839-43, 2005 28. Chesi M, Robbiani DF, Sebag 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 13:167-80, 2008 29. Chiecchio L, Dagrada GP, Protheroe RK, et al: Loss of 1p and rearrangement of MYC are associated with progression of smouldering myeloma to myeloma: sequential analysis of a single case. Haematologica 94:1024-8, 2009 30. Chapman MA, Lawrence MS, Keats JJ, et al: Initial genome sequencing and analysis of multiple myeloma.  
23  2018 Nature 471:467-72, 2011 31. Egan JB, Shi CX, Tembe W, et al: Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood 120:1060-6, 2012 32. Keats JJ, Chesi M, Egan JB, et al: Clonal competition with alternating dominance in multiple myeloma.  
Blood 120:1067-76, 2012 33. Walker BA, Wardell CP, Melchor L, et al: Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma. Blood 120:1077-86, 2012 34. Bahlis NJ: Darwinian evolution and tiding clones in multiple myeloma. Blood 120:927-8, 2012 35. Greaves M, Maley CC: Clonal evolution in cancer. Nature 481:306-13, 2012 36. Rasillo A, Tabernero MD, Sanchez ML, et al: Fluorescence in situ hybridization analysis of aneuploidization patterns in monoclonal gammopathy of undetermined significance versus multiple myeloma and plasma cell leukemia. Cancer 97:601-9, 2003 37. Bergsagel PL, Kuehl WM: Molecular pathogenesis and a consequent classification of multiple myeloma. J
Clin Oncol 23:6333-8, 2005 38. Kyle RA, Larson DR, Therneau TM, et al: Clinical course of light-chain smouldering multiple myeloma
(idiopathic Bence Jones proteinuria): a retrospective cohort study. Lancet Haematol 1:e28-e36, 2014 39. Rajkumar SV, Dimopoulos MA, Palumbo A, et al: International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15:e538-48, 2014 40. Rajkumar SV, Landgren O, Mateos MV: Smoldering multiple myeloma. Blood, 2015 41. Sehgal K, Das R, Zhang L, et al: Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets. Blood 125:4042-51, 2015 42. Anderson K, Lutz C, van Delft FW, et al: Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469:356-61, 2011 43. Barrett MT, Sanchez CA, Prevo LJ, et al: Evolution of neoplastic cell lineages in Barrett oesophagus. Nat Genet 22:106-9, 1999 44. Morgan GJ, Walker BA, Davies FE: The genetic architecture of multiple myeloma. Nat Rev Cancer 12:33548, 2012 45. Walker BA, Wardell CP, Melchor L, et al: Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia, 2013  
23  2018 46. Chng WJ, Huang GF, Chung TH, et al: Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma. Leukemia 25:1026-35, 2011 47. Lopez-Corral L, Sarasquete ME, Bea S, et al: SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status. Leukemia 26:2521-9, 2012 48. Paiva B, Gutierrez NC, Rosinol L, 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 119:687-91, 2012 49. Lohr JG, Stojanov P, Lawrence MS, et al: Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proceedings of the National Academy of Sciences of the United States of America 109:3879-84, 2012 50. Cibulskis K, Lawrence MS, Carter SL, et al: Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 31:213-9, 2013 51. Hammerman PS, Hayes DN, Wilkerson MD, et al: Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519-25, 2012 52. Chen CL, Rappailles A, Duquenne L, et al: Impact of replication timing on non-CpG and CpG substitution rates in mammalian genomes. Genome research 20:447-57, 2010 53. Lieberman-Aiden E, van Berkum NL, Williams L, et al: Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326:289-93, 2009 54. Beroukhim R, Getz G, Nghiemphu L, et al: Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proceedings of the National Academy of Sciences of the United States of America 104:20007-12, 2007 55. Eswaran J, Horvath A, Godbole S, et al: RNA sequencing of cancer reveals novel splicing alterations. Sci Rep 3:1689, 2013 56. Kothari V, Wei I, Shankar S, et al: Outlier kinase expression by RNA sequencing as targets for precision therapy. Cancer Discov 3:280-93, 2013 57. Yu M, Ting DT, Stott SL, et al: RNA sequencing of pancreatic circulating tumour cells implicates WNT
signalling in metastasis. Nature 487:510-3, 2012 58. Griffith M, Griffith OL, Mwenifumbo J, et al: Alternative expression analysis by RNA sequencing. Nat Methods 7:843-7, 2010 59. Rosenblatt J, Glotzbecker B, Mills H, et al: PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother 34:409-18, 2011  
23  2018 60. Azzi J, Moore RF, Elyaman W, et al: The novel therapeutic effect of phosphoinositide 3-kinase-gamma inhibitor AS605240 in autoimmune diabetes. Diabetes 61:1509-18, 2012 61. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al: Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood 123:3073-9, 2014 62. Paiva B, Gutierrez NC, Rosinol L, 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 119:687-91, 2012 63. Rajkumar SV, Harousseau JL, Durie B, et al: Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 117:4691-5, 2011  
| 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.              |             |                 |             |
| 40                                                                                                                                                                | Disabled, requires special care and  assistance.                 |                                                                           |             |                 |             |
| In bed >50% of the time. Capable  of only limited self-care, confined to bed or chair more than 50% of  waking hours.                                             |                                                                  |                                                                           |             |                 |             |
| 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.       |                 |             |
irb fda etc.) must also
23 2018 appendix b specimen

| Sample Time Point                                                                                                                         | Recipient                              | Sample Type                  | Shipping Method                   | Container1,2,4                                                               |
|-------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------|------------------------------|-----------------------------------|------------------------------------------------------------------------------|
| 3x10mL Purple Top  1x10mL Streck Tube                                                                                                     |                                        |                              |                                   |                                                                              |
| Peripheral Blood                                                                                                                          | Fridge pack same day                   |                              |                                   |                                                                              |
| DFCI                                                                                                                                      | Bone Marrow Aspirate                   | 2x10mL Purple Top            |                                   |                                                                              |
| Baseline                                                                                                                                  | Oragene Kit or Buccal  Swab2           | Ambient same day             | 2x Buccal Swabs or 1  Oragene Kit |                                                                              |
| Adaptive                                                                                                                                  | Bone Marrow Aspirate                   | Same day - Use kit  provided | 1x3ml Purple Top                  |                                                                              |
| Cycle 1 Day 1  (Pre Dose)                                                                                                                 | DFCI                                   | Peripheral Blood             | Fridge pack same day              | 2x10mL Purple Top  1x10mL Streck Tube                                        |
| Cycle 2-6 Day 1  (Predose)                                                                                                                | DFCI                                   | Peripheral Blood             | Fridge pack same day              | 2x10mL Purple Top  1x10mL Streck Tube 2x 10mL Purple Top  1x10mL Streck Tube |
| Peripheral Blood                                                                                                                          |                                        |                              |                                   |                                                                              |
| End of Cycle 6                                                                                                                            | DFCI                                   | Fridge pack same day         |                                   |                                                                              |
| (Cycle 7 Day 1)                                                                                                                           | Bone Marrow Aspirate                   | 2x10mL Purple Top            |                                   |                                                                              |
| Cycle 8-12 Day 1  (Predose)                                                                                                               | DFCI                                   | Peripheral Blood             | Fridge pack same day              | 2x10mL Purple Top  1x10mL Streck Tube 2x 10mL Purple Top  1x10mL Streck Tube |
| Peripheral Blood                                                                                                                          |                                        |                              |                                   |                                                                              |
| DFCI                                                                                                                                      | Fridge pack same day                   |                              |                                   |                                                                              |
| Confirm Complete  Response 3                                                                                                              | Bone Marrow Aspirate                   | 2x10mL Purple Top            |                                   |                                                                              |
| Adaptive                                                                                                                                  | Bone Marrow Aspirate                   | Same day - Use kit  provided | 1x3ml Purple Top                  |                                                                              |
| Peripheral Blood                                                                                                                          |                                        |                              |                                   |                                                                              |
| DFCI                                                                                                                                      | 2x 10mL Purple Top  1x10mL Streck Tube |                              |                                   |                                                                              |
| End of Treatment  and/or Disease  Progression                                                                                             | Fridge pack same day                   |                              |                                   |                                                                              |
| Bone Marrow Aspirate                                                                                                                      | 2x10mL Purple Top                      |                              |                                   |                                                                              |
| Clinically Indicated                                                                                                                      | DFCI                                   | Bone Marrow Aspirate         | Fridge pack same day              | 2x10mL Purple Top                                                            |
| 1 Purple Top= K2EDTA Tube; Streck Tube–Cell Free DNA collection tube-Please ensure you alert the lead site with enough notice if you need |                                        |                              |                                   |                                                                              |  
1 Purple Top= K2EDTA Tube; Streck Tube–Cell Free DNA collection tube-Please ensure you alert the lead site with enough notice if you need additional Streck tubes for your site.- All shipping materials are to be purchased and obtained by the external sites except for the buccal swabs and the Streck tubes, which will be provided by the lead site.  
2Buccal swabs and or Oragene kits will be provided by the lead site, and can be taken/sent at any time point during the trial 3 For definition of Complete Response, please refer to section 11.2.2 4 Streck Tubes should be drawn before any heparinized tubes if applicable
irb fda etc.) must also
local protocol # 16-242 version

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 Patrick Henrick (Patrick_Henrick@dfci.harvard.edu) and Alexandra Savell (AlexandraE_Savell@dfci.harvard.edu) to alert study team of shipment and include tracking number. Ship specimen(s) to: Irene Ghobrial, MD
Dana Farber Cancer Institute 77 Louis Pasteur Avenue HIM 240; MA551 Boston, MA 02115
irb fda etc.) must also
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)               |                       |                        |                                  |
| Pre-treatment/Baseline                           | Blood               | Aspirate              | Streck Top Purple Top  |                                  |
| Saliva                                           | Buccal Swab         |                       |                        |                                  |
| Cycle 1-12 Day 1 Specify Cycle                   | Blood               | Streck Top Purple Top |                        |                                  |
| Confirm Response                                 | Blood               | Aspirate              | Streck Top Purple Top  |                                  |
| Cycle 7 Day 1 (end of Cycle 6)                   | Blood               | Aspirate              | Streack Top Purple Top |                                  |
| End of Treatment                                 | Disease Progression | Blood                 | Aspirate               | Streck Top Purple Top Purple Top |
| Clinically Indicated/ Standard of Care           | Aspirate            | Blood                 | Streck Top             |                                  |
irb fda etc.) must also
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.  
23  2018 APPENDIX D: MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, GASTROINTESTINAL, HEPATIC, RENAL, SKIN, NEUROLOGICAL, AND PULMONARY ADVERSE EVENTS DUE TO NIVOLUMAB
irb fda etc.) must also
hepatic adverse event management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider imaging for
irb fda etc.) must also
gi adverse event management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. Opiates/narcotics
neurological adverse event management algorithm
gi adverse event management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.
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skin adverse event management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.  
  
Local Protocol \#: 16-242
Version Date: 23 January 2018
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pulmonary adverse event management algorithm

23  2018 APPENDIX E: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER DATA AND SAFETY MONITORING PLAN
Local Protocol \#: 16-242
Version Date: 23 January 2018  
23  2018  
| TABLE OF CONTENTS   |                                                          |                 |      |     |
|---------------------|----------------------------------------------------------|-----------------|------|-----|
| 1.                  | INTRODUCTION                                             | 96              |      |     |
| 1.1                 | PURPOSE                                                  | 96              |      |     |
| 1.2                 | MULTI-CENTER DATA AND SAFETY MONITORING PLAN DEFINITIONS | 96              |      |     |
| 2.                  | GENERAL ROLES AND RESPONSIBILITIES                       | 97              |      |     |
| 2.1                 | DF/HCC SPONSOR                                           | 97              |      |     |
| 2.2                 | COORDINATING CENTER                                      | 97              |      |     |
| 2.3                 | PARTICIPATING INSTITUTION                                | 98              |      |     |
| 3.                  | DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS           | 98              |      |     |
| 3.1                 | PROTOCOL DISTRIBUTION                                    | 99              |      |     |
| 3.2                 | PROTOCOLREVISIONS AND CLOSURES                           | 99              |      |     |
| 3.3                 | INFORMED CONSENTREQUIREMENTS                             | 99              |      |     |
| 3.4                 | IRB DOCUMENTATION                                        | 100             |      |     |
| 3.5                 | IRB RE-APPROVAL                                          | 100             |      |     |
| 3.6                 | PARTICIPANT CONFIDENTIALITY AND AUTHORIZATION STATEMENT  | 100             |      |     |
| 3.7                 | DF/HCC MULTI-CENTER PROTOCOL REGISTRATION POLICY         | 100             |      |     |
| 3.8                 | DF/HCCPROTOCOLCASE NUMBER                                | 101             |      |     |
| 3.9                 | SAFETY ASSESSMENTS AND TOXICITY MONITORING               | 103             |      |     |
| 3.10                | DATA MANAGEMENT                                          | 103             |      |     |
| 4.                  | REQUISITIONING                                           | INVESTIGATIONAL | DRUG | 104 |
| 5.                  | MONITORING: QUALITY CONTROL                              | 104             |      |     |
| 5.1                 | ONGOING MONITORING OF PROTOCOL COMPLIANCE                | 104             |      |     |
| 5.2                 | MONITORING REPORTS                                       | 105             |      |     |
| 5.3                 | ACCRUAL MONITORING                                       | 105             |      |     |
| 6.                  | AUDITING: QUALITY ASSURANCE                              | 105             |      |     |
| 6.1                 | AUDIT PLAN:                                              | 101             |      |     |
| 6.2                 | AUDIT PLAN: DF/HCC SPONSORED TRIALS                      | 106             |      |     |
| 6.3                 | AUDIT NOTIFICATION                                       | 106             |      |     |
| 6.4                 | AUDITREPORTS                                             | 106             |      |     |
| 6.5                 | PARTICIPATING INSTITUTION PERFORMANCE                    | 106             |      |     |  
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 serves as a reference for any sites external to DF/HCC that are participating in a DF/HCC clinical trial.
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1.1 purpose

To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 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 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. DF/HCC Office of Data Quality **(ODQ):** A group within DF/HCC responsible ensuring high-quality standards are used for data collection and the ongoing management of clinical trials, auditing, and data and safety monitoring. ODQ also coordinates quality assurance efforts related to multi-center clinical research. DF/HCC Clinical Trials Research Informatics Office **(CTRIO):** A group within DF/HCC responsible for providing a comprehensive data management platform for managing clinical trial data.
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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. - Act as the single liaison with the FDA - 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.  
- Maintain FDA correspondence, as applicable.  
- Review registration materials for eligibility and register participants from Participating Institutions in the DF/HCC clinical trial management system (CTMS).  
- Distribute protocol and informed consent document updates to Participating Institutions as needed.  
- Oversee the data collection process from Participating Institutions.  
23  2018
- 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 and submission to the DFCI IRB, as necessary.  
- 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 institutional requirements and to the Coordinating Center, in accordance with DF/HCC requirements.  
- Submit protocol deviations and violations to local IRB per institutional 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

23  2018 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 upon request. 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 for all interventional drug, biologic, or device research. 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.  
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 protocol 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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3.7 df/hcc multi-center protocol registration

See section 4.4 of the protocol document for specific registration details and logistics.
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3.7.1 participant registration

To register a participant, the following documents should be completed by the Participating Institution and faxed or e-mailed to the Research Project Manager at the lead site
- Copy of required laboratory tests including labs that satisfy inclusion criteria - Signed informed consent document
- HIPAA authorization form (if separate from the informed consent document)
- Completed Eligibility Checklist complete with appropriate signatures
- Study specific cover sheet The Coordinating Center will review the submitted documents in order to verify eligibility and consent. To complete the registration process, the Coordinating Center will:  
- Register the participant on the study with the DF/HCC Clinical Trial Management System (CTMS).  
- Upon receiving confirmation of registration, the Coordinating Center will inform the Participating Institution and provide the study specific participant case number.
Treatment may not begin without confirmation from the Coordinating Center that the **participant** has been registered. Enrollment can only occur during normal business hours, Monday through Friday from 8:00 AM to 5:00 PM Eastern Standard Time unless given ample notice to the lead site.
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3.7.2 initiation of therapy

Participants must be registered with the DF/HCC CTMS before the initiation of treatment or other protocolspecific interventions. Treatment and other protocol-specific interventions 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.
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3.7.3 eligibility exceptions

No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will be permitted. All Participating Institutions are required to fully comply with this requirement. The lead site will provide the appropriate paperwork to submit an eligibility exception request at the time of study start up.
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3.8 df/hcc protocol case number

At the time of registration, the following identifiers are required 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.  
23  2018 3.8.1 Protocol Deviations, Exceptions and Violations 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 IRB-approved 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 departure that was not prospectively *approved* by the IRB prior to its initiation or implementation.  
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. The deviation may not be implemented without all required approvals. All protocol violations must be sent to the Coordinating Center in a timely manner. The Coordinating Center will provide training for the requirements for the reporting of violations. 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.  
23  2018
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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 therapy 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 protocol 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/submit to their IRB according to their institutional policies and procedures.
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3.10 data management

DF/HCC CTRIO develops case report forms (CRF/eCRFs), for use with the protocol. These forms are designed to collect data for each study. DF/HCC CTRIO provides a web based training for all eCRF users.  
3.10.1 Data Forms Review Data submissions are monitored for timeliness and completeness of submission. If study forms are received with missing or questionable data, the submitting institution will receive a written or electronic query from the DF/HCC Office of Data Quality, Coordinating Center, or designee.  
23  2018 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 re-submitted in response. If study forms are not submitted on schedule, the Participating Institution will periodically receive a Missing Form Report from the Coordinating Center noting the missing forms.
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4. requisitioning investigational drug

The ordering of investigational agent is specified in the protocol 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 DF/HCC Office of Data Quality, provides quality control oversight for the protocol.
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5.1 ongoing monitoring of protocol

The Participating Institutions may be required to submit participant source documents to the Coordinating Center for monitoring. Participating Institution may also be subject to on-site monitoring conducted by the Coordinating Center. The DF/HCC lead site will implement ongoing monitoring activities to ensure that Participating Institutions are complying with regulatory and protocol requirements, data quality, and participant safety. Monitoring practices may include but are not limited to source data verification, and review and analysis of eligibility requirements, informed consent procedures, adverse events and all associated documentation, review of study drug administration/treatment, regulatory files, protocol departures reporting, pharmacy records, response assessments, and data management. 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  
23  2018 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
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remote/ 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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on-site monitoring

On-Site Monitoring: On-site monitoring will occur at least once per year depending on a site's accrual. 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.
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5.2 monitoring reports

The DF/HCC Sponsor will review all monitoring reports 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.
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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 a formal letter regarding accrual expectations, or termination. Due to the small patient population of this trial, the accrual minimum requirement is at least one patient every year.
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6. auditing quality assurance

Auditing is a method of Quality Assurance and involves 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, applicable Standard Operating Procedures (SOPs), and the Code of Federal Regulations (CFR).
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6.1 df/hcc internal audits

All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). Typically, 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.
neurological adverse event management algorithm
6.2 audit notifications

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.
neurological adverse event management algorithm
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 any reports to the DF/HCC ODQ per DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the DF/HCC Audit Committee would forward the final audit report and corrective action plan to the DFCI IRB as applicable.
neurological adverse event management algorithm
6.4 participating institution performance

The DF/HCC Sponsor, DFCI IRB, is charged with considering the totality of an institution's performance in considering institutional participation in the protocol. 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.
neurological adverse event management algorithm
protocol number 16-242

Principal **Investigator:** Irene Ghobrial, M.D.  
Protocol **Title:** Phase II Trial of the PD-1 Antibody Nivolumab in Combination with Lenalidomide and Low Dose Dexamethasone in Patients with High-Risk Smoldering Multiple Myeloma
Instruction Sheet for Participants Regarding Reproductive Risks
neurological adverse event management algorithm
pregnancy risk - all patients

You must never share lenalidomide (or other study drugs) with someone else. You must never donate blood while you are participating in this study and for at least 28 days after you have been discontinued from the study. You must receive counseling and complete phone surveys as required by the Revlimid REMS® program. Females of childbearing potential that might be caring for you should not touch the lenalidomide capsules or bottles unless they are wearing gloves. Any unused lenalidomide should be returned to the study staff.
neurological adverse event management algorithm
pregnancy risk - females

If you are a female of childbearing potential, you will be required to have a negative pregnancy test prior to receiving lenalidomide.  
- For the purposes of this study, a female of childbearing potential is a sexually mature female who: o Has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries)
o Has not been naturally postmenopausal for at least 24 consecutive months
(i.e., has had menses at any time during the preceding 24 consecutive months)
You will be required to use TWO reliable forms of birth control, one highly effective method and one additional effective method at the same time or practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) throughout lenalidomide therapy, including interruptions in therapy; and 2) for at least 28 days after discontinuation of lenalidomide. The use of birth control is required for 120 days following the last dose of nivolumab.
neurological adverse event management algorithm
pregnancy risk - males

Lenalidomide is present at very low levels in human semen of healthy men for three days after stopping the drug according to a study. For some men, such as men with kidney problems, lenalidomide may be present in semen for more than three days. For these reasons, to be safe, all male patients receiving lenalidomide must use a latex condom during any sexual contact with a pregnant female or with a female of childbearing potential while you are participating in this study, including during times when lenalidomide is temporarily stopped, and for at least 28 days after permanently stopping therapy, even if you have had a successful vasectomy. You must never donate blood, sperm, or semen while you are participating in this study and for at least 28 days after you have stopped therapy. In addition, men are required to continue to use birth control for 154 days following the last dose of nivolumab.  
Phase II Trial of the PD‐1 Antibody Nivolumab in Combination with Lenalidomide and Low Dose Dexamethasone in Patients with High‐Risk Smoldering Multiple Myeloma
neurological adverse event management algorithm
protocol #16-242

You are invited to take part in a clinical trial, a type of research. For purposes of this research, you will be referred to as a "participant". This research study is studying a targeted immunotherapy as a possible treatment for this diagnosis. Bristol‐Myers Squibb is supporting this research study by providing the study drug, Nivolumab. You are receiving this Information Sheet because Dana‐Farber Cancer Institute has a financial interest in Nivolumab, which may be affected by the outcome of this research. This is known as a potential "institutional conflict of interest."
Nivolumab is an investigational drug, which means that the intervention is being studied and has not been approved for your type of cancer by the FDA (U.S. Food and Drug Administration). It is possible that, as the result of this clinical trial and other clinical trials involving this drug that may follow, this investigational drug could be approved by the FDA, and become widely available for sale. Specifically, the drug being investigated involves a technology that was discovered through research conducted at DFCI. As a result, a concern exists that DFCI could be biased because it stands to benefit financially from the outcome of clinical trials involving this drug. Dana‐Farber Cancer Institute ("DFCI") is committed to ensuring that all of its research and clinical activities are conducted with integrity. As part of this commitment, DFCI fully discloses the existence of all actual or potential conflicts of interest to research participants, sponsors, and regulatory bodies. Also, we have made sure that appropriate steps have been taken to ensure the safety of research participants and the reliability of research results.  
First, DFCI will disclose the existence and nature of its financial interest to all research participants. Second, DFCI will disclose the existence and nature of its financial interest to all research collaborators and in all public presentations and publications of data related to this research.  
Finally, and most importantly, we want to be certain that all research participants are fully informed about the financial interest, and are able to consider this information in deciding whether to participate in this trial. To that end, if you have additional questions about DFCI's financial interests and their potential impact upon this clinical trial, or any of the steps taken by DFCI to safeguard the integrity of this research, please contact:
Roberta Driscoll, JD
Director, Office of Research Integrity Dana‐Farber Cancer Institute 450 Brookline Avenue, BP333 Boston, MA 02215‐5450 617‐632‐4557 Roberta_Driscoll@dfci.harvard.edu
16-242 phase ii trial of
participant self-administered drug diary patient

Take your medications exactly as prescribed by your doctor. See the next page for specific doses for each medication that you are taking on this study.  
- Keep capsules in the bottle(s) provided and do not transfer them to any other container. Store at room temperature.  
- Lenalidomide should be taken by mouth once per day for 21 days. Capsules must be swallowed whole with water at the same time each day. - Dexamethasone should be taken by the mouth. The days you will take dexamethasone will vary depending on your cycle. Please refer to the next page for a list of the appropriate days. Tablets must be swallowed whole and taken with food at the same time each day.  
- If you vomit after taking lenalidomide or dexamethasone, do NOT take another dose. Please note any vomiting in the **Comments** section of the diary on the next page.  
- If you miss a dose of lenalidomide and it has been less than 12 hours since the missed dose, take it as soon as you remember on the same day.  
If it has been more than 12 hours since missing a lenalidomide dose, you should not take the dose on that day, but take the next dose at the normal time on the following day.  
- If you miss a dose of dexamethasone, take it as soon as you remember on the same day. If you miss taking dexamethasone for the entire day, take your regular dose the next scheduled day (**do NOT take double** your regular dose to make up for the missed dose).  
- If you miss a dose please record "0" for Number **Taken** on the next page.  
- If you accidentally take an extra dose of lenalidomide in one day skip the next day's dose and record the extra dose on the next page and contact your study team immediately and seek emergency medical care.  
- Please bring any unused lenalidomide and all empty containers and diary to your next visit.
16-242 phase ii trial of
for clinic use only

information in the box to the right.  
| Staff Initials: Date Returned:                                          | # Lenalidomide capsules returned:   |
|-------------------------------------------------------------------------|-------------------------------------|
| # Lenalidomide capsules that should have been taken: Discrepancy Notes: |                                     |  
| Number Taken                                                                                                                                                                                                                                                                                                                    |               |              |    |       |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|--------------|----|-------|
| Lenalidomide                                                                                                                                                                                                                                                                                                                    | Dexamethasone | Comments     |    |       |
| STUDY PARTICIPANT SELF-ADMINISTERED DIARY  CYCLES 1-6                                                                                                                                                                                                                                                                           | Date          | vomited hour |    |       |
| Ex:                                                                                                                                                                                                                                                                                                                             | 6/1/2009      | 1            | 1  | later |
| Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 Day 21 Day 22 Day 23 Day 24 Day 25 Day 26 Day 27 Day 28                                                                                                                                      |               |              |    |       |
| Participant Identifier:                                                                                                                                                                                                                                                                                                         | Cycle #:      |              |    |       |
| Your MD  Phone  Your RN  Phone  STUDY DRUG INSTRUCTIONS: Take the following medications as indicated below.  Record the dose of each medication on the chart to  the right after taking each day. Lenalidomide: Cycles 1-6: mg by mouth on Days 1-21 Dexamethasone: Cycles 1-6: mg by mouth on Days 1, 8, 15 Patient Signature: | Date:         |              |    |       |
| Delegated Study Staff Signature:                                                                                                                                                                                                                                                                                                | Date:         |              |    |       |  
Your MD
Phone  
  
  
Phone
16-242 phase ii trial of
study drug instructions

Take the following medications as indicated below. Record the dose of each medication on the chart to the right after taking each day. Lenalidomide:
Cycles 7-12: mg by mouth on Days 1-21 Patient Signature: Date:  
| STUDY PARTICIPANT SELF-ADMINISTERED DIARY CYCLES 7-12 Participant Identifier: Cycle #:   |
|------------------------------------------------------------------------------------------|  
Delegated Study Staff Signature: Date:  
  
  
| Number Taken Lenalidomide                                                                                                                                                                     | Comments           |    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|----|
| Date                                                                                                                                                                                          | vomited hour later |    |
| Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 Day 21 Day 22 Day 23 Day 24 Day 25 Day 26 Day 27 Day 28Ex: | 6/1/2009           | 1  |  
| Number Taken                                                                                                                                                                                                                                                                                                                                                                                                                            |               |          |    |       |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|----------|----|-------|
| Lenalidomide                                                                                                                                                                                                                                                                                                                                                                                                                            | Dexamethasone | Comments |    |       |
| Date                                                                                                                                                                                                                                                                                                                                                                                                                                    |               |          |    |       |
| STUDY PARTICIPANT SELF-ADMINISTERED DIARY                                                                                                                                                                                                                                                                                                                                                                                               | vomited hour  |          |    |       |
| Ex:                                                                                                                                                                                                                                                                                                                                                                                                                                     | 6/1/2009      | 1        | 1  | later |
| Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 Day 21 Day 22 Day 23 Day 24 Day 25 Day 26 Day 27 Day 28                                                                                                                                                                                                                                              |               |          |    |       |
| CYCLES 7-12 FOR USE ONLY IF RECEIVING  DEXAMETHASONE IN MAINTENANCE Participant Identifier: Cycle #:  Your MD  Phone  Your RN  Phone  STUDY DRUG INSTRUCTIONS: Take the following medications as indicated below.  Record the dose of each medication on the chart to  the right after taking each day. Lenalidomide: Cycles 7-12: mg by mouth on Days 1-21 Dexamethasone: Cycles 7-12: mg by mouth on Days 1, 8, 15 Patient Signature: | Date:         |          |    |       |
| Delegated Study Staff Signature:                                                                                                                                                                                                                                                                                                                                                                                                        | Date:         |          |    |       |  
| DANA-FARBER CANCER INSTITUTE Nursing Protocol Education Sheet                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                     |                                                                                                 |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------|
| Protocol Number:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | 16-242                                                                                                                                                                                                                                                                                              |                                                                                                 |
| Protocol Name:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Phase II Trial of the PD-1 Antibody Nivolumab in Combination with Lenalidomide and Low  Dose Dexamethasone in Patients with High-Risk Smoldering Multiple Myeloma                                                                                                                                   |                                                                                                 |
| DFCI Site PI:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Irene Ghobrial, MD                                                                                                                                                                                                                                                                                  |                                                                                                 |
| DFCI Research Nurse:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Kaitlen Reyes, DNP; John Harran, Eileen Regan Laura Amweg, Kathleen Colson, Kristen Cummings, Heidi DiPietro, Meghan Leahy Ray                                                                                                                                                                      |                                                                                                 |
| Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol. Please also refer to ONC 15: Oncology Nursing Protocol Education Policy *** Remember to check the ALERT PAGE*** SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                     |                                                                                                 |
| Nivolumab is a fully human monoclonal antibody that targets the PD-1 cell surface membrane receptor. Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 and PD-L2, resulting in enhanced T-cell  proliferation and interferon-gamma (IFN-γ) release in vitro. Lenalidomide (REVLIMID) is a thalidomide analogue, is  an immunomodulatory agent with antiangiogenic properties. Dexamethasone is a synthetic adrenocortical steroid. - The Study Design is in Section 1.1 - The Study Rationale is in Section 2.9 - A cycle is defined as 28 days in Section 5.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                     |                                                                                                 |
| Study Design                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | -                                                                                                                                                                                                                                                                                                   | Nivolumab is dosed in fixed dosing, 240 mg IV                                                   |
| Dose  Calc.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | -                                                                                                                                                                                                                                                                                                   | Lenalidomide is dosed in fixed dosing, between 5-25 mg (increments of 5 mg for dose reductions) |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Dexamethasone is dosed in fixed dosing, 40 mg or 20 mg or 10 mg for dose reductions                                                                                                                                                                                                                 |                                                                                                 |
| Agent Administration Guidelines are found in Section 5.2 - Nivolumab is given IV every other week on Days 1&15; Lenalidomide is PO Days 1-21; Dexamethasone is  PO Days 1, 8, 15 for Cycles 1-6 ONLY - Nivolumab is given IV over 60 minutes (+/- 10 minutes); No standard premeds required, unless history of  infusion reaction. A 60 min post-infusion observation period is suggested, especially during first 2 cycles, but not mandatory per protocol. - The drugs may be administered in any order. - Criteria to treat DAY 1: ANC>1,000; PLT>50; Other drug related, non-heme tox <Grade 1 or baseline. - Criteria to treat DAY 15: For Lenalidomide: ANC>1,000; PLT>30; Hgb>8 Other drug related less than Grade 3 or baseline.  For Nivolumab: AST<90; ALT<156; Bilirubin<1.8; Creatinine<1.95 or <1.5 x baseline - Fasting is not required. - Lenalidomide capsules and Dexamethasone tablets should be swallowed whole, and should not be broken,  chewed or opened. Administration should be at approximately the same time each day. If a dose is missed and  less than 12 hours has elapsed since the missed dose, the patient may take the dose for that day. If more than  12 hours has elapsed since missing a dose at the normal time, the patient should not take the dose, but take  the next dose at the normal time on the following day. If a dose is missed, it should be taken as soon as  possible on the same day. If a dose is vomited, the dose should not be made up and the participant should continue with the regular schedule of the drug at the next dose. |                                                                                                                                                                                                                                                                                                     |                                                                                                 |
| Administration                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                     |                                                                                                 |
| Study Drug                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Dose Modifications/Dosing Delay for Toxicity are outlined in Section - This protocol uses NCI CTCAE criteria, version 4.03 - There are no dose modifications for Nivolumab, there are dose reductions per protocol for Lenalidomide and  Dexamethasone.                                             |                                                                                                 |
| Mods &  Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                     |                                                                                                 |
| Dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Concomitant Therapy Guidelines are in Section 5.3.1 - Stem cell mobilization and collection may be performed at time of best response or after 6 cycles of therapy. - Filgrastim is allowed, pegfilgrastim is NOT. - Transfusions and supportive care are allowed; bisphosphonate therapy included. |                                                                                                 |
| Con  Meds                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Study Calendar and Assessment Required data are outlined in Section 10 - The study calendar is in Section 10 - Vital signs: Before any infusion. - ECGs: One at screening and one at EOT. - NO PK's or biomarkers.                                                                                  |                                                                                                 |
| Required  Data Protocol #16-242: Drafted (9/7/16)(KAR)/Approved (12/20/16)(EMR)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                     |                                                                                                 |  
  
All study drugs require documentation of exact administration **time.**
Please be sure to DOCUMENT study medication **actual** UP/DOWN times in medical record (e.g. LMR, eMAR,
nursing notes). **Edit eMAR as needed to match the exact time given**.  
- If there is a discrepancy in the infusion time, delay in administration, or the infusion takes longer than is permitted by the guidelines of the protocol, please document the reason for the discrepancy in the medical record.  
Please be sure to also DOCUMENT any required observation periods, any additional vital signs, routes of administration, injection sites, etc.  
November XX, 2017  
 XXXXXXX XXXXXXXX XXXXXXXXX XXXXXXXXX Re: 16-242 A Phase II Trial of the PD-1 Antibody Nivolumab in Combination with Lenalidomide and Low Dose Dexamethasone in Patients with High-Risk Smoldering Multiple Myeloma ClinicalTrials.gov Identifier: NCT02903381
16-242 phase ii trial of
dear xxxxxxxx

We are reaching out to you to follow up on the recent closure of the clinical trial by the Food and Drug Administration that you had been enrolled on.  
On August 31st, 2017, the FDA requested that the company that makes this drug (BristolMyers Squibb) notify patients of safety concerns that were seen on two clinical trials using the drugs pembrolizumab (a similar drug to nivolumab), revlimid and dexamethasone. It was reported that there was an increased risk of death on those trials. This risk may also be associated with nivolumab. Although nivolumab is not the same drug, it works in a similar way and these findings may be relevant to your safety. We are formally requesting that you contact us immediately if you experience any new side effects. If you never received nivolumab, revlimid, or dexamethasone on this clinical trial, please retain this letter for reference. Please contact me at (617) 632-4198 or at Irene_Ghobrial@DFCI.HARVARD.EDU if you have any questions regarding the clinical hold, the future of the trial, or your safety as it relates to these findings. Sincerely,