chapter 4
4.3.3 evaluations required prior to

The following baseline evaluations to determine eligibility for LD chemotherapy must be performed less than or equal to 7 days prior to initiating LD chemotherapy unless otherwise noted, as specified in Table 4.3A  
1. History, physical examination, height, and weight 2. CBC with differential 3. Liver functions and blood chemistries: Serum creatinine, total bilirubin, AST, ALT. 4. Calculated or measured creatinine clearance 5. Pregnancy test, serum beta-HCG (sensitivity of at least 50 mIU/mL) for FCBP
6. Assessment for toxicities and adverse events 7. Laboratory Disease Evaluation (may be performed ≤ 14 days prior to initiating LD
chemotherapy)
a. Quantitative serum immunoglobulins b. Serum protein electrophoresis (SPEP) c. 24 hours urine to determine protein excretion, urine electrophoresis (UPEP) d. Immunofixation of urine and serum regardless of SPEP and UPEP results e. Serum free light chains (FLC) ratio 8. Bone Marrow Evaluation: local assessment of unilateral bone marrow biopsy and aspirate are required only to confirm CR in patients (may be performed less than 14 days prior to initiating LD chemotherapy).  
9. Coagulation Panel including partial thromboplastin time (PTT), international normalized ration (INR), and fibrinogen 10. Baseline evaluation for Neurotoxicity including Immune-effector Cell Encephalopathy (ICE) and Immune Effector Cell Associated Neurotoxicity (ICAN) (see Appendix H)
11. Protocol-required Samples for Correlative Studies and Future Research1 (Table 4.3B)
a. Bone marrow aspiration (16 mL) b. Peripheral blood (71 mL)
4.3.4 Evaluations and Requirements Prior to CAR T-Cell Infusion The following evaluations will be performed locally on the day of and prior to bb2121 infusion (all results are required prior to infusion except CRS panel):
1. History, physical examination, height, and weight  
2. CBC with differential 3. Liver functions and blood chemistries: Serum creatinine, total bilirubin, AST, ALT. 4. CRS panel: ferritin C-reactive protein 4.3.5 Evaluations and Requirements Following CAR T-Cell Infusion
Assessments will be performed on Days 4, 7, 10, 14, and 21 post bb2121infusion (unless otherwise indicated). More frequent evaluations may occur as clinically indicated. Refer to Table 4.3A for details on assessments to be performed:  
1. History, physical examination including height, and weight 2. CBC with differential 3. Evaluation for Neurotoxicity including Immune-effector Cell Encephalopathy (ICE)
and Immune Effector Cell Associated Neurotoxicity (ICAN) (see Appendix H)
4. Evaluation for CRS (see Appendix H) 5. CRS panel: ferritin and C-reactive protein 6. Assessment for toxicities and adverse events 7. Protocol-required Samples for Correlative Studies and Optional Future Research
(Table 4.3B):
a. Peripheral blood (16 mL) on Day 4, 7, 14, and 21 post-bb2121 infusion
The following assessments are required monthly for the first 3 months following bb2121 infusion then every 3 months thereafter until 12 months following bb2121 infusion (unless otherwise indicated). Refer to Table 4.3A for details on assessments to be performed:
1. History, physical examination height, and weight  
2. CBC with differential 3. Liver functions and blood chemistries: Serum creatinine, total bilirubin, AST, ALT 4. Pregnancy test, serum beta HCG (sensitivity of at least 50 mIU/mL) for FCBP
monthly until at least 1 year following lymphodepleting chemotherapy or 4 weeks following discontinuation of lenalidomide whichever is later. There are insufficient exposure data to provide any recommendation concerning the duration of contraception following treatment with bb2121. Any decision regarding contraception after bb2121 infusion should be discussed with the treating physician.
c. For FCBP that initiate lenalidomide:  
i. FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on therapy (including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide. Females with irregular menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while on therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (Appendix C).  
ii. The subject must follow the requirements of the Lenalidomide REMS program of the BMS/Celgene Corporation. This program provides education and counseling on the risks of fetal exposure, blood clots and reduced blood counts. The patient will be required to receive counseling every 28 days during treatment with lenalidomide, follow the pregnancy testing and birth control requirements of the program that are appropriate in order to take the telephone surveys regarding compliance with the program.  
5. Assessment for toxicities and adverse events
6. Evaluation for Neurotoxicity including Immune-effector Cell Encephalopathy (ICE)
and Immune Effector Cell Associated Neurotoxicity (ICAN)  
7. Laboratory Disease Evaluation a. Quantitative serum immunoglobulins b. Serum protein electrophoresis (SPEP) c. 24 hours urine to determine protein excretion, urine electrophoresis (UPEP) d. Immunofixation of urine and serum regardless of SPEP and UPEP results e. Serum free light chains ratios (FLC)
8 Bone Marrow Evaluation: local assessment of unilateral bone marrow biopsy and aspirate are required only to confirm CR in patients 9. Protocol-required Samples for Correlative Studies and Optional Future Research1
(Table 4.3B):
a. Peripheral blood (16 mL) on Day 60, 180, and 270 post-bb2121 infusion b. Peripheral blood (71mL) on Day 30, 90, 365 post-bb2121 infusion c. Bone Marrow Aspirate on Day 30 (14mL), 90 (16mL), 180 (8mL), 365
(16mL) post-bb2121 infusion
4.3.6 Pre-Maintenance Evaluations and Requirements The following evaluations to determine eligibility for maintenance initiation must be performed less than or equal to 14 days prior to the initiation of lenalidomide maintenance therapy unless otherwise noted below.  
1. History, physical examination including routine neurologic examination, height, and weight 2. Assessment for toxicities and adverse events 3. CBC with differential 4. Liver functions and blood chemistries: Serum creatinine, total bilirubin, AST, ALT. 5. Pregnancy test, serum beta-HCG (sensitivity of at least 50 mIU/mL) for FCBP
Women are required to have 2 pregnancy tests prior to the initiation of lenalidomide as follows (Appendix C)
a. The first is required within 10 to 14 days prior to prescribing lenalidomide, b. The second is required within 24 hours of prescribing lenalidomide.
4.3.7 Evaluations at the Time of Disease Progression  
1. Protocol-required Samples for Correlative Studies and Optional Future Research1
(Table 4.3B):
a. Peripheral blood (71mL)
b. Bone Marrow Aspirate (16mL)  
| Progression7                                                                                                                                    |                                                                               |                                                                                          |                                                                          |           |           |           |
|-------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|--------------------------------------------------------------------------|-----------|-----------|-----------|
| Disease                                                                                                                                         | X 6 X6                                                                        |                                                                                          |                                                                          |           |           |           |
| 365 (+/-  28 days) (+/- 28  days)  270  180 (+/-  28 days) 90 (+/-  7  days) 60 (+/-  7 days) 30 (+/- 7  days) 4, 7, 10,  14, 21  (+/- 2  days) | X                                                                             | X                                                                                        | X                                                                        | X         | X         |           |
| X                                                                                                                                               | X                                                                             | X                                                                                        | X                                                                        | X         | X         |           |
| Days Post bb2121 Infusion                                                                                                                       | X                                                                             | X 6 X                                                                                    | X                                                                        | X         | X         | X         |
| X                                                                                                                                               | X                                                                             | X                                                                                        | X                                                                        | X         |           |           |
| TABLE 4.3A: PATIENT CLINICAL ASSESSMENTS                                                                                                        | X X                                                                           | X12 X11 X 6 X X X13 X 6 X                                                                | Pregnancy test2 X12 X X9 X X                                             | X X10 X X | X X10 X X | X X10 X X |
| X X X X X                                                                                                                                       | X X                                                                           |                                                                                          |                                                                          |           |           |           |
| Maintenance  Screening  (< 14 days  prior to  maintenance  initiation)                                                                          |                                                                               |                                                                                          |                                                                          |           |           |           |
| Pre                                                                                                                                                 | X X X X                                                                       |                                                                                          |                                                                          |           |           |           |
| (< 7 days after  planned date of  bb2121  infusion)                                                                                             |                                                                               |                                                                                          |                                                                          |           |           |           |
| Pre-bb2121  Infusion  Screening /  bb2121  Infusion  (< 7 days prior  to initiating LD  Chemo) Screening  Pre-LD  Chemo  Leukapheresis  (< approximately  14 days postinitial enrollment) Enrollment  Screening  (< 30 days  prior to  enrollment)                                                                                                                                                 | X12 X                                                                         |                                                                                          |                                                                          |           |           |           |
| Pre                                                                                                                                                 | X                                                                             | X                                                                                        | X                                                                        | X         | X12       |           |
| Cardiac  Assessment: ECHO  or MUGA                                                                                                              | CBC, differential,  platelet count, liver  functions, and blood  chemistries1 |                                                                                          |                                                                          |           |           |           |
| Demographics and  Informed Consent                                                                                                              | Karnofsky  performance score                                                  | Infectious Disease  Markers: Hepatitis  and HIV  CRS Panel: ferritin  C-reactive protein | Oxygen saturation  by pulse oximetry Quantitative serum  immunoglobulins |           |           |           |
| Assessments                                                                                                                                     | History, physical  exam, weight and  height                                   | 24 Hour Urine for  UPEP, protein  excretion and  immunofixation                          |                                                                          |           |           |           |
| Study                                                                                                                                           | immunofixation                                                                |                                                                                          |                                                                          |           |           |           |
| SPEP and                                                                                                                                        |                                                                               |                                                                                          |                                                                          |           |           |           |
| Eligibility  Assessment8                                                                                                                        | Evaluation of  Creatinine  Clearance                                          |                                                                                          |                                                                          |           |           |           |  
BMT CTN 1902 Version 3.0 dated March 10, 2022 Blood and Marrow Transplant Clinical Trials Network BMT CTN 1902 Version 3.0 dated March 10, 2022 Blood and Marrow Transplant Clinical Trials Network  
| Progression7                                                                                                                                    |                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
|-------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Disease                                                                                                                                         | Toxicity assessment4 X5 X X5 X5 X5 X5 X5 X5 X5                                                                                                       | 1Blood chemistries include: serum creatinine, corrected serum calcium (if applicable), AST and ALT as required per protocol.  2 For female of childbearing potential: A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy;  or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).  3Bone Marrow aspirate and biopsy required only to confirm CR in patients if suspected due to other assessments, e.g. serology.  4The toxicity assessment will include a review of all toxicities including ICANS (immune-effector cell associated neurotoxicity syndrome), myelotoxicity and appropriate lab evaluations experienced during the entire  assessment period and the highest grade for each  toxicity during the assessment period will be recorded on the Toxicity or Myelotoxicity form in EDC using CTCAE version 5.  5 Toxicity Assessment will include Neurotoxicity Assessments (ICE and ICAN) and Myelotoxicity Assessments (see Appendix H) 6 CBC needs to be collected and results reported in CRF at the same time as optional  research samples are collected. 7 Only needed for patients that progress while in study follow up and optional research samples are being collected.  8Eligibility to proceed to next stage of trial will be assessed at each timepoint as indicated.  9Two pregnancy tests required prior to the initiation of lenalidomide: The first required within 10 to 14 days prior to prescribing lenalidomide and the second required within 24 hours of prescribing lenalidomide (see  Appendix C).  10To be performed ≤ 14 days prior to initiating LD chemotherapy. 11CBC with differential required within 24 hours prior to leukapheresis to determine ALC.  12To be performed ≤ 14 days prior to enrollment and after ICF has been obtained.  13Only CBC with differential required. |
| 365 (+/-  28 days) (+/- 28  days)  270  180 (+/-  28 days) 90 (+/-  7  days) 60 (+/-  7 days) 30 (+/- 7  days) 4, 7, 10,  14, 21  (+/- 2  days) | X                                                                                                                                                    | X3 X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| X                                                                                                                                               |                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Days Post bb2121 Infusion                                                                                                                       | X                                                                                                                                                    | X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| X                                                                                                                                               | X10 X X                                                                                                                                              | X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| X X10 X X                                                                                                                                       | X X X                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Maintenance  Screening  (< 14 days  prior to  maintenance  initiation)                                                                          |                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Pre                                                                                                                                                 | (< 7 days after  planned date of  bb2121  infusion)                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Pre-bb2121  Infusion  Screening /  bb2121  Infusion  (< 7 days prior  to initiating LD  Chemo) Screening  Pre-LD  Chemo  Leukapheresis  (< approximately  14 days postinitial enrollment) Enrollment  Screening  (< 30 days  prior to  enrollment)                                                                                                                                                 | X12 X                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Pre                                                                                                                                                 | Local assessment of  unilateral bone  marrow aspirate and  biopsy  Coagulation Panel  including PTT, INR,  and fibrinogen  Evaluation for  CRS/ICANS |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Assessments                                                                                                                                     | Serum free light  chain ratio                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Study                                                                                                                                           |                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |  
BMT CTN 1902 Version 3.0 dated March 10, 2022 Blood and Marrow Transplant Clinical Trials Network TABLE 4.3B: SAMPLE COLLECTION TIME POINTS  
| Disease Progression 1                                                                         | 16                                                             | 71                                          |                                                               |    |    |                     |    |    |                     |                                  |
|-----------------------------------------------------------------------------------------------|----------------------------------------------------------------|---------------------------------------------|---------------------------------------------------------------|----|----|---------------------|----|----|---------------------|----------------------------------|
| X                                                                                             | X                                                              | X                                           | X                                                             | X  | X  | X                   | X  |    |                     |                                  |
| 4 7 14 21 30 60 90 180 270 365                                                                | X                                                              | X                                           | X                                                             | X  | 16 | X X X X X X X X X X | X  | X  | X X X X X X X X X X | 71 16 16 16 16 71 16 71 16 16 71 |
| Days Post CAR-T Cell Infusion                                                                 | X2 X X                                                         | X X                                         | 16 8                                                          |    |    |                     |    |    |                     |                                  |
| X                                                                                             | X                                                              | X                                           | X                                                             |    |    |                     |    |    |                     |                                  |
| 14                                                                                            |                                                                |                                             |                                                               |    |    |                     |    |    |                     |                                  |
| X                                                                                             | X                                                              | X                                           | X                                                             |    |    |                     |    |    |                     |                                  |
| Leuka- pheresis Pre-LD Chemo                                                                  | 16                                                             |                                             |                                                               |    |    |                     |    |    |                     |                                  |
| X                                                                                             | X                                                              | X                                           | X                                                             | X  | X  | X                   | X  | X  |                     |                                  |
| Total Maximum Marrow Volume (mL)                                                              |                                                                |                                             |                                                               |    |    |                     |    |    |                     |                                  |
| Bone Marrow Aspirate                                                                          |                                                                |                                             |                                                               |    |    |                     |    |    |                     |                                  |
| MRD, BCMA expression and Immune  Profiling Assessment (6mL)                                   | CAR-T Cell expansion and persistence  (2 mL)                   |                                             |                                                               |    |    |                     |    |    |                     |                                  |
| Optional Repository Sample for Future  Research (6 mL)                                        | Peripheral Blood                                               | CAR-T Cell expansion and persistence  (8mL) | Optional Repository Sample for Future  Research - PBMC (45mL) |    |    |                     |    |    |                     |                                  |
| Optional Repository Sample for Future  Research - Serum (8mL) Total Maximum Blood Volume (mL) |                                                                |                                             |                                                               |    |    |                     |    |    |                     |                                  |
|                                                                                               |                                                                |                                             |                                                               |    |    |                     |    |    |                     |                                  |
| MRD Assessment by NGS (2 mL)                                                                  | Leukapheresis  Leukapheresis product for bb2121  manufacturing |                                             |                                                               |    |    |                     |    |    |                     |                                  |
| Immune Reconstitution (10mL)                                                                  |                                                                |                                             |                                                               |    |    |                     |    |    |                     |                                  |
| Sample Collection                                                                             |                                                                |                                             |                                                               |    |    |                     |    |    |                     |                                  |  
1 Only required for patients that progress while in study follow up 2 Only Immune Profiling Assessment done from Day 30 sample
chapter 4
4.4 data reporting 4.4.1 criteria

Forms that are not entered into the EDC system, Advantage eClinical® within the specified time will be considered delinquent. A missing form will continue to be requested either until the form is entered into the EDC and integrated into the Data and Coordinating Center's (DCC) master database, or until an exception is granted and entered into the Missing Form Exception File.
chapter 4
internal data monitoring

It is the responsibility of the site PI to ensure the validity of all patient data as well as the safety of all patients.
chapter 4
data monitoring and auditing

The Data Safety and Monitoring Board (DSMB) for the BMT CTN will convene as per standard procedure to review serious toxicities and adverse events for the purpose of determining whether the trial should be modified or stopped. Triggers for referral to the DSMB are described in the Interim Analysis and Stopping Guidelines of **Section 5.3.** If the monitoring of the safety endpoints described in **Section 5.3** results in a trigger for consultation with the DSMB, the DSMB may make recommendations about whether to continue accrual.
chapter 4
records

Any publication or presentation will refer to patients by a unique patient number and not by name to assure patient confidentiality.
chapter 4
4.4.2 reporting patient deaths

Recipient death information must be entered into the EDC within 24 hours of knowledge of the patient's death via a Death Form. If the cause of death is unknown at that time, it need not be recorded at that time. However, once the cause of death is determined, the form must be updated in EDC. In addition, any death occurring from the infusion of bb2121 through 60 days following the infusion (or longer to include 21 days of lenalidomide maintenance) must also be reported via the Adverse Event Reporting process described in section 4.5 below.  
4.4.3 Center for International Blood and Marrow Transplant Research (CIBMTR) Data Reporting
Centers participating in BMT CTN trials must register pre- and post-transplant outcomes on all consecutive hematopoietic stem cell transplants done at their institution during their time of participation to the Center for International Blood and Marrow Transplant Research (CIBMTR). Registration is done using procedures and forms of the Stem Cell Transplant Outcomes Database (SCTOD). Enrollment in BMT CTN 1902 must be indicated on the SCTOD pre-transplant registration form. Additionally, CIBMTR pre- and post- transplant Comprehensive Report Forms must also be submitted for all patients enrolled on this trial. CIBMTR forms will be submitted directly to the CIBMTR at the times specified on the Form Submission Schedule. Patients will be followed by the CIBMTR from time of autologous transplant through 15 years post-transplant.
chapter 4
4.5 adverse event reporting

AE reporting requirements are summarized below and in table 4.5. Any unanticipated serious adverse events (SAEs) from time of enrollment through the study defined follow up are required to be reported. All SAEs must be reported from the infusion of bb2121CAR-T therapy through 60 days after the infusion completes or through 21 days of lenalidomide maintenance, whichever is longer. All grades of non-serious AEs must also be reported from the infusion of bb2121 CAR-T therapy through the longer of either 60 days after the infusion completes or through 21 days of lenalidomide maintenance either by 1) reporting of all grades of toxicities anticipated for the participant population captured on the Toxicity or Myelotoxicity Form or 2) completion of the Adverse Event Form (single page only) for any event not captured on the Toxicity or Myelotoxicity Form. In addition, any SAEs occurring after that 60-day period/21 days of lenalidomide maintenance up to disease progression assessed as related to the investigational product bb2121 must be reported. Any occurrence of grade 4 myelotoxicity after initiating lenalidomide that persists for more than 4 weeks despite interruption/discontinuation of lenalidomide is also required to be reported as an SAE, as outlined in section 4.5.4.1.  
From the 61st day following the completion of the bb2121 infusion or the 22nd day of lenalidomide maintenance, only non-serious AEs captured through the Toxicity and Myelotoxicity Form are required to be reported. All reported SAEs are to be followed up until resolved, judged to be no longer clinically significant, or until they become chronic to the extent that they can be fully characterized. SAEs related to lenalidomide after 21 days of maintenance should be reported to BMS/Celgene under the voluntary reporting mechanism. Infections and deaths are collected separately in EDC as this is a study endpoint; however, should an infection or death meet the SAE criteria and be assessed by the investigator as related to bb2121, the infection or death must also be reported following the SAE reporting guidelines. Underlying disease relapse events are collected in the EDC separately because they are part of the endpoint analysis. Events of underlying disease relapse are not to be reported as AEs/SAEs for this study.
chapter 4
table 4.5 ae reporting phases

| Enrollment - 60 days post  completion of bb2121 infusion  or 21 days of lenalidomide  maintenance, whichever is  longer                        | 61 days post completion of infusion or  22nd day of lenalidomide  maintenance, whichever is longer - completion of AE reporting*   |    |
|------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------|----|
| Unanticipated SAEs or grade 4  anticipated event not collected  elsewhere in the study  database (following protocolspecific MOP Guidelines)                                                                                                                                                |                                                                                                                                    | X  |
| All SAEs»                                                                                                                                      | X                                                                                                                                  |    |
| SAEs related to bb2121                                                                                                                         | X                                                                                                                                  | X^ |
| Infections that are SAEs and  related to bb2121                                                                                                | X                                                                                                                                  | X  |
| Grade 4 myelotoxicity after  initiating lenalidomide  persisting for more than 4  weeks despite  interruption/discontinuation of  lenalidomide | X                                                                                                                                  | X  |
| Deaths related to b2121                                                                                                                        | X                                                                                                                                  | X  |
| All anticipated AEs for the  patient population captured via                                                                                   | X                                                                                                                                  | X  |
| the Toxicity Form  All anticipated hematologic  AEs for the patient population  captured via the Myelotoxicity  Form+                          | X                                                                                                                                  | X  |
| All AEs (not captured through  the Toxicity Form)                                                                                              | X                                                                                                                                  |    |  
*Completion (whichever is longer) of reporting will occur at 1) completion of study defined follow-up, death or a withdrawal criterion outlined in section 2.9; 2) progression of disease; OR 3) following diagnosis of a subsequent neoplasm meeting a criterion in section 4.5. » Any unanticipated SAE from time of enrollment through the study defined follow up are required to be reported and all SAEs are to be reported from bb2121 CAR-T therapy through 60 days post infusion. ^Any SAE assessed by the investigator as related to bb2121 after the patient meets a criterion to stop reporting SAEs will still require reporting.  
+ The Myelotoxicity Form will capture data on grade 4 myelotoxicities including whether the study lenalidomide is interrupted/disrupted and the duration of the interruption/disruption, along with a brief summary of the clinical details for grade 4 myelotoxicities that cause lenalidomide to be held for > 4 weeks.
chapter 4
4.5.1 definitions

Adverse Event: An AE is any untoward medical occurrence in a patient administered an investigational product or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease that is temporally associated with the use of a medical (investigational) product, whether or not related to the investigational product. Serious Adverse Event: An SAE, as defined per 21 CFR 312.32, is any adverse event that results in one of the following outcomes, regardless of causality and expectedness:
chapter 4
x results in death

x **Is life-threatening**. Life-threatening means that the person was at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction which hypothetically might have caused death had it occurred in a more severe form.  
x **Requires or prolongs inpatient hospitalization** (i.e., the event required at least a 24-hour hospitalization or prolonged a hospitalization beyond the expected length of stay). Hospitalization admissions and/or surgical operations scheduled to occur during the study period but planned prior to study entry are not considered SAEs if the illness or disease existed before the person was enrolled in the trial, provided that it did not deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier than planned).  
x **Results in persistent or significant disability/incapacity**. Disability is defined as a substantial disruption of a person's ability to conduct normal life functions.
chapter 4
x is a congenital anomaly

x **Is an important medical event when**, based upon appropriate medical judgment, it may jeopardize the patient and require medical or surgical intervention to prevent one of the outcomes listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.  
Medical and scientific judgment should be exercised in deciding whether expected reporting is also appropriate in situations other than those listed above. For example, important medical events may not be immediately life threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the outcomes listed in the definition above (e.g., suspected transmission of an infectious agent by a medicinal product is considered an SAE). Any event is considered a SAE if it is associated with clinical signs or symptoms judged by the investigator to have a significant clinical impact.  
x **An adverse event can be Anticipated or Unanticipated in regard to the patient**
population for this study. Anticipated adverse events are those that have been previously identified as resulting from administration of the agent. For the purposes of this study, an adverse event is considered anticipated when it appears in the current adverse event list, the Investigator's Brochure, the package insert or is included in the informed consent document as a potential risk.  
x **Unanticipated adverse events** are those that vary in nature, intensity or frequency from information in the current adverse event list, the Investigator's Brochure, the package insert, or when it is not included in the informed consent document as a potential risk.  
4.5.2 Classification of Adverse Events by Severity The severity refers to the intensity of the reported event. The Investigator must categorize the severity of each reportable SAE according to the NCI CTCAE version 5.0. CTCAE guidelines can be referenced at the following website: http://ctep.cancer.gov/reporting/ctc.html. For any term that is not specifically listed in the CTCAE scale, intensity will be assigned a grade of one through five using the following CTCAE guidelines:
1. **Grade 1**: Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only; intervention not indicated  
2. **Grade 2**: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living 3. **Grade 3**: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting selfcare activities of daily living 4. **Grade 4**: Life-threatening consequences; urgent intervention indicated
5. **Grade 5**: Death related to AE
4.5.3 Classification of Adverse Events by Relationship to Investigational Product The relationship of each reported event to the study treatment will be assessed by the Investigator; after careful consideration of all relevant factors such as (but not limited to) the underlying study indication, coexisting disease, concomitant medication, relevant history, pattern of the SAE, temporal relationship to any study treatment interventions and de-challenge or re-challenge according to the following guidelines:  
1. **Possibly, Probably, or Definitely Related:** there is a reasonable possibility that the study treatment caused the event. A relationship of possibly, probably or definitely related to the investigational product is considered related for the purposes of regulatory authority reporting.  
2. **Unlikely, or Not Related:** There is no reasonable possibility that the investigational product caused the event. An unlikely or not related relationship to the investigational product is not considered related for the purposes of regulatory authority reporting.
chapter 4
4.5.4 required adverse event reporting

Adverse event reporting will be consistent with BMT CTN procedures (protocol-specific Manual of Procedures), unless otherwise specified in section 4.5 above. The protocolspecific MOP defines reporting based on the terms Unexpected and Expected; however, for this study, the reporting will be based on the terms Unanticipated and Anticipated in addition to the MOP definition of Unexpected and Expected. SAEs that require reporting as specified in section 4.5 will be reported through an expedited AE reporting system via an EDC. Life-threatening and fatal SAEs must be reported within 24 hours of knowledge of the event. All other SAEs must be reported within one business day of knowledge of the event. Events entered in EDC will be reported using NCI's CTCAE Version 5.0. Non-serious AEs will be reported using NCI's CTCAE Version 5.0 as specified in section 4.5. For anticipated AEs, this may include reporting at regular intervals as defined on the Form Submission Schedule, including calendar-driven eCRFs (e.g., Toxicity) or eventdriven eCRFs (e.g., Relapse/Progression, Infection, Secondary Graft Failure and Death).  
The Data and Safety Monitoring Board (DSMB) will receive reports of all unanticipated/unexpected SAEs deemed to be related to bb2121 or maintenance therapy upon review by the BMT CTN Medical Monitor. A summary of all reported SAEs will be reviewed by the DSMB annually. Since this study is under an FDA Investigational New Drug, all suspected and unexpected fatal or life-threatening adverse events are reported to the FDA within seven calendar days after receipt of the information from the site, following FDA guidelines. All suspected and unexpected other serious adverse events are reported to the FDA within fifteen days of receipt of the information (21 CFR 312.32). Unexpected for regulatory reporting will be assessed by the BMT CTN Medical Monitor and will include events that are not included in the bb2121 Investigator's Brochure. If the Medical Monitor assesses the event to be unrelated to the study, then the event will not require expedited reporting but will be included in a summary report issued annually. In addition, any event of grade 4 myelotoxicity after initiating lenalidomide and persisting for more than 4 weeks despite interruption/discontinuation of lenalidomide will be reported in an expedited fashion to the FDA. Safety reporting to the FDA will be done by the BMT CTN based upon date of initial entry on the Adverse Event Forms and requires no additional action from the participating site.
chapter 4
4.5.4.1 adverse event reporting of

Patients who develop neutropenia and thrombocytopenia (myelotoxicity) after initiation of lenalidomide that persists for more than 4 weeks despite interruption/discontinuation of lenalidomide are required to be reported in an expedited fashion via the Adverse Event Form, along with completion of the calendar-driven Myelotoxicity Form. These events will be assessed by the BMT CTN Medical Monitor and will be reported to the FDA as an expedited safety report. 4.5.4.2 Adverse Event Reporting Following Progression If a patient meets the protocol defined definition of progression (Section 3.1.2), SAEs and non-serious AEs are no longer required to be reported on the Adverse Event Form once the patient is more than 60 days from the completion of bb2121 or 21 days of lenalidomide maintenance, whichever is longer. Any bb2121-related SAEs would require reporting following the SAE reporting guidelines.
chapter 4
4.5.4.3 adverse event reporting following

Participants on this study are at risk of developing subsequent neoplasms. While subsequent neoplasms do not require expedited reporting, unless meeting one of the other criteria for AE/SAE reporting, the diagnosis of a subsequent neoplasm may alter reporting required for other AEs/SAEs. Adverse Event reporting following a subsequent neoplasm is dependent on the treatment received.  
x If a patient experiences a subsequent neoplasm resulting in initiation of nonprotocol systemic therapy, SAEs are no longer required to be reported once the patient is more than 60 days from completion of bb2121 or 21 days of lenalidomide maintenance, whichever is longer.  
x If a patient experiences a subsequent neoplasm that does *not* result in initiation of non-protocol systemic therapy, Adverse Events will continue to be reported per section 4.5 of the protocol.  
x Any bb2121-related SAEs would be reported until end of study.  
x Requests to discontinue Adverse Event Reporting for events that do not meet the criteria above will be considered on a case-by-case basis.
chapter 4
4.5.4.4 pregnancy reporting

Pregnancies, suspected exposure of a pregnant woman (including female partner of a male patient and exposure to lenalidomide while dispensing) and suspected pregnancies (including a positive pregnancy test regardless of age or disease state) of a female subject occurring at any time after the subject received bb2121 infusion therapy or lenalidomide; or within 28 days of the last dose of lenalidomide, 1 year after the last dose of LD chemo, are considered immediately reportable events. Therapy with lenalidomide is to be discontinued immediately and any unused drug should be returned. The pregnancy, suspected pregnancy, or positive pregnancy test must be reported through the expedited AE reporting system in EDC. The female subject should be referred to an obstetriciangynecologist, preferably one experienced in reproductive toxicity for further evaluation and counseling. The Investigator should ensure that the pregnant participant or pregnant partner of a male participant has consulted a general practitioner or gynecologist as soon as possible and that the contact details of the healthcare provider who is following the pregnancy are provided to the investigator. The Investigator will follow the female subject until completion of the pregnancy and must notify BMT CTN immediately about the outcome of the pregnancy (either normal or abnormal outcome) using the expedited AE reporting system in EDC. If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the investigator should report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious criteria, it must be reported as an SAE using the expedited AE reporting system in EDC, within 24 hours of the investigator's knowledge of the event. All neonatal deaths that occur in connection with *in utero* exposure to lenalidomide should be reported within 28 days of birth, without regard to causality through the expedited AE reporting system in EDC. In addition, any infant should be followed for 1 year after birth and report any SAE through the expedited AE reporting system within 24 hours of the Investigator's knowledge of the event. After 1 year any suspected SAE event should be reported to BMS/Celgene.
chapter 4
male subjects

If a female partner of a male subject taking investigational product becomes pregnant, the male subject receiving bb2121 therapy or lenalidomide should notify the Investigator, and the pregnant female partner should be advised to call her healthcare provider immediately. Attempts should be made to obtain consent from the female partner so that the information in section 4.5.4.3 can be provided for female partners of male participants and pregnancy outcomes. 4.5.5 Reporting of Special Situations There are other special situations that require reporting through the AE expedited reporting system in EDC. If any of the following events occur, they are required to be reported within one business days of the site's knowledge of the event, if the event occurs from the start of LD chemo through 21 days of lenalidomide or 60 days following bb2121, whichever is later:  
x Mishandling or misuse of bb2121 upon receipt of the product at the treatment center x Overdose, abuse and misuse that meets one of the criteria of a serious adverse event o Overdose, as defined for this protocol, refers to lenalidomide and bb2121 dosing only.  
o On a per dose basis, an overdose is defined as the following amount over the protocol-specified dose of lenalidomide or bb2121 assigned to a given patient, regardless of any associated adverse events or sequelae.  
PO any amount over the protocol-specified dose IV 10% over the protocol-specified dose o On a schedule or frequency basis, an overdose is defined as anything more frequent than the protocol required schedule or frequency.  
o On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified rate.  
o Complete data about drug administration, including any overdose, regardless of whether the overdose was accidental or intentional, should be reported in the case report form.  
x Medication errors that meet one of the criteria of a serious adverse event x Occupational exposure of any kind x Public health emergency x Any lot release criteria that is out of specification x BMS/Celgene product technical complaint whether or not it leads to an adverse event o Technical complaints can include but not limited to delivery of bb2121 in a defective bag or other issues with the product itself.
Each of the above listed other special situations are to be considered medically important, even if no other serious criteria apply. These are immediately reportable via the expedited AE reporting system in EDC and must be reported within one business day of the Investigator's first knowledge of the event. Any product that is out of specification for any lot release criteria, the event will be reported to the FDA as part of the escalation pathway.
chapter 4
chapter 5 5 statistical considerations

This study is designed as a single-arm Phase II multi-center trial to investigate the use of anti- BCMA CAR T-cells to upgrade post autologous HCT responses among patients with MM. The primary endpoint is complete response (CR) by 6 months following initiation of LD chemotherapy. We plan to enroll n=40 patients on this trial in order to get at least n=33 evaluable patients receiving the final selected dose of bb2121 infusion. There will be a safety run-in with staggered enrollment (see below, section 5.1.3) to assess for excess early toxicity of CAR T cells in this new clinical setting or prolonged cytopenias that limit resumption of maintenance lenalidomide; this run-in will start with the standard CAR T
cell dose of 450 x10 6 cells and may include up to 6 patients at this dose; if there are toxicity concerns, the dose will be reduced to 300 x 10 6 cells which will then be the selected dose for this study. Only patients who are assigned to receive the selected dose in the run in will be evaluable for the primary endpoint. Once the final dose is selected for further enrollment, we will enroll up to 40 total patients at that dose, including those in the run-in. Assuming the potential for dose de-escalation after the first 6 patients were enrolled in the run in phase and at least 1 patient dropping out from enrollment before initiation of LD chemotherapy, this will result in at least n=33 evaluable patients at the final selected dose. It is estimated that 13 months of accrual will be necessary to enroll the targeted sample size after completion of the safety run in. Accrual will be reported by race, ethnicity, gender, and age.
chapter 4
5.1.1 study duration

Participants will be followed on trial for 12 months after initiation of CAR T cell infusion for primary, secondary, and exploratory endpoints. 5.1.2 Randomization and Blinding This is a single arm trial with no randomization and no blinding. 5.1.3 Safety Run-In and Staggered Enrollment 5.1.3.1 Toxicities that will Govern Safety Run-In and Stagger. The following toxicities will trigger expansion of the safety run-in to six subjects or study pause depending on their frequency:  
a) Failure to start maintenance lenalidomide within 60 days of bb2121 infusion and continue with dose ≥5 mg/day for 21 days continuously without development of sustained grade 4 (failure to resolve to grade ≤3 within 7 days with supportive care, which may include filgrastim) neutropenia or thrombocytopenia.  
b) Occurrence of grade 4 or higher cytokine release syndrome.
chapter 4
5.1.3.2 progress through safety run-in

During the safety run-in, subjects will be enrolled in groups of 3. The second subject in each group will not proceed with lymphodepleting chemotherapy or bb2121 infusion until the preceding subjects starts lenalidomide by 60 days after bb2121 infusion. The third subject in each group will not proceed with lymphodepleting chemotherapy or bb2121 infusion until the first patient completes at least 21 days of lenalidomide maintenance and the second subject is able to start lenalidomide maintenance by 60 days after bb2121 infusion. Of note, according to section 2.3.5, subjects must be ≥30d post-infusion and have achieved ANC >1000/mm3 and platelet count ≥75,000/mm3 before initiating maintenance therapy. At discretion of the sponsor, enrollment and bb2121 manufacturing for subsequent subjects may proceed during post-infusion waiting period of preceding subjects. The first 3 subjects will be followed until they have completed 21 days of maintenance therapy without interruption due to hematologic toxicity before additional subjects are enrolled. If none of the first 3 subjects experience toxicities in section 5.1.3.1, enrollment will proceed without further inter-patient stagger. If 1 of the first 3 subjects experience a toxicity in section 5.1.3.1, an additional 3 subjects will be enrolled with intra-patient stagger as detailed in the preceding paragraph. If 2 of the toxicities in section 5.1.3.1 above occur during the safety run-in, the safety run-in will restart with the bb2121 dose reduced to 300 x 106 cells. If 2 of the toxicities in section 5.1.3.1 occur during the safety run-in after dose de-escalation, further bb2121 infusions and enrollment will be paused for further review.  
  
The primary endpoint is achieving a complete response or better (CR or sCR) as assessed by the 6-month time point after BCMA CAR T-cell therapy in MM patients with suboptimal disease responses after an autologous HCT and lenalidomide maintenance. The primary objective of this clinical trial is to estimate the proportions of patients achieving CR by 6 months, along with 90% confidence intervals, and to determine whether the use of bb2121 to upgrade post autologous HCT responses is sufficiently promising to warrant further study. Data from BMT CTN 0702 suggests that less than 10% of patients not in CR after autologous HCT and 6 months of maintenance therapy will get patients into CR within a subsequent 6 months of maintenance therapy (see Table 1.1.4). We will use a hypothesis testing framework to assess the potential efficacy of the addition of bb2121 cells to upgrade post autologous transplant responses. Specifically, we will test the null hypothesis that the 6-month probability of CR is less than or equal to 10% against the alternative that it is greater than 10%, using a one-sided 5% significance level.
chapter 4
5.2 sample size considerations

Assuming a 5% one-sided significance level, a sample size of n=33 or more evaluable patients receiving BCMA CAR T-cell therapy at the final selected dose will have at least 90% power to conclude that the 6-month CR rate is greater than 10% when the true 6month CR rate is 30% (a 20% absolute improvement over the unpromising rate), using an exact binomial test. Furthermore, the expected margin of error of the 90% confidence interval when the observed 6-month CR rate is 30% is approximately +/-13%, assuming an evaluable sample size of n=33.
chapter 4
5.3 interim analysis and stopping

Assuming the trial will enroll at least 33 patients, additional safety monitoring will include three safety endpoints, CRS, ICANS and non-relapse mortality. For CRS the occurrence of at least two cases of grade 4 CRS (ASTCT Grading) will trigger a DSMB review. For ICANS, the occurrence of at least one event of grade 4 ICANS will trigger a DSMB review. For non-relapse mortality within 28 days of bb2121 cell infusion, based on the expected infrequency (less than 1% based on rate in BMT CTN 0702 within 28 days following second autologous HCT) of the event, the occurrence of two or more non-relapse deaths within 28 days of infusion will trigger a DSMB review. In addition, the safety monitoring rule will also include bone marrow dysfunction/failure and prolonged cytopenias. For bone marrow dysfunction or failure, there are two rules that will trigger DSMB review: 1) the occurrence of one bone marrow failure requiring CT rescue; and 2) if 15% of patients are unable to start lenalidomide maintenance by Day 60 after CAR-T infusion. A DSMB review will also be triggered if 15% of patients who are able to start lenalidomide maintenance are unable to sustain therapy due to cytopeniadriven interruption. Interruption of maintenance is defined as stopping maintenance cycles due to cytopenias and inability to resume for more than 60 days. Thresholds for discontinuation of maintenance are based on table 2.4.6, and details of 15% stopping rule for being unable to start or sustain lenalidomide maintenance are given below in Table 5.3.
chapter 4
table 5.3 stopping rule for

| # of patients   | # of events   |
|-----------------|---------------|
| 1-6             | 1             |
| 7-13            | 2             |
| 14-20           | 3             |
| 21-26           | 4             |
| 27-33           | 5             |  
At a point that any of these monitoring rules are triggered, the NHLBI will be notified in order that the DSMB can be advised to review the data. Policies and composition of the DSMB are described in the protocol's Manual of Procedures. The stopping guidelines serve as a trigger for consultation with the DSMB for additional review.
chapter 4
5.4 demographic and baseline characteristics

Demographic and baseline characteristics will be summarized for all participants. Characteristics to be examined may include: age, gender, race/ethnicity, Karnofsky performance status, cytogenetics,/ LDH,/ Beta 2 microglobulin, lines/types of initial systemic anti-myeloma therapy, interval from diagnosis of symptomatic MM to enrollment, interval from initial systemic therapy to enrollment, Light chain disease, Chemo vs. nonchemo mobilization, timing from transplant to enrollment and to CAR T-Cell infusion, duration of lenalidomide therapy, initial response at enrollment, myeloma risk status
chapter 4
5.5 analysis populations and general

All patients starting LD chemotherapy prior to receiving a bb2121 infusion on study will be included in the primary analysis population. Time to event analyses will be started at the time of LD chemotherapy. Analyses for the primary and secondary endpoints will use the primary analysis population, except as otherwise specified. The primary analysis will occur once all patients have been followed for 6 months and data is locked. The primary analysis population will also be used for all analyses of safety data at the selected dose. Note that if there is a dose de-escalation in the run-in phase before selecting the final dose, then outcomes of patients at the initial higher dose will be described separately.
chapter 4
5.5.2 general analysis guidelines

Primary analyses for the primary, secondary, and exploratory endpoints will use the primary analysis population. Analyses of each endpoint in each population will follow the analysis plans as described below in sections 5.6 - 5.8. We expect minimal missing data (less than 5%) for the primary endpoint and secondary endpoints based on past experience with transplant and cellular therapy trials. If more than 10% of a key primary or secondary outcome is missing, we will apply an appropriate imputation method and conduct corresponding sensitivity analyses. If there is a dose de-escalation in the run-in stage, analyses as described below will apply to the final selected dose, while patients at the higher dose will be summarized separately in a descriptive manner due to the small numbers of patients at that dose.
chapter 4
5.5.3 as treated analysis

The analysis plan will include as treated analysis among patients who received CAR T cell infusion including patients who received OOS product. All outcomes will be analyzed in this cohort.
chapter 4
5.6 analysis of primary endpoint

If there is no censoring prior to 6 months and prior to achieving a CR, then the probability of CR by 6 months will be estimated using proportions. 90% confidence intervals will be provided based on exact binomial distributions. A one-sided exact binomial test comparing the estimated proportion of patients in CR by 6 months against a null hypothesis or uninteresting value of 10% will be conducted using a 5% one-sided significance level. If there is censoring present prior to 6 months and prior to achieving a CR, then the probability of CR by 6 months will be estimated using the cumulative incidence technique, with death as a competing risk and patients alive without CR at last contact considered censored. 90% confidence intervals for the cumulative incidence will be computed using the complementary log-log transformation.
chapter 4
5.7 analysis of secondary endpoints

Analysis of secondary endpoints will be primarily descriptive, using estimates along with 90% confidence intervals, as detailed below.
chapter 4
5.7.1 response to treatment

The proportion of patients achieving an upgrade in their response at any timepoint, and the proportion of patients who achieve MRD negativity at any timepoint will be described.  
Duration of response upgrade will be summarized using the Kaplan-Meier estimate, where death or loss of response upgrade are considered events, and the time to event is measured as the time from documentation of response upgrade to death, loss of response upgrade, or last contact.
chapter 4
5.7.2 progression-free survival (pfs)

PFS survival will be estimated using the Kaplan-Meier estimator. Progression of disease or death from any cause will be considered events and surviving patients without disease progression will be censored at the date of last contact. A point estimate and 90% confidence interval will be provided for the probability of PFS at 12 months.
chapter 4
5.7.3 non-relapse mortality (nrm)

NRM will be estimated using the cumulative incidence function, treating progression as a competing event. A point estimate and 90% confidence interval will be provided for the cumulative incidence at 100 days, 6 months and 12 months post-transplant. 5.7.4 Progression of Disease Progression will be estimated using the cumulative incidence function, treating death prior to progression as a competing event. A point estimate and 90% confidence interval will be provided for the probability of progression at 12 months post-transplant. 5.7.5 Incidence of Cytokine Release Syndrome (CRS) Proportions of patients who experience CRS will be tabulated by grade (according to ASTCT criteria) and time period after infusion of CAR T-cells. 5.7.6 Incidence of Prolonged Cytopenias Proportions of patients who experience prolonged cytopenias will be tabulated. 5.7.7 Incidence of Neurotoxicity (ICANS) Proportions of patients who experience neurotoxicity (according to ASTCT criteria) will be tabulated by grade. 5.7.8 Feasibility of Reinitiation of Lenalidomide Maintenance Time to reinitiation of lenalidomide maintenance therapy following CAR T cell infusion will be summarized using the cumulative incidence estimator, treating death as a competing risk. Cumulative incidence at 180 days post infusion will be summarized along with a 90% confidence interval.
chapter 4
5.8 analysis of exploratory endpoints

Quantitative summaries of CAR T-cell expansion measurements (median, range, IQR) will be provided at specified timepoints. Peak CAR T-cell expansion will be compared between subjects who are and are not in CR at 1 year, and between subjects who are and are not progression-free at 1 year, using Mann-Whitney Wilcoxon tests.
chapter 4
5.8.2 car t-cell persistence

Persistence will be summarized on each patient using AUC over the first 6 months or using presence of detectable CAR T-cells at 6 months post bb2121infusion. AUC will be compared between subjects who are and are not in CR at 1 year, and between subjects who are and are not progression-free at 1 year, using Mann-Whitney Wilcoxon tests.  
Presence of detectable CAR T cells at 6 months post infusion will be compared between subjects who are and are not in CR at 1 year, and between subjects who are and are not progression-free at 1 year, using chi-square test or Fisher's exact test as appropriate. 5.8.3 BCMA Expression BCMA expression will be compared between baseline and post-CAR-T infusion using Wilcoxon signed rank tests. 5.8.4 Immune Reconstitution Quantitative summary measures (median, range, IQR) will be provided for lymphocyte subsets at baseline and various time points after CAR T cell infusion.
chapter 4
5.8.5 overall survival

Overall survival will be estimated using the Kaplan-Meier estimator. Death from any cause will be the event and surviving patients will be censored at the date of last contact. A point estimate and 90% confidence interval will be provided for the probability of OS at 12 months.
chapter 4
5.8.6 overall toxicity

All greater than or equal to grade 3 toxicities according to CTCAE version 5.0 will be categorized by SOC and preferred term (PT) using the MedDRA dictionary, and the number of AEs will be summarized by SOC, PT, peak grade. The number and percentage of participants with at least 1 grade 3 or higher AE will be summarized by SOC and PT. Detailed listings of unexpected SAEs, including severity and relationship to treatment, will be presented.
chapter 4
5.8.7 infections

The number of grade 2 or higher infections and the number of patients experiencing infections will be tabulated by type of infection, severity, and time period after infusion of BCMA CAR T-cells.
appendix a criteria for symptomatic
all three required

1. Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or presence of a biopsy-proven plasmacytoma 2. Monoclonal protein present in the serum and/or urinea 3. Myeloma defining events (1 or more)
a. Myeloma- related organ dysfunctionb:
i. Calcium elevation in the blood (serum calcium greater than 10.5 mg/l or upper limit of normal)
ii. Renal insufficiency (serum creatinine greater than 2mg/dl)
iii. Anemia (hemoglobin less than 10 g/dL)
iv. Lytic bone lesions or osteoporosisc
b. Any one or more of the following biomarkers of malignancy:  
i. Clonal bone marrow plasma cell percentage greater than or equal to 60%
ii. Involved: uninvolved serum free light chain ratio greater than or equal to 100 iii. Greater than1 focal lesion of MRI
*Note: These criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage. Stage IA becomes smoldering or indolent myeloma.  
a If no monoclonal protein is detected (nonsecretory disease), then ≥30% monoclonal bone marrow plasma cells and/or a biopsy-proven plasmacytoma required.  
b A variety of other types of end organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma related.  
c If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures)
are the sole defining criteria, then greater than or equal to 30% plasma cells are required in the bone marrow.
*Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. The Hematology Journal (2003) 4, 379–398
appendix b laboratory procedures
collection of mandatory samples bb2121

Bone marrow aspirate and peripheral blood will be collected for patients who consent to the BMT CTN 1902 study. Sample collection will be performed periodically throughout the study and will provide clinical samples required for correlative laboratory testing associated with critical immunologic study endpoints.  
¾ **Leukapheresis Sample for bb2121 manufacturing and cell content**
evaluation: A required sample of a sufficient quantity of peripheral blood mononuclear cells (PBMCs) collected via leukapheresis is required for the production of the bb2121 investigational product. Leukapheresis sample should be collected per the BMT CTN 1902 SOPs. Once the sample is collected at the specified time point, it will be shipped on the day of collection directly to the BMS/Celgene manufacturing facility. Additionally, the study team will request from the BMS/Celgene manufacturing facility, three 1.8 mL cryopreserved aliquots of both the leukapheresis and the final CAR T-cell product to be sent to the BMT CTN Biorepository for a future study team correlative to perform an extensive cell composition analysis for each product.  
¾ **Research Samples for Laboratory Correlatives Associated with Immunologic**
Endpoints: Required research samples for study-specific immunologic correlatives include the collection of blood and marrow aspirate samples as summarized in the table below (and in table 4.3B). The correlative studies include (1) MRD assessment & BCMA expression by flow cytometry, (2) MRD assessment by NGS, (3) Peripheral blood immune reconstitution and marrow immune profiling by flow cytometry, and (4) the evaluation of CAR T-Cell expansion and persistence. Once the samples are collected at specified time points, they will be shipped on the day of collection directly to either a specified ancillary study laboratory for processing and testing or BMT CTN Biorepository for processing and long-term research aliquot storage. These samples will be tracked through GlobalTrace. Detailed procedures regarding specimen collection schedules, procedures and shipping instructions will be found in the BMT CTN 1902 Research Sample Information Guide.
appendix b laboratory procedures
collection of optional bmt ctn

Bone marrow aspirate, peripheral blood PBMC, and serum, will be collected and stored to support some planned correlative studies and future research. Once the samples are collected at the transplant center at specified time points, they will be shipped on the day of collection to the BMT CTN Central Processing Laboratory for final processing and storage at the BMT CTN Research Repository. The collection, processing, and shipping of these biospecimens are summarized in the table below (and in table 4.3B). These samples will be tracked through GlobalTrace. Detailed procedures regarding specimen collection schedules, procedures and shipping instructions will be found in the BMT CTN 1902 Research Sample Information Guide.  
BMT CTN 1902 Version 3.0 dated March 10, 2022 Blood and Marrow Transplant Clinical Trials Network  
| BMS/ Celgene  Manufacturing  Facility  Per BMS/Celgene bb2121  manufacturing guidance                |                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
|------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|------------------------------------------------------------------------------------------|------------------------------|
| Shipping Location                                                                                    | Laboratory                                                                                                                                                                                                                                                             | BMT CTN  Research  Repository                                                                                                                                                                                                                                   | RPCI Lab                                                                                                                                                                                                                    | oratory                      |                                                                                          |                              |
| RPCI  ambient temperature on the  day of collection to RPCI by  priority overnight FED EX  delivery. |                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| sample will be shipped at                                                                            |                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| Bone marrow aspirate                                                                                 | ambient temperature on the  day of collection to the BMT  CTN Research Repository  by priority overnight FED EX  delivery.                                                                                                                                             |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| sample will be shipped at                                                                            |                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| Bone marrow aspirate                                                                                 |                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| Shipping Specifications                                                                              | Blood sample tube will be  shipped at ambient  temperature on the day of  collection to the PRCI laboratory by priority  overnight FED EX delivery.                                                                                                                    |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| Mandatory Research Samples Associated with bb2121 Manufacturing and Immunologic Study Endpoints      | At the time of leukapheresis, ≤ approximately 14 days following  enrollment                                                                                                                                                                                            | chemotherapy; at days 30, 90,  180 and 365 post-bb2121  infusion; and at the time of  disease progression (if  applicable).  Note: Only Immune Profiling  Assessment done from Day 30  sample                                                                   | chemotherapy; at days 90, 180  and 365 post-bb2121 infusion;  and at the time of disease                                                                                                                                    | progression (if applicable). | chemotherapy; at days 30, 90,  and 365 post-bb2121 infusion;  and at the time of disease | progression (if applicable). |
| Dates Samples Obtained                                                                               | Prior to initiation of LD                                                                                                                                                                                                                                              | Prior to initiation of LD                                                                                                                                                                                                                                       | Prior to initiation of LD                                                                                                                                                                                                   |                              |                                                                                          |                              |
| Sample Collection Summary                                                                            | Collect bone marrow aspirate  sample and place 6 mL into a  green top plastic BD  Vacutainer® tube, containing  Sodium-Heparin anticoagulant.  Gently mix sample by inversion  8-10 times to mix sample well  with heparin anticoagulant.  6 mL Bone  Marrow  Aspirate | Collect bone marrow aspirate  sample and place 2 mL into a  lavender top plastic BD  Vacutainer® tubes containing  EDTA anticoagulant. Gently  mix sample by inversion 8-10  times to mix sample well with  the EDTA anticoagulant. 2 mL Bone  Marrow  Aspirate | Collect blood sample and place  10 mL into a green top plastic  BD Vacutainer® tube,  containing Sodium-Heparin  anticoagulant. Gently mix  sample by inversion 8-10 times  to mix sample well with heparin  anticoagulant. |                              |                                                                                          |                              |
| Per BMS/Celgene bb2121  manufacturing guidance                                                       |                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| Sample Type                                                                                          | Peripheral  Blood                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| Leukapheresis  Sample for  bb2121                                                                    | manufacturing                                                                                                                                                                                                                                                          | Peripheral  Blood                                                                                                                                                                                                                                               |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| 10 mL                                                                                                |                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| Assessment by  NGS                                                                                   | Reconstitution                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| MRD & BCMA                                                                                           | Expression  Assessment  And                                                                                                                                                                                                                                            | Immune  Profiling                                                                                                                                                                                                                                               |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| Purpose                                                                                              | Immune                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |
| MRD                                                                                                  |                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                             |                              |                                                                                          |                              |  
BMT CTN 1902 Version 3.0 dated March 10, 2022 Blood and Marrow Transplant Clinical Trials Network  
| Shipping Location                                                                                                                                                                                                                                                                                       | BMT CTN  Research  Repository                                                                                                                       | BMT TCN  Research  Repository   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|
| Shipping Specifications                                                                                                                                                                                                                                                                                 |                                                                                                                                                     |                                 |
| Bone marrow aspirate  sample tube will be shipped  at ambient temperature on  the day of collection to the  BMT CTN Research  Repository by priority  overnight FED EX delivery.  chemotherapy; at days 30, 90  and 365 post bb2121 infusion;  and at the time of disease  progression (if applicable). |                                                                                                                                                     |                                 |
| Blood sample tube will be  shipped at ambient  temperature on the day of  collection to the BMT CTN  Research Repository by  priority overnight FED EX  delivery.                                                                                                                                       |                                                                                                                                                     |                                 |
| Mandatory Research Samples Associated with bb2121 Manufacturing and Immunologic Study Endpoints                                                                                                                                                                                                         | chemotherapy; at days 4, 7, 14,  21, 30, 60, 90, 180, 270, and  365 post bb2121 infusion; and at  the time of disease progression  (if applicable). |                                 |
| Dates Samples Obtained                                                                                                                                                                                                                                                                                  | Prior to initiation of LD                                                                                                                           | Prior to initiation of LD       |
| Sample Collection Summary                                                                                                                                                                                                                                                                               |                                                                                                                                                     |                                 |
| Collect bone marrow aspirate  sample and place 2 mL into a  lavender top plastic BD  Vacutainer® tube, containing  EDTA anticoagulant. Gently  mix sample by inversion 8-10  times to mix sample well with  EDTA anticoagulant  2 mL  Bone  Marrow  Aspirate                                            |                                                                                                                                                     |                                 |
| Collect blood sample and  place 8mL into a lavender top  plastic BD Vacutainer® tube,  containing EDTA  anticoagulant. Gently mix  sample by inversion 8-10  times to mix sample well with  EDTA anticoagulant.                                                                                         |                                                                                                                                                     |                                 |
| Sample Type                                                                                                                                                                                                                                                                                             | Peripheral  Blood                                                                                                                                   |                                 |
| 8 mL                                                                                                                                                                                                                                                                                                    |                                                                                                                                                     |                                 |
| Expansion and  Persistence                                                                                                                                                                                                                                                                              |                                                                                                                                                     |                                 |
| CAR T Cell                                                                                                                                                                                                                                                                                              |                                                                                                                                                     |                                 |
| Purpose                                                                                                                                                                                                                                                                                                 |                                                                                                                                                     |                                 |  
BMT CTN 1902 Version 3.0 dated March 10, 2022 Blood and Marrow Transplant Clinical Trials Network  
| Shipping Specifications                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                           |                                           |                               |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------|-------------------------------|
| Shipping /Storage Location                                                                                                                                                                                                              | BMT CTN  Research  Repository                                                                                                                                                                                                                                                                                                                             | BMT CTN  Research  Repository             | BMT CTN  Research  Repository |
| Serum blood tube will be                                                                                                                                                                                                                | shipped at ambient  temperature on the day of  collection, to the BMT CTN  Research Repository by  priority overnight FED EX  delivery for processing and  final frozen storage of serum  aliquots.                                                                                                                                                       |                                           |                               |
| Bone marrow aspirate tube  will be shipped at ambient  temperature on the day of  collection, to the BMT CTN  Research Repository by  priority overnight FED EX  delivery for processing and  final frozen storage of  marrow aliquots. | Peripheral blood tubes will  be shipped at ambient  temperature on the day of  collection, to the BMT CTN  Research Repository by  priority overnight FED EX  delivery for processing and  final frozen storage of  PBMC aliquots. chemotherapy; at days 30, 90,  and 365 post-bb2121 infusion;  and at the time of disease  progression (if applicable). |                                           |                               |
| Mandatory Biorepository Samples Supporting Additional Planned Research Sample Collections Studies                                                                                                                                       | and 365 post-bb2121CAR T Cell  infusion; and at the time of  disease progression (if  applicable).                                                                                                                                                                                                                                                        |                                           |                               |
| chemotherapy; at days 30, 90,                                                                                                                                                                                                           | chemotherapy; at days 4, 7, 14,  21, 30, 60, 90, 180, 270, and  365 post-bb2121 infusion; and at  the time of disease progression  (if applicable).                                                                                                                                                                                                       |                                           |                               |
| Sample Collection Summary Dates Samples Obtained                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                           |                                           |                               |
| Prior to initiation of LD                                                                                                                                                                                                               | Prior to initiation of LD                                                                                                                                                                                                                                                                                                                                 |                                           |                               |
| Prior to initiation of  lymphodepleting LD                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                           |                                           |                               |
| Collect bone marrow aspirated  sample and place 6 mL into a  green top plastic BD  Vacutainer® tube, containing  Sodium-Heparin anticoagulant.  Gently mix sample by  inversion 8-10 times to mix                                       | sample well with heparin  anticoagulant.                                                                                                                                                                                                                                                                                                                  |                                           |                               |
| Bone Marrow  Aspirate                                                                                                                                                                                                                   | Collect blood sample in a  Red/Gray Top BD SST™ Tube  with Silica Clot Activator &  Polymer Gel. Let sample sit  upright in rack for 30-60  minutes. Centrifuge for 10  minutes. Gel barrier will form                                                                                                                                                    | separating the serum  specimen from clot. |                               |
| Peripheral  Blood  (serum)                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                           |                                           |                               |
| 8mL                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                           |                                           |                               |
| Collect blood sample in green  top plastic BD Vacutainer® tubes, containing SodiumHeparin anticoagulant. Gently  mix sample by inversion 8-10  times to mix sample well with  heparin anticoagulant.                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                           |                                           |                               |
| Sample Type                                                                                                                                                                                                                             | Peripheral  Blood                                                                                                                                                                                                                                                                                                                                         |                                           |                               |
| 45 mL                                                                                                                                                                                                                                   | Future Research                                                                                                                                                                                                                                                                                                                                           |                                           |                               |
| 6 mL                                                                                                                                                                                                                                    | Future Research                                                                                                                                                                                                                                                                                                                                           | Future Research                           |                               |
| Purpose                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                           |                                           |                               |
appendix c risks of fetal
risks associated with pregnancy

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. An embryofetal development study in animals indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy. The teratogenic effect of lenalidomide in humans cannot be ruled out.  
Therefore, a risk minimization plan to prevent pregnancy must be observed.  
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has the effect of the lenalidomide on human eggs and sperm. The risks to a fetus are not known. However, because lenalidomide is related to thalidomide, and thalidomide is known to cause severe birth defects, the following requirements must be observed.  
Females of childbearing potential (FCBP)† must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. The two methods of reliable contraception must include one highly effective method (i.e., intrauterine device (IUD), hormonal [birth control pills, injections, or implants], tubal ligation, partner's vasectomy) and one additional effective (barrier) method (i.e., latex condom, diaphragm, cervical cap). FCBP must be referred to a qualified provider of contraceptive methods if needed.
appendix c risks of fetal
criteria for females of childbearing

This protocol defines a female of childbearing potential as a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
appendix c risks of fetal
contraception

Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual contact during the following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; 3) during dose interruptions; and 4) for at least 28 days after study treatment discontinuation. The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception:
Highly effective methods:
Intrauterine device (IUD) Hormonal (birth control pills, injections, implants) Tubal ligation Partner's vasectomy Additional effective methods:
Male condom Diaphragm Cervical Cap Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception the patient should switch to one of the effective methods listed above. The risk of venous thromboembolism continues for 4 to 6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment with dexamethasone. Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia.
appendix c risks of fetal
pregnancy testing

The following pregnancy testing guidelines will be used throughout the study. Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be performed for females of childbearing potential, including females of childbearing potential who commit to complete abstinence, as outlined below.
appendix c risks of fetal
female subjects

x FCBP must have two negative pregnancy tests (minimum sensitivity of 50 mIU/mL)
prior to prescribing study drug. The first pregnancy test must be performed within 10-14 days prior to prescribing study drug and the second pregnancy test must be performed within 24 hours prior to prescribing study drug (prescriptions must be filled within 7 days as required by Lenalidomide REMS). The subject may not receive study drug until the Investigator has verified that the results of these pregnancy tests are negative.  
x FCBP must commit either to abstain continuously from heterosexual intercourse or to use TWO methods of reliable birth control AT THE SAME TIME—one highly effective form of contraception and one additional effective contraceptive method
as defined below. Contraception must begin 4 weeks prior to initiating treatment with lenalidomide, during therapy, during dose interruptions, and continuing for at least 1 year following bb2121 infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests, or 4 weeks following discontinuation of lenalidomide, whichever comes later.
appendix c risks of fetal
male subjects

x Agree to use a condom during sexual contact with a pregnant female or a FCBP,
even if he has undergone a successful vasectomy, from screening through at least 1 year following bb2121 infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests; or 4 weeks following discontinuation of lenalidomide whichever is later.
appendix c risks of fetal
all subjects

x Only enough lenalidomide for one cycle of therapy may be dispensed with each cycle of therapy.  
x If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a male study subject during study participation, lenalidomide must be immediately discontinued.  
  
  
Lenalidomide REMS for Study Participants Lenalidomide REMS **description:** A program that allows patients enrolled in authorized clinical trials access to free Revlimid® (Lenalidomide) through the Lenalidomide REMS program.  
Access to the Lenalidomide REMS Program:
1. All physicians must be registered prescribers of REVLMID in the Lenalidomide REMS Program. All clinical sites must have access to the Lenalidomide REMS program 1) Prescriber enrolls in the Lenalidomide REMS online or calls the Lenalidomide REMS.  
2) Prescriber is registered within 15 minutes. 3) Registration confirmation is provided to prescriber's office. 4) Lenalidomide REMS Kit is sent to prescriber's office (overnight). The starter kit will contain the following:
x Prescriber Guide to Lenalidomide REMS
x Patient Resource Pack 2. **All studies must have an FDA letter of IND exemption or an active IND, active**
IRB approval and BMS/Celgene required regulatory documents 3. **Patients must sign the research specific IRB-approved informed consent and**
be enrolled in a BMS/Celgene-approved Medical Affairs clinical trial using Revlimid® **(lenalidomide)**
4. The Lenalidomide REMS must be contacted to confirm if a patient needs to be registered by calling 1-888-423-5436 5. Patients must also sign the appropriate Patient-Physician Agreement Form
(PPAF) and follow all the procedures of the Lenalidomide REMS Program 1) Patient and Prescriber complete the PPAF together. 2) The form is faxed to the Lenalidomide REMS or submitted electronically to the Lenalidomide REMS. 3) Patient is registered within 15 minutes. 4) Confirmation is sent to prescribing office notifying them that the patient is now enrolled.  
6. Patients and prescribers must take the phone surveys as required by the Lenalidomide REMS Program (The PPAF generated for the patient determines which phone survey questions will be asked). An authorization number is provided at the completion of the phone survey, the authorization number along with the patient risk category must be noted on the prescription form. Patient Survey requirements:
x For men: Do not need to call Lenalidomide REMS the first month but must call monthly starting the second month.  
x For females of non-reproductive potential: Must call for the first month and then call every 6 months after.  
x For females of reproductive potential: Must call for the first month and then every month after.
appendix c risks of fetal
prescribing revlimid (lenalidomide) in the

x BMS/Celgene Medical Affairs Operations will activate the study with the designated Lenalidomide REMS Pharmacy upon receipt of all required regulatory documents.  
x The designated Lenalidomide REMS Pharmacy will not dispense or ship Revlimid®
(lenalidomide) prior to BMS/Celgene's notification of activation.  
x Prescription information MUST BE entered using the BMT CTN 1902 Lenalidomide REMS study specific electronic prescription form. This form can be found on the BMT CTN SharePoint website (https://bmtctnsp.net)
x **An authorization number** and the patient's risk category must be on the prescription form at the time of faxing.  
x Prescriptions for Revlimid® (lenalidomide) must be sent to the designated Lenalidomide REMS Pharmacy x Only a 28-days' supply of Revlimid® (lenalidomide) may be provided per cycle and sent to the actual address noted on the **Lenalidomide REMS electronic study** specific prescription form.  
x **The Lenalidomide REMS Pharmacy will verify the authorization number** and complete the patient counseling.
appendix c risks of fetal
protocol compliance and drug return

x Patients will be required to return unused drug to the study site for destruction per institutional guidelines.  
x Sites may request that patients maintain a diary and/or to bring their bottles in for a pill count at each visit in order to review "patient compliance."
important information about lenalidomide rems
protocol compliance and drug return

x To avoid fetal exposure REVLIMID®(lenalidomide) is only available under a special restricted distribution program called Lenalidomide REMS
x Only prescribers registered with Lenalidomide REMS can prescribe REVLIMID® (lenalidomide)
x Only Lenalidomide REMS contract pharmacies can dispense REVLIMID® (lenalidomide) x In order to receive REVLIMID® (lenalidomide), patients must enroll in Lenalidomide REMS and agree to comply with the requirements of the Lenalidomide REMS program  
x Information about REVLIMID® (lenalidomide) and the Lenalidomide REMS program can be obtained by calling the Lenalidomide REMS toll-free at 1-888-423-5436, or at www. LENALIDOMIDEREMS.com
important information about lenalidomide rems
how to fill a revlimid

1. Healthcare provider (HCP) instructs patient to complete patient survey 2. HCP completes survey 3. HCP completes patient prescription form 4. HCP obtains Lenalidomide REMS authorization number 5. HCP provides authorization number on patient prescription form  
| 6.   | HCP faxes form, including prescription   |
|------|------------------------------------------|  
| 7.   | HCP advises patient that a representative from a Lenalidomide REMS contract pharmacy will contact them   |
|------|----------------------------------------------------------------------------------------------------------|  
| 8.   | Lenalidomide REMS contract pharmacy conducts patient education                                |
|------|-----------------------------------------------------------------------------------------------|
| 9.   | Lenalidomide REMS contract pharmacy calls for confirmation number                             |
| 10.  | Lenalidomide REMS contract pharmacy ships LENALIDOMIDE with the FDA-approved MEDICATION GUIDE |
appendix e
human subjects 1. subject consent

A conference will be held with the patient, and family to discuss this study and alternative treatments available for the treatment of multiple myeloma. The conference will be conducted by the Principal Investigator or other designated physician. Potential risks associated with the study interventions should be discussed as objectively as possible. Consent will be obtained using an IRB-approved consent. The BMT CTN will provide a template of the consent form to each center. Each center will customize the template according to their local requirements and submit it for review by the local Internal Review Board (IRB). The DCC will verify the adequacy of the consent forms prior to submission to the IRB. Each center must provide evidence of IRB approval.
appendix e
2. confidentiality

Confidentiality will be maintained by individual names being masked and assigned a patient identifier code. The code relaying the patient's identity with the ID code will be kept separately at the center. The ID code will be transmitted to the network.
appendix e
3. participation of women and

Women and ethnic minorities and other populations will be included in this study. Accrual of women and minorities at each center will be monitored to determine whether their rates of enrollment are reflective of the distribution of potentially eligible women and minorities expected from data reported to the CIBMTR and from published data on incidence of MM in these groups. Centers will be notified if their rates differ significantly from those expected and asked to develop appropriate recruitment strategies.
appendix e
appendix f karnofsky performance status

| Index                            | Specific Criteria                                                              | General                                                                                                               |
|----------------------------------|--------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------|
| 100                              | Normal, no complaints, no evidence  of disease.                                | Able to carry on normal activity; no special care  needed.                                                            |
| 90                               | Able to carry on normal activity,  minor signs or symptoms of disease.         |                                                                                                                       |
| 80                               | Normal activity with effort, some  signs or symptoms of disease.               |                                                                                                                       |
| 70                               | Care for self, unable to carry on  normal activity or to do work.              |                                                                                                                       |
| 60                               | Requires occasional assistance from                                            | Unable to work, able to live at home and care for                                                                     |
| others but able to care for most | most personal needs, varying amount of                                         |                                                                                                                       |
| needs.                           | assistance needed.                                                             |                                                                                                                       |
| 50                               | Requires considerable assistance  from others and frequent medical  care       |                                                                                                                       |
| 40                               | Disabled, requires special care and  assistance.                               |                                                                                                                       |
| 30                               | Severely disabled, hospitalization  indicated, but death not imminent.         | Unable to care for self, requires institutional or  hospital care or equivalent, disease may be  rapidly progressing. |
| 20                               | Very sick, hospitalization necessary,  active supportive treatment  necessary. |                                                                                                                       |
| 10                               | Moribund                                                                       |                                                                                                                       |
| 0                                | Dead                                                                           |                                                                                                                       |
appendix e
appendix g bb2121 infusion process

bb2121 must be delivered to the pre-defined department responsible for receiving cell products, thawed at the infusion site in a ~37°C water bath or approved thawing instrument and infused immediately within 1 hour; alternately, bb2121 may be thawed in the appropriate cell manipulation facility and administered as soon as possible within a maximum of 1 hour after thawing. If multiple drug product bags are to be administered to meet the protocol assigned dose, each bag will be thawed and administered 1 bag at a time within a maximum of 1 hour for each bag until the appropriate volume and corresponding CAR T-cell dose has been administered. In the event of a delay in completing the planned bb2121 infusion within 1 hour of thaw, bb2121 should still be administered; the reason for the delay should be recorded in the eCRF and the Sponsor will be notified. All procedures involving bb2121 must be performed using aseptic techniques by trained personnel. See bb2121 Product Receipt, Preparation, and Administration Manual for more detail.
appendix e
bb2121 premedication

Premedication should occur approximately 30 minutes prior to the infusion and should include acetaminophen 650 mg orally and diphenhydramine 12.5 mg IV or 25 to 50 mg orally (or equivalent). Subjects should not receive corticosteroids as pre-medication.
appendix e
bb2121 infusion

bb2121 will be given on Day 0 (+ 14-day window), after lymphodepletion on Days -5, -4 and -3 at a target dose of 150 to 450 × 106 CAR T-cells/infusion with a minimum dose of 150 × 106 CAR+ T cells/infusion.  
On Day 0, bb2121 will be administered IV through non-filtered tubing (**IMPORTANT—AN** IN-LINE LEUKOCYTE FILTER MUST NOT BE USED). A central venous access device, such as a Hickman line or peripherally inserted central catheter (PICC) line, may be utilized and is encouraged in subjects with poor peripheral access. Vital signs are to be monitored prior to bb2121 infusion, midway through the infusion, upon completion of the infusion, and then every 15 minutes thereafter for the first hour, and hourly for the next 4 hours. Infusion reactions, including anaphylaxis, will be managed according to the medical judgment of the physician overseeing the infusion.
appendix e
dose for subjects for whom

bb2121 is manufactured on a per-subject basis and there is expected to be heterogeneity in the number of CAR T-cells that are manufactured for each subject. Subjects who have product manufactured with a dose of less than 150 x 106 CAR T-cells may proceed to a 2nd leukapheresis procedure for a second attempt at bb2121 manufacturing. The administered bb2121 dose may be composed of more than one manufactured product from the same subject.
appendix h management guidelines for
(1) cytokine release syndrome (crs)

Administration of cellular products such as chimeric antigen receptor (CAR)-expressing T cells can be associated with cytokine-associated toxicity due to systemic production and release of various cytokines into the circulation. Cytokine-associated toxicity, also known as cytokine release syndrome (CRS), is a toxicity that occurs as a result of immune activation.[58, 59]
appendix h management guidelines for
(1.1) pathophysiology of crs

The hallmark of CRS is immune activation resulting in elevated inflammatory cytokines. CRS clinically manifests when large numbers of lymphocytes (B cells, T cells, and/or natural killer cells) and/or myeloid cells (macrophages, dendritic cells, and monocytes) become activated with therapeutic monoclonal antibody (mAb) infusions, most notably anti-CD3 (OKT3), anti-CD52 (alemtuzumab), and anti-CD20 (rituximab), and the CD28 super-agonist, TGN1412. CRS is also frequently observed following administration of bispecific T cell engaging antibodies for leukemia, and adoptive cellular immunotherapies for cancer, most notably CAR T cells. Incidence, time to onset and severity of CRS due to CAR T cells is at least partially dependent on the infused cell dose and tumor burden/antigen density, presumably due to more rapid and higher levels of CAR T cell activation. Onset of CRS symptoms typically occurs days to occasionally weeks after the CAR T cell infusion, usually preceding maximal *in vivo* T cell expansion. CRS is associated with elevated interferon gamma (IFN ), interleukin (IL)-6, and tumor necrosis alpha (TNF ) levels, and increases in IL-2, granulocyte macrophage colony-stimulating factor (GM-CSF), IL-10, IL-8, IL-5, and fractalkine although the patter of elevated cytokines varies among subjects.[60, 61] IL-6 has been identified as a central mediate of toxicity in CRS. IL-6 is a pleiotropic cytokine with anti-inflammatory and proinflammatory properties. High levels of IL-6, present in the context of CRS, likely initiates a proinflammatory IL-6-mediated signaling cascade.
appendix h management guidelines for
(1.2) clinical presentation of crs

CRS is characterized by high fever, fatigue, nausea, headache, dyspnea, tachycardia, rigors, hypotension, hypoxia, myalgia/arthralgia, and anorexia. Clinical symptoms and severity of CRS are highly variable (**Table H1**),[58] and management can be complicated by concurrent conditions. CRS usually occurs within two weeks after infusion.[64]
x Fever, especially high fever (≥ 38.5 °C or ≥ 101.3 °F), is a commonly observed hallmark of CRS, and many features of CRS mimic infection. Hence, infection must be considered in all subjects presenting with CRS symptoms, and appropriate cultures must be obtained, and empiric antibiotic therapy initiated per institutional standard of care.  
x Less common symptoms associated with CRS include cardiac dysfunction, adult respiratory distress and/or hepatic failure, coagulopathies, disseminated intravascular coagulation, and capillary leak syndrome.  
x Neurologic toxicity has been observed concurrently with CRS.  
x With other CAR T cell products, CRS has been reported in a few cases to be associated with findings of macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH), and the physiology of the syndromes may overlap. Table H1: Clinical Signs and Symptoms Associated with CRS  
| Organ System     | Symptoms                                                                                                                                                                                        |
|------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Constitutional   | Fever ± rigors, malaise, fatigue, anorexia,  myalgia, arthralgia, nausea, vomiting, headache                                                                                                    |
| Respiratory      | Tachypnea, hypoxemia  Tachycardia, widened pulse pressure,                                                                                                                                      |
| Cardiovascular   | hypotension, increased cardiac output (early),  potentially diminished cardiac output (late)                                                                                                    |
| Coagulation      | Elevated D-dimer, hypofibrinogenemia ± bleeding                                                                                                                                                 |
| Renal            | Acute kidney injury, azotemia                                                                                                                                                                   |
| Gastrointestinal | Nausea, vomiting, diarrhea                                                                                                                                                                      |
| Skin             | Rash                                                                                                                                                                                            |
| Hepatic          | Transaminitis, hyperbilirubinemia  Headache, mental status changes, confusion,  delirium, word finding difficulty or frank aphasia,  hallucinations, tremor, dysmetria, altered gait,  seizures |
| Neurologic*      |                                                                                                                                                                                                 |  
*Adapted from Lee 2014,[58] Neurologic symptoms are typically reversible and can occur independent of CRS.  
Neurologic symptoms should be graded and treated independently even if overlapping with CRS.  
(1.3) Clinical management of CRS Across various CAR T cell products, early manifestations of CRS can predict more severe toxicity for both CRS and neurotoxicity.  
Subjects with B-cell acute lymphoblastic leukemia (ALL) and high burden of disease are at high risk of developing CRS.[64] Subjects with non-Hodgkin lymphoma (NHL) who have high baseline tumor burden (measured by the sum of product of the perpendicular diameters [SPD] or high serum lactate dehydrogenase [LDH ≥ 500 U/L] prior to the start of lymphodepletion) also have a higher risk of developing CRS and/or neurotoxicity.[65]
High baseline levels of other commonly measured inflammatory markers, such as ferritin and C-reactive protein (CRP), were also associated with CRS. It should be noted that, although useful for identifying subjects at higher risk for developing CRS, CPR, ferritin, and serum cytokine levels should not be used for CRS clinical management/treatment decisions in the absence of other clinical signs and symptoms of CRS; for example, a subject with an elevated CRP but no concomitant symptoms may not require intervention. Thus, close observation of these subjects is strongly recommended.  
| CRS parameter                                          | Grade 1                                                    | Grade 2                     | Grade 3          | Grade 4                                                                                    |
|--------------------------------------------------------|------------------------------------------------------------|-----------------------------|------------------|--------------------------------------------------------------------------------------------|
| Fever1                                                 | Temperature ≥ 38                                           | Temperature ≥ 38            | Temperature ≥ 38 | Temperature ≥ 38                                                                           |
| °C                                                     | °C                                                         | °C                          | °C               |                                                                                            |
| Requiring a  vasopressor with  or without  vasopressin | Requiring multiple  vasopressors  (excluding  vasopressin) |                             |                  |                                                                                            |
| With Hypotension                                       | None                                                       | Not requiring  vasopressors | Requiring highflow nasal  cannula3,  facemask,  nonrebreather  mask, or Venturi  mask                  | Requiring positive  pressure (eg.,  CPAP, BiPAP,  intubation and  mechanical  ventilation) |
| Requiring low-flow                                     |                                                            |                             |                  |                                                                                            |
| And/or2 Hypoxia                                        | None                                                       | nasal cannula3 or  blow-by  |                  |                                                                                            |  
Adapted from Lee 2018[28]. Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading.  
1 Fever is defined as temperature ≥ 38 °C not attributable to any other cause. In patients who have CRS then receive antipyretics or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.  
2 CRS grade is determined by more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5 °C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS.  
3 Low-flow nasal cannula is defined as oxygen delivered at ≤ 6 L/min. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at > 6 L/min.  
Detailed CRS management guidelines are shown in **Figure H1**. Treatment should be individualized for each subject's clinical needs. This guidance emphasizes the importance of early intervention for grade 2 CRS, or in the setting of a rapid onset or rapid progression of CRS symptoms, to prevent the development of severe (grade 3 or greater) CRS and neurotoxicity. In some cases, tocilizumab, an anti-IL-6R-antibody, may be required to treat toxicities such as severe CRS. Please refer to the currently approved tocilizumab (Actemra®) prescribing information. Tocilizumab (Actemra®) has been approved by the Food and Drug Administration (FDA) for the treatment of CAR T cell-induced severe or lifethreatening CRS in adults. The preferred dose to intervene in adult subjects with CRS is 8 mg/kg (maximum 800 mg) IV. If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, additional doses of tocilizumab may be administered. Other anti-IL-6 agents, if available, should be considered in the event of severe CRS not responding to tocilizumab and corticosteroids. Dosing of any other anti-IL-6 agent should be per prescribing information.
appendix h management guidelines for
figure h1 cytokine release syndrome

| CRS                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Tocilizumab*                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Corticosteroids†                                         |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|
| Grade1                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                          |
| Grade 1  Symptoms require symptomatic treatment only (e.g., fever, nausea,  fatigue, headache, myalgia,  malaise).                                                                                                                                                                                                                                                                                                                                                   | If onset 72 hours or more after infusion, treat symptomatically. If onset less than 72 hours after infusion, consider tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800  mg).                                                                                                                                                                                                                                                                                                                                                                    | Consider  dexamethasone 10 mg  IV every 24 hours.        |
| Grade 2  Symptoms require and  respond to moderate  intervention.                                                                                                                                                                                                                                                                                                                                                                                                    | Administer tocilizumab 8 mg/kg IV over 1  hour (not to exceed 800 mg).                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Consider  dexamethasone 10 mg  IV every 12 to 24  hours. |
| Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen.                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                          |
| Oxygen requirement less than  40% FiO2 or hypotension  responsive to fluids, or low dose of one vasopressor, or Grade 2  organ toxicity.                                                                                                                                                                                                                                                                                                                             | Limit to a maximum of 3 doses in a 24-hour period;  maximum total of 4 doses.  If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate  dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours).  If no improvement within 24 hours or continued rapid progression, switch to  methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day.  After 2 doses of tocilizumab, consider alternative anti-cytokine  agents. Do not exceed 3 doses of tocilizumab in 24 hours, or 4  doses in total. |                                                          |
| Grade 3  Symptoms require and respond to aggressive intervention.                                                                                                                                                                                                                                                                                                                                                                                                    | Per Grade 2.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Administer dexamethasone 10  mg IV every 12 hours.       |
| If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate  dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours).  If no improvement within 24 hours or continued rapid progression, switch to  methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day.  After 2 doses of tocilizumab, consider alternative anti-cytokine agents.  Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                          |
| Grade 4  Fever, oxygen requirement greater than  or equal to 40% FiO2, or hypotension  requiring high-dose or multiple  vasopressors, or Grade 3 organ toxicity,  or Grade 4 transaminitis.  Life-threatening symptoms.                                                                                                                                                                                                                                              | Per Grade 2.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Administer dexamethasone 20  mg IV every 6 hours.        |
| Requirements for ventilator support, continuous veno-venous hemodialysis  (CVVHD), or Grade 4 organ toxicity  (excluding transaminitis).                                                                                                                                                                                                                                                                                                                             | After 2 doses of tocilizumab, consider alternative anti-cytokine agents. Do not exceed 3  doses of tocilizumab in 24 hours, or 4 doses in total.  If no improvement within 24 hours, consider methylprednisolone (1-2 g, repeat every 24  hours if needed; taper as clinically indicated) or other anti-T cell therapies.                                                                                                                                                                                                                            |                                                          |  
In the most unresponsive cases additional treatment with T cell depleting therapies such as cyclophosphamide should be considered.[66]
appendix h management guidelines for
(2) neurologic toxicities

CAR T cell therapy is associated with unique neurologic toxicities. Neurologic symptoms may include altered mental status, aphasia, altered level of consciousness, and seizures or seizure-like activity. The start of neurologic symptoms has been noted between 3 to 23 days (median 10 days) [62] after CAR T cell infusion and in severe cases may require admission to the intensive care unit (ICU) for frequent monitoring, respiratory support, or intubation for airway protection. The symptoms are variable and generally occur as CRS is resolving or after CRS resolution.
appendix h management guidelines for
(2.1) pathophysiology of neurologic toxicities

The pathogenesis of neurotoxicity is poorly defined. Subjects with NHL who have high baseline tumor burden (measured by SPD or high serum LDH (≥ 500 U/L) prior to the start of lymphodepletion) also have a higher risk of developing neurotoxicity.[65] In addition, severe neurotoxicity has also been reported in subjects with B-cell ALL and higher disease burden at the time of CD19 directed CAR T cell infusion.[67]
Peak levels of IL-6, IFN- , ferritin, and CRP are significantly higher in subjects who develop any grade or grade ≥3 neurotoxicity.[68, 69] In a study treating NHL subjects with a CD19-directed CAR using a CD28 costimulatory domain, development of grade ≥3 neurologic events and CRS correlated with elevation of various cytokines, including IL-6, IL-15, and IL-2R . Subjects with CRS-independent grade ≥3 neurologic events had higher CAR T cell levels and specific cytokines, including IL-2, GM-CSF, and ferritin.[31]
Protein levels in the cerebrospinal fluid (CSF) are usually elevated in patients with neurotoxicity, compared to baseline measurements, suggesting disruption of the bloodbrain barrier. Other organ dysfunction (hepatic and renal), as well as hypoxemia, and infection, might also contribute to the encephalopathy.[70] In another study, it has been reported that evidence for cytokine-mediated endothelial activation causes coagulopathy, capillary leak, and blood-brain barrier disruption allowing transit of high concentrations of systemic cytokines into the CSF.[67]
Current American Society of Blood and Marrow Transplant (ASBMT) Consensus Grading refers neurotoxicity observed CAR T cell therapy as immune effector cell-associated neurotoxicity syndrome (ICANS).[28]
(2.1) Clinical Management of Neurologic Toxicities The optimal management of CAR T cell-induced neurotoxicity is unknown at this time. These management guidelines represent the current state of knowledge. Management should also be guided as per institutional or standard clinical practice, and as determined by the investigator or treating physician and/or consulting neurologist. A thorough neurologic evaluation, including electroencephalogram (EEG), magnetic resonance imaging (MRI) or computed tomography (CT) scan of the brain and diagnostic lumbar puncture and frequent monitoring of cognitive function should be considered. Please refer to **Table H2** for encephalopathy assessment tool for grading of ICANS, and **Table H3** for the ASBMT ICAN Consensus Grading for adults.
appendix h management guidelines for
table h2 encephalopathy assessment tools

| CARTOX-10 [70]                                                        | ICE                                                                                                                                                      |             |       |        |        |       |
|-----------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|-------|--------|--------|-------|
| Orientation:                                                          | orientation                                                                                                                                              | to          | year, | month, | city,  |       |
| hospital, president/prime minister of country of  residence: 5 points | Orientation:                                                                                                                                             | orientation | to    | year,  | month, | city, |
| hospital: 4 points                                                    |                                                                                                                                                          |             |       |        |        |       |
| Naming: ability to name 3 objects (e.g., point to                     | Naming: ability to name 3 objects (e.g., point to                                                                                                        |             |       |        |        |       |
| clock, pen, button): 3 points                                         | clock, pen, button): 3 points                                                                                                                            |             |       |        |        |       |
| Writing: ability to write a standard sentence (e.g.,                  | Writing: ability to write a standard sentence (e.g.,                                                                                                     |             |       |        |        |       |
| "Our national bird is the bald eagle"): 1 point                       | "Our national bird is the bald eagle"): 1 point                                                                                                          |             |       |        |        |       |
| Attention: ability to count backwards from 1000 by                    | Attention: ability to count backwards from 1000 by                                                                                                       |             |       |        |        |       |
| 10: 1 point                                                           | 10: 1 point  Following commands: ability to follow simple  commands (e.g., "Show me 2 fingers" or "Close  your eyes and stick out your tongue"): 1 point |             |       |        |        |       |  
Adapted from Lee 2018 [28]. CARTOX-10 (left column) has been updated to the ICE tool (right column). ICE adds a command-following assessment in place of 1 of the CARTOX-10 orientation questions. The scoring system remains the same. Scoring: 10, no impairment.  
7-9, grade 1 ICANS: 3-6, grade 2 ICANS: 0-2, grade 3 ICANS: 0 due to patient unarousable or unable to perform ICE assessment, grade 4 ICANS.