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5.1 correlative studies for research

Note regarding research Biospecimen collection: If any of the below time points fall on a federal holiday then, we may collect research blood on the next day. 5.1.1 Biospecimen collection before the start of the conditioning chemotherapy:  
One heparinized syringe containing 2-2.5 mL of bone marrow aspirate to be sent to the Surgery Branch Cell Production Facility SB-CPF, Bldg. 10 3W-3808, Phone: 240-858-
3755..It will be used in functional assays to see if anti-BCMA-CAR T cells can recognize the patient's multiple myeloma cells.  
Blood will be collected for research purposes. A total of 12 CPT tubes (8 mL each of blood will be collected prior to initiation of the conditioning chemotherapy regimen. This is a total of 96 mL of blood. Some of this blood will be used for immunology assays and some will be used for RCR assays. This blood can be collected on different days as long as a total of 12 CPT tubes are collected prior to the start of the chemotherapy and within 14 days of the start of the chemotherapy. Send to the Surgery Branch Cell Production Facility SB-CPF, Bldg. 10 3W-3808, Phone: 240-858-3755  
16 mL of blood will be drawn to obtain serum for research purposes (2 SST tubes, 8 mL
per tube) within 14 days prior to the start of the chemotherapy. Send to the Figg lab.  
An apheresis is required to obtain cells used to prepare the anti-BCMA CAR T cells that are administered on this protocol. After sufficient cells are processed for all possible clinical needs, the left over apheresis cells can be cryopreserved for research use. Note that these cells would simply be discarded if not used for research.
Specimens will be cryopreserved and assays will be performed retrospectively.  
5.1.2 Biospecimen collection Day 0 and after anti-BCMA-CAR T-cell infusion during the required hospitalization Every Monday, Wednesday, and Friday during hospitalization, starting on the first Monday, Wednesday, or Friday after the CAR T-cell infusion and lasting up until 14 days after infusion of anti-BCMA-CAR-transduced T cells, 56 mL of patient peripheral blood will be obtained (6 CPT tubes 8 mL each and 1 SST tube 8 mL). Also, 1 SST tube (8 mL) will be drawn on the morning of CAR cell infusion prior to infusion of CAR T cells. 1 SST tube (8 mL) will be drawn on the first Sunday after CAR T-cell infusion. The 1 SST tube will be sent to Figg lab The 6 CPT tubes sent to Surgery Branch Cell Production Facility SB-CPF, Bldg. 10 3W-3808, Phone: 240-8583755.  
Additional research blood may be collected at any time during the clinical course at the discretion of the PI (within the volume restriction limits) allowing for the research studies already outlined in this protocol to be performed at the time of an unanticipated clinical event, if necessary to address the objectives of the study.  
5.1.3 Biospecimen collection during outpatient follow-up
Patients will return for outpatient follow-up clinic visits 2 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months and 12 months after the anti-BCMA- CAR T-cell infusion. After the 12-month follow-up appointment patients will return for follow-up every 6 months. The specimens listed below will be performed at each outpatient clinic visit during the first year of follow up.  
6 CPT tubes of Research Blood (48 mL) will be collected to obtain blood for immunological testing. Send CPT tubes to Surgery Branch Cell Production Facility SB-CPF, Bldg. 10 3W-3808, Phone: 240-858-3755.
1 SST tube (8 mL) of Research Blood will be obtained for serum collection. The SST tubes will be sent to Figg lab.  
NOTE: After 1 year research blood collected will be reduced to 4 CPT tubes at each visit.  
At the 2 week, 2 month and 6 month, 18 month, 30 month and 42 month follow-ups, bone marrow aspirate and biopsy will be performed and the aspirate will be cryopreserved.  
5.1.4 Immunological Testing T-cell assays: Direct immunological monitoring will consist of quantifying CD3+ T cells that express the anti-BCMA CAR by quantitative PCR, and/or by flow cytometry. These assays will be performed to measure the persistence and estimate the proliferation of the infused CAR+ T cells. A quantitative PCR assay or a flow cytometry assay will be used to quantitate CAR+ T cells at all post-infusion time-points up to at least 3 to 6 months after infusion, and CAR+ T cell analysis will continue until the CAR+ T cell level drops to undetectable levels unless a stable low level of CAR+ T cells is present at more than a year after infusion. The absolute number of CAR+ PBMC will be estimated by multiplying the percentage of CAR+ PBMC by the absolute number of lymphocytes plus monoctyes per microliter of blood. Ex vivo immunological assays will be used to measure the BCMA-specific functional activity of the CAR+ T cells and will consist of assays such as intracellular cytokine staining and anti-CD107a degranulation assays. Immunological assays will be standardized by the inclusion of pre-infusion recipient PBMC and in some cases an aliquot of the engineered T cells cryopreserved at the time of infusion.  
Studies of patient T-cell and antibody immune responses against the CAR will be carried out.  
Serum cytokine levels will also be measured by enzyme-linked immune sorbent assays. Gene expression studies might be performed on patient multiple myeloma cells and on the infusion CAR T cells of each patient. Methods used will be either Nanostring and/or RNAseq (RNA sequencing).  
Patients' blood samples will be obtained and undergo analysis for detection of replication competent retroviruses (RCR) by PCR **prior to cell infusion and at 3 and 6 months,** and at one year post cell administration. Monitoring for RCR will be discontinued if all patient samples have been negative for RCR at the 12 month time-point .. If any posttreatment samples are positive, further analysis of the RCR and more extensive patient follow-up will be undertaken, in consultation with the FDA. RCR PCR assays detect the Gibbon Ape Leukemia Virus (GALV) envelop gene and are performed under contract by the National Gene Vector Laboratory at Indiana University The results of these tests are maintained by the contractor performing the RCR tests and by the Surgery Branch (SB) research team.  
Due to nature of these studies, it is expected that expansion of specific T-cell clones will be observed as T-cell proliferate in response to the targeted antigen. Therefore, care will be taken to track T-cell persistence, but presence of an oligoclonal T cell population does not indicate an insertional mutagenesis event. If any patient shows a high level of persistence of CAR gene transduced cells or an increasing population of CAR gene transduced T cells at month 6 or later (by FACS staining or qPCR), the previously archived samples will be subjected to techniques that would allow the identification of predominant clonal populations of transduced cells. Such techniques may include T cell cloning or LAM-PCR. If a predominant or monoclonal T cell clone derived from CAR
gene transduced cells is identified during the follow-up, the integration site and sequence will be identified and subsequently analyzed against human genome database to determine whether the sequences are associated with any known human cancers. If a predominant integration site is observed, the T cell cloning or LAM-PCR test will be used at an interval of no more than three months after the first observation to see if the clone persists or is transient. In all instances where monoclonality is persistent and particularly in instances where there is expansion of the clone, regardless of whether or not the sequence is known to be associated with a known human cancer, the subject should be monitored closely for signs of malignancy, so that treatment, if available, may be initiated early.
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5.1.5 additional biopsies and additional

Patients might be asked to undergo biopsies or additional blood draws as clinically indicated. Additional blood draws might be necessary to investigate T cell responses and serum cytokine levels in cases of clinical events such as rapid regressions of malignancy or toxicity. . These biopsies will only be performed if minimal morbidity is expected based on the procedure performed and the granulocyte and platelet count. Biopsy tissue will be processed in the NCI Laboratory of Pathology. Remainder material from such biopsies studies will be performed to evaluate the antigen expression by the tumor and to evaluate the reactivity of lymphocyte from these biopsies. In addition the presence of transduced cells may be quantitated.
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5.1.6 future studies

Blood and tissue specimens collected in the course of this research project may be banked and used in the future to investigate new scientific questions related to this study the patient provides consent for this. However, this research may only be done if the risks of the new questions were covered in the consent document. If new risks are associated with the research (e.g. analysis of germ line genetic mutations) a protocol amendment will be required and informed consent will be obtained from all research subjects to whom these new studies and risks pertain.
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5.2 sample storage tracking and

5.2.1 Samples Sent to Figg Lab
Venous blood samples will be collected in either a 4-mL or an 8-mL SST tube to be processed for serum and stored for future research.  
o Record the date and exact time of draw on the tube. Blood tubes may be kept in the refrigerator until pick-up.
o For sample pick-up, page 102-11964.  
o For immediate help, call 240-760-6180 (main Blood Processing Core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number).  
o For questions regarding sample processing, contact the Blood Processing Core
(BPC) at NCIBloodcore@mail.nih.gov or 240-760-6180.  
o The samples will be processed, barcoded, and stored in the Figg lab until requested by the investigator.
After delivery to the SB-CPF, peripheral blood mononuclear cell samples will be sent to the Head, Clinical Support Laboratory Clinical Services Program, Applied/Developmental Directorate Frederick National Laboratory for Cancer Research for processing and cryopreservation. They will be stored long-term at the NCI Frederick Repository.
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5.2.2 sample storage tracking and

Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. All samples will be sent to Blood Processing Core (BPC) and/or SB-CPF for processing and/or and storage until they are distributed to the designated place of analysis as described in the protocol. Samples will not be sent outside NIH without appropriate approvals and/or agreements, if required.
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5.2.2.1 samples managed by dr.

Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
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5.2.2.1.2 sample data collection

All samples sent to the Blood Processing Core (BPC) (Dr. Figg's lab) will be barcoded, with data entered and stored in the Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix limited to defined Figg lab personnel, who are issued individual user accounts. Installation of Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password restricted login screen. Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced back to patients without Labmatrix access. The data recorded for each sample includes the patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well as box and freezer location. Patient demographics associated with the clinical center patient number are provided in the system. For each sample, there are notes associated with the processing method (delay in sample processing, storage conditions on the ward, etc.). 5.2.2.1.3 Sample Storage and Destruction Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C according to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a researcher named on the protocol. All requests are monitored and tracked inLabmatrix. All researchers are required to sign a form stating that the samples are only to be used for research purposes associated with this trial (as per the IRB-approved protocol) and that any unused samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that the samples requested are being used in a manner consistent with IRB approval. Following completion of this study, samples will remain in storage as detailed above. Access to these samples will only be granted following IRB approval of an additional protocol, granting the rights to use the material. If, at any time, a patient withdraws from the study and does not wish for their existing samples to be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed or returned to the patient, if so requested. The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of section 7.2. Sample bar-codes are linked to patient demographics and limited clinical information. This information will only be provided to investigators listed on this protocol, via registered use of the Labmatrix. It is critical that the sample remains linked to patient information such as race, age, dates of diagnosis and death, and histological information about the tumor, in order to correlate genotype with these variablesSample Storage, Tracking, and Disposition for Surgery Branch Samples received by the Surgery Branch research lab will be tracked using password protected web-based NCI database Labmatrix. All specimens will be tracked for date of receipt in the Surgery Branch lab, date analyzed, date returned to the originating hospital and/or date destroyed. Specimens will be stored in a locked laboratory cabinet or refrigerators in a locked research lab. All specimens will be entered into Labmatrix with identification and storage location. Access to the stored specimens will be restricted. Access to Labmatrix will be granted upon PI approval only. It is the responsibility of the NCI PI to ensure that the specimens are being used and stored in a manner consistent with IRB approval. All samples are stored in monitored freezers/refrigerators in 3NW NCI-SB laboratories at specified temperatures with alarm systems in place.
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5.2.3 protocol completion/sample destruction

All specimens obtained in the protocol are used as defined in the protocol. If the patient withdraws consent, the participant's data will be excluded from future distributions, but data that have already been distributed for approved research use will not be able to be retrieved. The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be made per the requirements of section 7.2.
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5.2.4 samples for genetic/genomic analysis

Samples for gene expression analysis will use RNAseq and/or NanostringTM. These studies will be used to determine gene expression in multiple myeloma cells and infusion CAR T cells. The purpose of these studies is to assess gene expression at the RNA level not to study germline mutations. 5.2.4.1 Description of the scope of genetic/genomic analysis RNAseq and/or NanostringTM will be used to determine gene expression in multiple myeloma cells and infusion CAR T cells. The purpose of these studies is to assess gene expression at the RNA level not to study germline mutations. One purpose of these studies is to determine if different levels of gene expression in malignant cells are associated with response to CAR T-cell therapy. Another purpose of these studies is to determine if different levels of gene expression in infusion CAR T cells are associated with anti-malignancy responses caused by CAR T cells or persistence of CAR T cells.
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5.2.4.2 certificate of confidentiality

As part of study efforts to provide confidentiality of subject information, this study has obtained a Certificate of Confidentiality, which helps to protect personally identifiable research information. The Certificate of Confidentiality allows investigators on this trial to refuse to disclose identifying information related to the research participants, should such disclosure have adverse consequences for subjects or damage their financial standing, employability, insurability or reputation. The informed consent includes the appropriate coverage and restrictions of the Certificate of Confidentiality.
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5.2.4.3 management of results

The analyses that we perform in our laboratory are for research purposes only; they are not nearly as sensitive as the tests that are performed in a laboratory that is certified to perform genetic testing. Changes that we observe unrelated to our research may or may not be valid. Therefore, we do not plan to inform participants of the results of testing on the tissue and blood that is performed in our research lab. However, subjects will be contacted if a clinically actionable gene variant is discovered. Clinically actionable findings for the purpose of this study are defined as disorders appearing in the American College of Medical Genetics and Genomics recommendations for the return of incidental findings that is current at the time of primary analysis. (A list of current guidelines is maintained on the CCR intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists) Subjects will be contacted at this time with a request to provide a blood sample to be sent to a CLIA certified laboratory. The CLIA testing may be funded by the PI or the CCR. If the research findings are verified in the CLIA certified lab, the subject will be referred to the NCI Genetics Branch for genetic counseling on the implications of the results. Subjects that do not wish to return to the NCI will be referred to a local genetics health care provider (at their expense). This is the only time during the course of the study that incidental findings will be returned. No interrogations regarding clinically actionable findings will be made after the primary analysis.
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6 data collection and evaluation

Data will be prospectively collected and entered into an in-house password protected electronic system /database (NCI C3D database) , ensuring data accuracy, consistency and timeliness. The NCI PI, research nurse , and designated members of the research team will have access to these data via web access. The principal investigator, associate investigators/research nurses and/or a contracted data manager will assist with the data management efforts.. Primary and final analyzed data will have identifiers so that research data can be attributed to an individual human subject participant. The medical record will maintain complete records on each patient including any pertinent supplementary information obtained from outside laboratories, outside hospitals, radiology reports, laboratory reports, or other patient records. The NCI C3D will serve as the primary source from which all research analyses will be performed. Data collection will include the patient history, specialty forms for pathology, radiology, toxicity monitoring, and relapse data and an off-study summary sheet, including a final assessment by the treating physician. All AEs, will be followed until return to baseline or stabilization of event. Document AEs from the first study intervention, Study Day 1, through 30 days after the study treatment was last administered. Beyond 30 days after the last intervention, only adverse events which are serious and related to the study intervention need to be recorded, unless otherwise noted in Section 6.1.1. End of study procedures: Data will be stored according to HHS , FDA regulations and NIH Intramural Records Retention Schedule as applicable. Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurredthis will be reported expeditiously per requirements in section **7.2.1**. 6.1.1 Adverse event recording  
Grade 1 adverse events will not be recorded. All Grade 2 events will be recorded regardless of attribution up to at least 30 days after CAR T-cell infusion After 30 days after CAR T-cell infusion Grade 2 adverse events that will be recorded:
a. Unexpected events that are possibly, probably, or definitely related to the research.  
b. Expected events that are probably or definitely related to the study interventions will be recorded only for the first year after the infusion..  
c. All Infections proven by culture, PCR, antigen detection or other laboratory methods will be recorded for the first year after infusion regardless of attribution.  
d. Any serious events that are deemed clinically significant by the PI  
Version Date: April 26, 2021 All grade 3, 4, and 5 adverse events will be recorded regardless of attribution.
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6.2 data sharing plans

6.2.1 Human Data Sharing Plan I will share human data generated in this research for future research as follows: x__ Coded, linked data in an NIH-funded or approved public repository. _x__ Coded, linked data in BTRIS (automatic for activities in the Clinical Center) _x__ Coded, linked or identified data with approved outside collaborators under appropriate agreements.
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how and where will the

Data will be shared through: x__ An NIH-funded or approved public repository. Insert name or names: ClinicalTrials.gov. _x__ BTRIS (automatic for activities in the Clinical Center) _x__ Approved outside collaborators under appropriate individual agreements.  
_x__ Publication and/or public presentations.
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when will the data be

_x__ Before publication. _x__ At the time of publication or shortly thereafter.
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6.3 genomic data sharing plan

Unlinked genomic data will be deposited in the database of genotypes and phenotypes (dbGaP) in compliance with the NIH Genomic Data Sharing Policy.
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6.4 response criteria

Responses will be categorized by using the International Uniform Response Criteria for Multiple myeloma 2016 updated version.111 Multiple myeloma staging will be conducted at the 2 week follow-up appointment and at each subsequent follow-up appointment. The appropriate staging studies will need to be determined for each patient because of the variability in multiple myeloma. 6.4.1 Important Considerations on response criteria  
Response criteria for all categories and subcategories of response except CR and sCR are applicable only to patients who have 'measurable' disease by at least one of the three measurements as defined below All responses must be confirmed to be stable in two evaluations made at any time.
6.4.1.1 Definition of measurable disease16 Any one or combination of these abnormalities defines measurable disease:  
Serum M-protein greater or equal to 1.0 g/dL (10 g/L).  
Urine M-protein greater or equal to 200 mg/24 h. Serum FLC assay: involved FLC level greater or equal to10 mg/dL (100 mg/L)
provided serum FLC ratio is abnormal.  
Presence of a biopsy-proven plasmacytoma Bone marrow plasma cells >30% of total bone marrow cells
6.4.1.2 Laboratory tests for measurement of M-protein Serum M-protein level is quantitated using densitometry on SPEP except in cases where the SPEP is felt to be unreliable such as in patients with IgA monoclonal proteins migrating in the beta region. If SPEP is not available or felt to be unreliable (e.g., in some cases of IgA myeloma) for routine M-protein quantitation during therapy, then quantitative immunoglobulin levels on nephelometry or urbidometry can be accepted. However, this must be explicitly reported, and only nephelometry can be used for that patient to assess response and SPEP and nephelometric values cannot be used interchangeably.  
Urine M-protein measurement is estimated using 24-h UPEP only. (Random or 24 h urine tests measuring kappa and lambda light chain levels are not reliable and are not recommended)
6.4.1.3 Suggested follow-up to meet response criteria Patients with measurable disease by both SPEP and UPEP need to be followed by both SPEP and UPEP for response assessment and categorization; Except for assessment of sCR, CR, and VGPR, patients with "measurable disease" restricted to the SPEP will need to be followed routinely only by SPEP;
Patients with "measurable disease" restricted to the UPEP will need to be followed routinely only by UPEP;
Patients with "measurable disease" in either SPEP or UPEP or both will be assessed for response only based on these two tests and not by the FLC assay; FLC response criteria are only applicable to patients without measurable disease in the serum or urine, and to fulfill the requirements of the category of sCR;
Bone marrow is required only for categorization of CR
For good clinical practice patients should be periodically screened for light chain escape with UPEP or serum FLC assay.  
Plasmacytomas can be staged at baseline and followed for response with CT scans by measuring target lesions with the sums of the products of the diameters method. For purposes of defining CR, masses greater than 2.0 cm will be considered abnormal.
6.4.2 International Myeloma Working Group uniform response criteria:  
6.4.2.1 Stringent Complete Remission (sCR)
CR as defined below plus o Normal FLC ratio and o Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence or flow cytometry (only1 bone marrow evaluation is needed).  
6.4.2.2 Complete Remission (CR)
Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and 5% or less plasma cells in bone marrow (only 1 bone marrow evaluation is needed)
No evidence of progressive or new bone lesions if radiographic studies were performed
(X-Rays not required in absence of clinical indication) Comments: To be considered a CR,  
**Both** serum and urine immunofixation must be carried out and be negative regardless of the size of baseline M-protein in the serum or urine; Patients with negative UPEP values pretreatment still require UPEP testing to confirm CR and exclude light chain or Bence–Jones escape 6.4.2.3 Very Good Partial Remission (VGPR)
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein **plus** urine M-protein level <100mg per 24 h No evidence of progressive or new bone lesions if radiographic studies were performed
(X-Rays not required in absence of clinical indication)
90% decrease in the sum of the products of the the diameters of soft tissue plasmacytomas is required.  
6.4.2.4 Partial Remission (PR)
50% or greater reduction of serum M-protein and 90% or greater reduction in 24-h urinary M-protein (or to less than 200mg per 24 h) and 50% or greater reduction in the size of soft tissue plasmacytomas, if present at baseline No evidence of progressive or new bone lesions if radiographic studies were performed
(X-Rays not required in absence of clinical indication)
Only if the serum and urine M-protein are not measurable (as per definition in section 6.4.1.1),  
50% or greater decrease in the difference between involved and uninvolved FLC levels is required (in lieu of the serum and urine M-protein criteria).
6.4.2.5 Stable Disease (SD)
Not meeting criteria for CR, VGPR, PR or progressive disease
(Not recommended for use as an indicator of response; stability of disease is best described by providing the time to progression estimates)  
All response categories require two consecutive assessments made at **any time** before the institution of any new therapy; Confirmation with repeat bone marrow biopsy not needed.  
Presence/absence of clonal cells is based upon the κ/λ ratio. An abnormal κ/λ ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is κ/λ ration of greater than 4:1 or less than 1:2.
6.4.2.6 Progressive Disease (PD)a Requires one or more of the following:
Increases of greater or equal to 25% from the lowest post-treatment (nadir) value in  
o Serum M-component (minimum absolute increase of 0.5g/dL) or o Urine M-component (minimum absolute increase of 200mg/24h) or o Percentage of bone marrow plasma cells (minimum absolute percentage of 10%) o Only in patients without measurable serum and urine M-protein levels: The difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL. The FLC ratio must be abnormal.  
Definite development of new bone lesions or clear increase in size of on or more bone lesion(s) (must be 50% or greater increase of a lesion at least 1 cm in longest length at nadir) on CT scan or new plasmacytoma 2.0 cm or larger on CT scan.  
50% or more increase in the sum of the products of the diameters of multiple soft tissue plasmacytomas or 50% or more increase in the size of a single soft tissue plasmacytoma.
Development of hypercalcemia solely attributable to the disease (corrected serum calcium >11.5 mg/dL)
aAll relapse categories require 2 consecutive assessments made at any time before classification as relapse or progression or institution of a new therapy.  
6.4.3 Minimal residual disease (MRD) criteria (requires complete response as defined above)
Sustained MRD-negative MRD negativity in the marrow (next generation flow (NGF) or next generation sequencing (NGS) or both) and by imaging as confirmed at least with assessments at least 1 year apart.  
Flow MRD-negative-Absence of aberrant clonal plasma cells in the bone marrow by NGF using EuroFlow standard operating procedures or equivalent; must have sensitivity of one in 105 nucleated cells.
Sequencing MRD-negative-absence of clonal plasma cells by NGS on bone marrow aspirate with a method with sensitivity of 1 in 105 nucleated cells.  
Imaging plus MRD-negative-MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT or decrease to less than mediastinal blood pool SUV or decrease to less than that of surrounding normal tissue.
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6.5 toxicity criteria

The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
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7 nih reporting requirements/data and

Please refer to definitions provided in Policy 801: Reporting Research Events found here.
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7.2 ohsrp office of compliance

Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies. 7.2.2 IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.
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7.3 nci clinical director reporting

Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death.
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7.4 institutional biosafety committee (ibc)

The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or lifethreatening experience associated with the use of anti-BCMA CAR T cells as soon as possible but in no event later than 7 calendar days of initial receipt of the information. Serious adverse events that are unexpected and associated with the use of the anti-BCMA CAR-expressing T cells, but are not fatal or life-threatening, must be reported to the NIH IBC as soon as possible, but not later than 15 calendar days after the investigator'sinitial receipt of the information.  
Adverse events may be reported by using the FDA Form 3500a.
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7.4.2 annual reports to ibc

Within 60 days after the one-year anniversary of the date on which the IBC approved the initial protocol, and after each subsequent anniversary until the trial is completed, the Principal Investigator (or delegate) shall submit the information described below. Alternatively, the IRB continuing review report can be sent to IBC in lieu of a separate report. Please include the IBC protocol number on the report.
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7.4.2.1 clinical trial information

A brief summary of the status of the trial in progress or completed during the previous year. The summary is required to include the following information:
the title and purpose of the trial  
clinical site the Principal Investigator clinical protocol identifiers participant population (such as disease indication and general age group, e.g., adult or pediatric);
the total number of participants planned for inclusion in the trial; the number entered into the trial to date whose participation in the trial was completed; and the number who dropped out of the trial with a brief description of the reasons the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, or fully completed, if the trial has been completed, a brief description of any study results.  
7.4.2.2 Progress Report and Data Analysis
Information obtained during the previous year's clinical and non-clinical investigations, including:  
a narrative or tabular summary showing the most frequent and most serious adverse experiences by body system a summary of all serious adverse events submitted during the past year a summary of serious adverse events that were expected or considered to have causes not associated with the use of the gene transfer product such as disease progression or concurrent medications if any deaths have occurred, the number of participants who died during participation in the investigation and causes of death a brief description of any information obtained that is pertinent to an understanding of the gene transfer product's actions, including, for example, information about dose-response, information from controlled trials, and information about bioavailability.
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7.5 nih required data and

The clinical research team will meet on a weekly basis when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior patients. All data will be collected in a timely manner and reviewed by the principal investigator. Events meeting requirements for expedited reporting as described in section **7.2.1** will be submitted within the appropriate timelines.The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
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7.5.2 safety monitoring committee (smc)

This protocol will require oversight from the Safety Monitoring Committee (SMC). Initial review will occur as soon as possible after the annual IRB continuing review date. Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more frequently as may be required by the SMC. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within the review period. Written outcome letters will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
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8 sponsor protocol/ safety reporting

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (ICH E6 (R2))
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8.1.2 serious adverse event (sae)

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
Death,  
A life-threatening adverse event (see 8.1.3) Inpatient hospitalization or prolongation of existing hospitalization o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the study), a planned hospitalization for pre-existing condition, or a procedure required by the protocol, without a serious deterioration in health, is not considered a serious adverse event.  
o A hospitalization/admission that is solely driven by non-medical reasons (e.g.,
hospitalization for patient or subject convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria.
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions A congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
8.1.3 Life-threatening
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32) 8.1.4 Severity The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0. 8.1.5 Relationship to Study Product All AEs will have their relationship to study product assessed using the terms: related or not related.  
Related - There is a reasonable possibility that the study product caused the adverse event. Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event.  
Not Related - There is not a reasonable possibility that the administration of the study product caused the event.
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8.2 assessment of safety events

AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution. SAEs will be:  
Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  
Recorded on the appropriate SAE report form, the medical record and captured in the clinical database.  
Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events recorded from the time of first investigational product administration must be reported to the sponsor.
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8.3 reporting of serious adverse

Any AE that meets a protocol-defined serious criterion or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form. All SAE reporting must include the elements described in section 8.2. SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and instructions can be found at: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+InstructionFollowing the assessment of the SAE by OSRO, other supporting documentation of the event may be requested by the OSRO Safety and should be provided as soon as possible.
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8.4 reporting pregnancy

All required pregnancy reports/follow-up to OSRO will be submitted to: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. Forms and instructions can be found here: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions.  
8.4.1 Maternal exposure If a patient becomes pregnant during the study, the study treatment should be discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy become known, Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented.
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8.4.2 paternal exposure

Male patients should refrain from fathering a child or donating sperm during the study and for 4 months after the last dose of receiving protocol treatment. Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until (*120 days)* after the last dose should, if possible, be followed up and documented.
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8.5 regulatory reporting for studies

Following notification from the investigator, CCR, the IND sponsor, will report any suspected adverse reaction that is both serious and unexpected . CCR will report an AE as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the study product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potential serious risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 312.32. All serious events will be reported to the FDA at least annually in a summary format.
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9 clinical monitoring

As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring program. The CCR's program allows for confirmation of: study data, specifically data that could affect the interpretation of primary and secondary study endpoints; adherence to the protocol, regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on:
Informed consent process  
Eligibility confirmation Drug administration and accountability Adverse events monitoring Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating center. This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct.
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10 statistical considerations 10.1 statistical

The primary endpoint of this trial is to determine the safety of administering anti-BCMA-CARexpressing T cells to patients with multiple myeloma. The primary approach for assessing this endpoint will be through a dose escalation. Exploratory objectives of this trial are to measure any anti-malignancy effect that might occur, to assess the feasibility of administering anti-BCMA-CAR-expressing T cells, and to measure persistence, function, and gene expression of anti-BCMA-CAR-expressing T cells.
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10.2 sample size determination

The sample size of this clinical trial will be determined by the requirements of the doseescalation scheme. A maximum of 30 treated patients will be needed to complete the dose escalation scheme, and an additional 12-patient expansion group will be treated at the MTD. The 12-patient expansion group to better characterize the MTD is needed because of the substantial variability between patients receiving infusions of CAR T cells. The total number of treated patients will be a maximum of 42 including patients who may be re-enrolled. We estimate that 120 patients will need to be screened at the NIH to recruit up to 42 treated patients.  
The trial uses a dose-escalation design, with 5 dose levels and a -1 dose level if needed. The number of anti-BCMA-CAR-expressing T cells transferred for each dose level is as follows:  
| Dose level -1   | 0.4x106  CAR+ T cells per kg of recipient bodyweight   |
|-----------------|--------------------------------------------------------|
| Dose level 1    | 0.75x106  CAR+ T cells per kg of recipient bodyweight  |
| Dose level 2    | 1.5x106  CAR+ T cells per kg of recipient bodyweight   |
| Dose level 3    | 3.0x106  CAR+ T cells per kg of recipient bodyweight   |
| Dose level 4    | 6.0x106  CAR+ T cells per kg of recipient bodyweight   |
| Dose level 5    | 12.0x106  CAR+ T cells per kg of recipient bodyweight  |  
Patients will be enrolled sequentially; therefore, enrollment will not proceed to a higher dose level until all patients have been treated on the prior dose level. If sufficient cells cannot be grown to meet the criteria for the assigned dose level, the patient will receive the dose of cells called for by one dose level lower than the assigned dose level. If sufficient cells cannot be grown to meet the dose requirement called for one dose level lower than the assigned dose level, the treatment will be aborted. If a DLT occurs in an additional patient entered at a lower dose due to cell growth limitations, accrual will continue at this level as described in the doseescalation scheme in section **3.1.4**. Accrual will be halted at the higher level until accrual at the lower level is complete as described above. Should none of the first 3 patients treated on a dose level experience a DLT, the first patient can be infused on the next higher dose level after a 28-day delay following CAR T-cell infusion of the third patient. Should 1 of 3 patients experience a DLT at a particular dose level, three more patients would be treated at that dose level. If 1/6 patients have a DLT at a particular dose level, the first patient can be infused on the next higher dose level after a 28-day delay following CAR
T-cell infusion of the 6th patient.If a level with 2 or more DLTs in 3-6 patients has been identified, 3 additional patients will be accrued at the next-lowest dose for a total of 6, in order to further characterize the safety of the MTD. The MTD is the dose at which a maximum of 1 of 6 patients has a DLT. After a MTD is defined, additional patients can be treated on this trial: up to 12 total additional recipients can be treated after a MTD is established in order to better define safety and toxicity at that dose level. If treatment of at least 3 patients on each dose level is completed without establishing a MTD, a maximum feasible dose can be declared, and up to 12 additional patients can be treated at the maximum feasible dose level. If cell growth limitations preclude administration of the maximum tolerated dose to a patient in the expansion group, the patient will receive as many cells as possible up to the MTD. DLTs that occur in patients receiving a repeat treatment will not affect the dose escalation of patients receiving an initial treatment. However, excessive DLTs among re-treatments will result in a discontinuation of this practice. Specifically, if 2 of the first 3 patients re-treated, 3 or more of the first 6 re-treated patients, 4 or more out of the first 9 re-treated patients, or greater than 1/3 of the total patients receiving a repeat treatment experiences a DLT during repeat treatment, then repeat treatments will be discontinued altogether.
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10.3 populations for analyses

All treated patients will be included in the safety analysis dataset. 10.4 STATISTICAL A**NALYSES** 10.4.1 General Approach This is a standard 3+3 dose escalation study. Toxicity data will be obtained and used to determine the MTD of the treatment. 10.4.2 Analysis of the Primary Endpoints The toxicity obtained on each patient will be determined and used to report the number of patients at each dose level who experience a DLT, following standard phase I procedures. 10.4.3 Analysis of the Secondary Endpoint(s) There are no secondary endpoints. 10.4.4 Safety Analyses The study will determine the toxicity experienced on each patient enrolled on the trial and report this by dose level.  
10.4.5 Baseline Descriptive Statistics None will be provided in a formal manner; brief descriptions may be incorporated in a final report. 10.4.6 Planned Interim Analyses Toxicity will be evaluated at each dose level as the patients accrue to the trial. Stopping criteria are described in section **3.9.** 10.4.7 Sub-Group Analyses None 10.4.8 Tabulation of individual Participant Data None
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10.4.9 exploratory analyses

The degree of persistence of anti-BCMA-CAR-transduced T cells will be evaluated by a quantitative measure (flow cytometry and/or quantitative PCR) in all patients. Serum cytokine levels and T-cell gene expression levels are other important exploratory assessments. Antimalignancy effects will be measured by clinical response and categorized according to the International Uniform Response Criteria for Multiple Myeloma (Section 6.4). The clinical multiple myeloma responses will be interpreted cautiously in the context of a pilot study which may be used to guide parameters for study in future protocols if warranted. All other evaluations of exploratory objectives will be performed using exploratory techniques. No formal adjustment for multiple comparisons will be used since the evaluations are being done to generate hypotheses. Exploratory assessments will include analysis for associations between clinical outcomes such as severity of toxicity and serum cytokine levels or severity of toxicity and blood CAR T-cell levels. Parametric and nonparametric tests will be used as appropriate.
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11 human subjects protections 11.1

The patients to be entered in this protocol have multiple myeloma which is an almost always incurable disease; moreover, patients will have progressive or relapsed myeloma despite at least 3 prior therapies. These patients have limited life expectancies. Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the eligibility criteria. To date, there is no information that suggests that differences in disease response would be expected in one group compared to another. Efforts will be made to extend accrual to a representative population, but in this preliminary study, a balance must be struck between patient safety considerations and limitations on the number of individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the need to explore gender and ethnic aspects of clinical research on the other hand. If differences in outcome that correlate to gender or to ethnic identity are noted, accrual may be expanded or a follow-up study may be written to investigate those differences more fully.  
MM remains an incurable disease despite recent advances in therapy.  
Over the last 40 years and throughout the most recent era of improved therapy with novel agents, the depth of the disease response to therapy (including T- cells targeting B-cell maturation antigen) has remained the single most predictive factor for event free and overall survival in MM
Therefore, improving the rate and depth of responses remains a high priority for clinical research in MM.  
This justifies the enrollment of all subjects with MM eligible for T- cells targeting B-cell maturation antigen in this phase I/II study in an attempt to improve the clinical outcome while feasibility and safety are being evaluated.  
Because patients on previous trials of CAR T cells have experienced hypotension, tachycardia, prolonged fevers, neurological toxicities, and depressed myocardial function. In many cases these toxicities were severe enough to require intensive care unit admission. We will limit enrollment to patients 70 years of age or less because based on our admittedly limited experience with prior CAR-T cell clinical trials, younger patients tolerate and recover from these toxicities better than elderly patients.
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11.2 participation of children

Children will not be enrolled on this study. Multiple myeloma is extremely uncommon in children; moreover, since the efficacy of this experimental procedure is unknown, it does not seem reasonable to expose children to this risk without further evidence of benefit.
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11.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section **11.4** ), all subjects will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify an LAR, as needed .Please see section **11.5.1** for consent procedure.
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11.4 evaluation of benefits and

The experimental treatment has a chance to provide clinical benefit though this is unknown. A goal of this study is to improve upon the number of patients who may benefit from adoptive cell therapy by using genetically-modified T-cells. This specific protocol is being performed to evaluate a genetically modified T-cell therapy for multiple myeloma, which is an almost always incurable disease. Only patients with multiple myeloma who have progressive or relapsed myeloma despite at least 3 prior lines of therapy will be enrolled. The risks of the study fall into 3 general categories (see section 12 for details). First, chemotherapy that could cause cytopenias is part of the protocol. As with any chemotherapy that causes neutropenia and thrombocytopenia, this chemotherapy could cause toxicities such as infections and bleeding. The second category of toxicity is cytokine-release type toxicities such as high fevers, tachycardia, hypotension and neurological toxicities such as delirium, obtundation, myoclonus, seizures, headache, and transient focal neurological toxicities including aphasia and focal paresis. These cytokine-release-type toxicities have been detected in other clinical trials of CAR T cells during the first 2 weeks after anti-BCMA CAR T cells were infused.4,107 The third main category of toxicity is direct damage to normal tissues by the CAR T
cells. This could happen because of unexpected expression of BCMA on normal cells or because of unexpected cross-reactivity of the anti-BCMA CAR with proteins other than BCMA in vivo. Another potential toxicity of anti-BCMA CAR T cells is hypogammaglobulinemia due to depletion of plasma cells and mature B cells. Hypogammaglobulinemia has been a complication of many patients on clinical trials of anti-BCMA CAR-expressing T cells.4,33 Hypogammaglobulinemia in these patients was routinely treated with infusions of intravenous immunoglobulins.4 The gammaretroviral vector used in this trial inserts into the T-cell DNA of patients, so in theory, insertional mutagenesis could occur, but insertional mutagenesis has not occurred in any of the hundreds of patients treated with mature T cells that were genetically modified by gammaretroviral vectors.35-37 The success of this clinical trial cannot be predicted at this time. Because all patients in this protocol have advanced multiple myeloma and limited life expectancies the potential benefit is thought to outweigh the potential risks. It is also anticipated that this study will provide scientific information relevant to tumor immunotherapy.
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11.4.1 risk to family or

Family members or relatives may or may not want to be aware of familial tendencies or genetic risks of disease which may cause anxiety about possible future health problems. Patients will be notified of any medically significant and actionable incidental findings. Study results will not be shared with patients. 11.4.2 Risks of exposure to Ionizing Radiation The procedures for performing the CT scans will follow clinical policies, no special procedures apply to these additional assessments for research purposes. In summary, subjects may receive additional radiation exposure from up to eight (8) CT head+ Neck +CAP and five (5)18FDGPET/CT scans in the first year of the study.  
The total additional radiation dose for research purposes will be approximately 16.9 rem in the first year of the study. This amount is more than would be expected from everyday background radiation. Being exposed to too much radiation can cause harmful side effects such as an increase in the risk of cancer. The risk of getting cancer from the radiation exposure in this study is 1.7 out of 100 (1.7%) and of getting a fatal cancer is 0.8 out of 100 (0.8%).
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11.4.3 risks of scans and

If contrast dye is used, there is a small chance of developing an allergic reaction from the contrast material including gadolinium, which may cause symptoms ranging from mild itching or a rash to severe difficulty breathing, shock or rarely, death. The contrast material may also cause kidney problems. Gadolinium for research MRI scans will not be given to patients who have impaired kidney function or who received gadolinium within the previous month.Common reactions include pain in the vein where the contrast was given, a metallic or bitter taste in the mouth , headache, nausea and a warm or flushing feeling that lasts from 1-3 minutes. An IV line may need to be inserted for administration of the contrast agent or anesthetic, which may cause pain at the site where the IV is placed and there is a small risk of bruising or infection 11.4.4 Risks of blood Sampling Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 11.4.5 Risks of Bone marrow aspiration and biopsy Side effect of bone marrow aspiration and biopsy may feel a pressure sensation when the needle is being inserted and a pulling sensation and brief pain as the marrow is withdrawn. Potential complications of this procedure are local bleeding, pain at the site, and infection. Both of these are very rare. Bleeding can be stopped by applying local pressure and an infection can be treated with antibiotics. 11.4.6 Risks of Intravenous Catheter Side effect of placing some catheters include pain, bleeding, infection and rarely, collapsed lung. The long- term risks of the catheter rarely include infection and clotting of veins. 11.4.7 Risks of Apheresis The risks of apheresis are similar to whole blood donation and include pain and bruising at the needle insertion site in the arms, lightheadedness, dizziness, nausea, and rarely fainting due to a rare reflex reaction to needle placement and to the temporary decrease in blood volume during apheresis. It may also feel tingling around your mouth or in your fingers caused by a blood thinner given during the procedure. The tingling may reduce by giving calcium containing chewable antacid. All the symptoms usually go away within a few minutes of stopping the procedure.
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11.5 consent process and documentation

The informed consent document will be provided to the participant or consent designee(s) (e.g., legally authorized representative [LAR] if participant is an adult unable to consent) for review prior to consenting. A designated study investigator will carefully explain the procedures and tests involved in this study, and the associated risks, discomforts and benefits. In order to minimize potential coercion, as much time as is needed to review the document will be given, including an opportunity to discuss it with friends, family members and/or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to entry onto the study. The initial consent process as well as re-consent, when required, may take place in person or remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with local policy, including HRPP policy 303) per discretion of the designated study investigator and with the agreement of the participant/consent designee(s). Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant/consent designee, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed. 11.5.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation For participants addressed in section **11.3**, an LAR will be identified consistent with Policy 403 and informed consent obtained from the LAR, as described in Section **11.5**.
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12 regulatory and operational considerations

This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written notification, documenting the reason for study suspension or termination, will be provided by the suspending or terminating party to study participants, investigators, funding agency, the Investigational New Drug (IND) sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit schedule. Circumstances that may warrant termination or suspension include, but are not limited to:  
Determination of unexpected, significant, or unacceptable risk to participants Demonstration of efficacy that would warrant stopping Insufficient compliance to protocol requirements Data that are not sufficiently complete and/or evaluable Determination that the primary endpoint has been met Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
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12.2 quality assurance and quality

The clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation and completion. An individualized quality management plan will be developed to describe a site's quality management. Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution. Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and reported in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.
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12.3 conflict of interest policy

The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the National Cancer Institute has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.
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12.4 confidentiality and privacy

Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorized third party without prior written approval of the sponsor. All research activities will be conducted in as private a setting as possible. The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records. The study participant's contact information will be securely stored at the/each clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be transmitted to and stored at the National Cancer Institute Center for Cancer Research (NCI CCR). This will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by the clinical site(s) and by NCI CCR research staff will be secured and password protected. At the end of the study, all study databases will be archived at the NIH. To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the National Institutes of Health (NIH). This certificate protects identifiable research information from forced disclosure. It allows the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to participants.
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13 pharmaceutical information

Note: The commercial drugs used in this study will not alter labelling of the FDA approved drugs and nor does the investigation involve a route of administration or dosage level in use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.
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13.1 retroviral vector containing the

The retroviral vector supernatant (MSGV-FHVH33-CD8BBZ) encoding a CAR directed against BCMA was prepared and preserved following cGMP conditions in the University of Cincinnati Medical Center Vector Production Facility. The retroviral vector utilizes the MSGV retroviral vector backbone and consists of 7007 bps including the 5' LTR from the murine stem cell virus (promoter), packaging signal including the splicing donor (SD) and splicing acceptor sites, the anti-BCMA CAR protein containing a signal peptide from human CD8-alpha signal sequence, the fully-human heavy chain variable region 316833 (FHVH33), CD8 (hinge and transmembrane), CD28 (cytoplasmic region), and TCR zeta (cytoplasmic region), followed by the murine stem cell virus 3'LTR.  
The supernatant will be stored at –80oC or shipped on dry ice and stored in the Dept. of Transfusion Medicine, NIH or at FisherBiosciences, Rockville, MD. Both storage facilities are equipped with around-the-clock temperature monitoring. Upon request, supernatant will be delivered on dry ice to be used in *in vitro* transductions of T cells. There will be no re-use of the same unit of supernatant for different patients. Retroviral titer has been shown to be stable after immediate thawing and immediate use. Handling of the vector should follow the guidelines of Biosafety Level-2 (BSL-2). The specific guidelines for Biosafety Level-2 (BSL-2) can be viewed at http://bmbl.od.nih.gov/sect3bsl2.htm 13.1.2 Toxicities Please refer to section 1.2.11 13.1.3 Administration procedures: Please see section **Error! Reference source not found.**.
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13.2 commercial agents

Please refer to the US approved package insert for the full prescribing information here:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails 13.2.1 Cyclophosphamide 13.2.1.1 Source Cyclophosphamide will be purchased by the NIH Clinical Center Pharmacy Department from commercial sources and is supplied as a lyophilized powder in various vial sizes. 13.2.1.2 Administration procedures The cyclophosphamide used in this regimen will be given as Intravenous infusion over 30 minutes. 13.2.2 FLUDARABINE 13.2.2.1 Source Fludarabine monophosphate will be purchased by the NIH Clinical Center Pharmacy Department from commercial sources and is supplied as a white, lyophilized powder. Each vial contains 50  
Version Date: April 26, 2021 mg of fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH. Fludarabine is stored at room temperature. 13.2.2.2 Administration procedures Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Fludarabine is administered as an IV infusion in 100 mL 0.9% sodium chloride, USP over 15 to 30 minutes.  
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14 references

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5. Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. *Clinical Cancer* Research. 2013;19(8):2048-2060.  
6. Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. *Journal of Experimental Medicine.* 2005;202(7):907-912.  
7. Kochenderfer JN, Yu Z, Frasheri D, Restifo NP, Rosenberg SA. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. *Blood.* 2010;116(19):3875-3886.  
8. North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. Journal of Experimental Medicine. 1982;155(4):1063-1074.
9. Palumbo A, Anderson K. Multiple myeloma. *New England Journal of Medicine.*
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58. Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. *Nature* Biotechnology. 2002;20(1):70-75.  
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61. Cheadle EJ, Hawkins RE, Batha H, O'Neill AL, Dovedi SJ, Gilham DE. Natural expression of the CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells. *Journal of Immunology.* 2010;184(4):18851896.  
62. Brentjens RJ, Santos E, Nikhamin Y, et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. *Clinical Cancer Research.* 2007;13(18 Pt 1):5426-5435.  
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64. Porter CD, Collins MK, Tailor CS, et al. Comparison of efficiency of infection of human gene therapy target cells via four different retroviral receptors. *Human Gene Therapy.* 1996;7(8):913-919.  
65. Jensen MC, Popplewell L, Cooper LJ, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. *Biology of Blood and Marrow Transplantation.* 2010;16(9):1245-1256.  
66. Kochenderfer JN, Somerville RPT, Lu T, et al. Lymphoma Remissions Caused by AntiCD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin15 Levels. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;35(16):1803-1813.  
67. Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. *Science Translational Medicine.* 2016;8(355).
68. Laabi Y, Gras MP, Carbonnel F, et al. A new gene, BCM, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant T cell lymphoma. *EMBO Journal.* 1992;11(11):3897-3904.  
69. Laabi Y, Gras MP, Brouet JC, Berger R, Larsen CJ, Tsapis A. The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed. Nucleic Acids Research. 1994;22(7):1147-1154.  
70. Novak AJ, Darce JR, Arendt BK, et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: A mechanism for growth and survival. *Blood.* 2004;103(2):689-694.  
71. Neri P, Kumar S, Fulciniti MT, et al. Neutralizing B-cell-activating factor antibody improves survival and inhibits osteoclastogenesis in a severe combined immunodeficient human multiple myeloma model. *Clinical Cancer Research.* 2007;13(19):5903-5909.  
72. Bellucci R, Alyea EP, Chiaretti S, et al. Graft-versus-tumor response in patients with multiple myeloma is associated with antibody response to BCMA, a plasma-cell membrane receptor. *Blood.* 2005;105(10):3945-3950.  
73. Moreaux J, Legouffe E, Jourdan E, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. *Blood.* 2004;103(8):3148-3157.  
74. Thompson JS, Schneider P, Kalled SL, et al. BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population. *Journal of Experimental Medicine.* 2000;192(1):129-135.  
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78. O'Connor BP, Raman VS, Erickson LD, et al. BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells. *Journal of Experimental Medicine.* 2004;199(1):91-97.  
79. Ng LG, Sutherland APR, Newton R, et al. B cell-activating factor belonging to the TNF
family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. *Journal of Immunology.* 2004;173(2):807-817.  
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85. Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing antiCD19 chimeric antigen receptors. *Nat Rev Clin Oncol.* 2013;10(5):267-276.  
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87. Lee JC, Hayman E, Pegram HJ, et al. In vivo inhibition of human CD19-targeted effector T cells by natural T regulatory cells in a xenotransplant murine model of B cell malignancy. *Cancer Res.* 2011;71(8):2871-2881.  
88. Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. *Clin Cancer Res.* 2013;19(8):2048-2060.  
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15 appendices

| ECOG Performance Status Scale*                                                             |                                                                                                                                                                                       |
|--------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                                                                                      | Descriptions                                                                                                                                                                          |
| 0                                                                                          | Normal activity. Fully active, able to carry on all pre-disease  performance without restriction. Symptoms, but ambulatory. Restricted in physically strenuous activity,              |
| 1                                                                                          | but ambulatory and able to carry out work of a light or sedentary nature  (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, but |
| 2                                                                                          | unable to carry out any work activities. Up and about more than 50%  of waking hours.                                                                                                 |
| 3                                                                                          | In bed >50% of the time. Capable of only limited self-care, confined to  bed or chair more than 50% of waking hours.                                                                  |
| 4                                                                                          | 100% bedridden. Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair.                                                                                |
| 5                                                                                          | Dead.                                                                                                                                                                                 |
| * As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., |                                                                                                                                                                                       |
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15.1 appendix a-performance status criteria

* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
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15.2 appendix bdata collection elements

All of the following elements will be recorded in the C3D database:
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a. patient enrollment

Date of birth, age, gender, race, ethnicity Height Weight ECOG
Date of original diagnosis Stage at diagnosis Plasmacytoma present: Yes or No Tumor Histology and date of confirmation BCMA expression by tumor type of tissue studied and date of confirmation Date of Informed Consent signature, consent version and date of registration Baseline History/Physical Baseline Symptoms Prior therapy Prior radiation Prior Bone Marrow Biopsy that includes the percent of plasma cells and BCMA
results Findings of consultations done at screening
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b. study drug administration and

Dates anti-BCMA-CAR-transduced T cells given Dose level, actual dose in CAR+ T cells/kg, schedule and route given Height, weight, and body surface area at start of each course Response assessment for each restaging performed Concomitant medications will not be collected in C3D
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c. laboratory and diagnostic test

1. All Clinical laboratory and diagnostic test results done at screening and until day 30 post infusion with the following exceptions: Diagnostic tests which are not specified in the protocol, and if the results are not needed to document the start or end of an adverse event that requires reporting. Serologies such as CMV, HSV, EBV, toxoplasmosis, adenovirus,, TTV data that were not need for eligibility will not be collected.  
2. All staging studies including serum protein electrophoresis, urine protein electrophoresis, serum free light chains, bone marrow biopsy reports, flow cytometry reports, serum immunoglobulin reports including beta-2 microglobulin, complete blood count and differential reports, serum creatinine reports, TBNK results, serum protein, urine albumin, serum calcium (including ionized), ESR and CRP results. MRI, X-ray (including skeletal survey), and CT scan results will only be reported if they were used for staging.  
D. Adverse Events Please see section **6.1.1**Adverse Event Recording
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e. tumor response and measurements

Restaging studies performed at protocol specified time points and as clinically indicated.  
Any physical exam findings will be collected as Adverse Events and labs results. Years 5-15 follow-up is only for survival.
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f. off study

Date and reason for off study Date and cause of death Autopsy findings if available
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15.3 appendix c guidelines for

Infusions of CAR T cells are often complicated by significant acute toxicities in the first 2 to 3 weeks after the infusion. In many cases the toxicities correlate with serum inflammatory cytokine levels. The toxicities most often experienced by patients receiving infusions of CAR T cells include, but are not limited to, tumor lysis syndrome, fever, fatigue, hypotension, tachycardia, acute renal failure, and neurological toxicities such as aphasia, ataxia, headache, somnolence, and coma. Fever is usually the first toxicity to occur. Note these are guidelines that might require modification based on clinical circumstances of each patient, and failure to exactly follow these guidelines is not a protocol deviation or violation.  
Administration of corticosteroids should be avoided if possible to avoid killing or impairing the function of the CAR T cells.
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general supportive care guidelines

1. All patients with significant malignancy burdens and without a contradiction such as allergy should be started on allopurinol at the time of the start of the chemotherapy conditioning regimen or 1 day before the CAR T cell infusion. The suggested allopurinol dose is 200 to 300 mg/day with a possible loading dose of 300 to 400 mg.  
2. Vital signs should be checked a minimum of every 4 hours during hospitalization.  
Increasing the time interval between vital sign checks for patient convenience or other reasons should be avoided.
3. Strict ins and outs should be recorded on all patients. 4. As a minimum, keep hemoglobin greater than 8.0 g/dL and platelets greater than 20K/microliter.  
5. Administer fresh frozen plasma (FFP) for a PTT 1.5-fold or more above the upper limit of normal.  
6. For patients with an increased PTT, check the fibrinogen level and keep the fibrinogen level above 100 mg/dL with cryoprecipitate.
7. Fevers should be treated with acetaminophen and comfort measures. NSAIDs and corticosteroids should be avoided.  
8. Patients with a heart rate persistently higher than 115/minute and fever should have vital signs checked every 2 hours.  
9. Patients who are neutropenic and febrile should be receiving broad-spectrum antibiotics. 10. Avoid meperidine due to seizure risk. 11. Minimize benzodiazepine use to avoid aggravating delirium. 12. Patients on this protocol will be placed on strict fall precautions including instructions to get out of bed only with assistance under the following conditions:
1. Any history of syncope or near-syncope within 1 month before CAR T-cell infusion or any time after CAR T-cell infusion.  
2. Any blood pressure reading of less than 100 mm Hg systolic blood pressure after antiCD19 CAR T-cell infusion if 100 mm Hg is lower than the patients baseline systolic blood pressure.  
3. Heart rate greater than 100 beats per minute.  
13. Any patient with syncope, near-syncope, or light-headedness will have orthostatic blood pressure and heart rate checked and receive intravenous fluids as appropriate. These patients will also receive an ECG.  
14. A CBC will be obtained twice daily while the patient is inpatient. If the absolute neutrophil count becomes less than 500/microliter, Filgrastim will be initiated at a dose of 300 micrograms daily for patients under 70 kg in weight and a dose of 480 micrograms daily for patients over 70 kg in weight only in patients with absolute neutrophil counts less than 500/microliter. Filgrastim will be discontinued as soon as the absolute neutrophil count recovers to 2000/microliter.  
15. Hypotension is a common toxicity requiring intensive care unit (ICU) admission. In general patients should be kept well-hydrated. Maintenance I.V. fluids (normal saline (NS) should be started on most patients with high fevers especially if oral intake is poor or the patient has tachycardia. I.V. fluids are not necessary for patients with good oral intake and mild fevers. For patients who are not having hypotension or tumor lysis syndrome, a generally even fluid balance should be strived for after allowing for insensible fluid losses in patients with high fevers. The baseline systolic blood pressure is defined for this protocol as the average of all systolic blood pressure readings obtained during the 24 hours prior to the CAR T-cell infusion. The first treatment for hypotension is administration of IV NS boluses.
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patients with a systolic blood

Patients with a systolic blood pressure less than 90 mm Hg should receive a 1 L
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ns bolus if this is

These I.V. fluid management suggestions may need to be modified based on the clinical characteristics of individual patients such as pulmonary status, cardiac function, edema and other factors.  
16. Patients receiving more than 1 fluid bolus for hypotension should have a stat EKG and troponin, and a cardiac echocardiogram as soon as possible.
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icu transfer

Patients should be transferred to the ICU after consultation with the ICU physicians under these circumstances. Patients not meeting these criteria could also require ICU admission at the discretion of the clinical team caring for the patient.  
Systolic blood pressure less than 70% the patient's baseline blood pressure and less than 100 mm Hg after administration of a 1L NS bolus.  
Anytime the systolic blood pressure is less than 90 mm Hg after a 1L NS bolus. Continuous tachycardia with a heart rate higher than 125 beats per minute on at least 2 occasions separated by 2 hours.  
Oxygen requirement of more than a 4L standard nasal cannula
1. All patients transferred to the ICU for hypotension or tachycardia should have a stat EKG
and a cardiac echocardiogram within 6 hours of the time of transfer.  
2. Patients with hypotension not responding to IV fluid resuscitation should be started on norepinephrine at doses called for by standard ICU guidelines.  
3. Patients should have a cardiac echocardiogram and an EKG within 6 hours of starting norepinephrine.  
4. Patients in the ICU should get twice-daily labs (CBC with differential, acute care panel, mineral panel, hepatic panel, uric acid, LDH. Patients in the ICU should also get a daily troponin level).  
5. Patients receiving vasopressors should have a cardiac echocardiogram at least every other day.
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immunosuppressive drug administration

In general, immunosuppressive drugs are administered in a stepwise escalation based on toxicity severity. The first immunosuppressive drug administered is usually tocilizumab. If toxicity does not improve after tocilizumab, treatment progresses to intermediate-dose or high-dose methylprednisolone. For certain severe toxicities listed below, high-dose methylprednisolone must be given immediately.
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tocilizumab administration

Tocilizumab should be administered under the following circumstances if the listed disorders are thought to be due to cytokine release from CAR T cells. Tocilizumab is administered at a dose of **8 mg/kg** infused IV over 1 hour (dose should not exceed 800 mg).  
Left ventricular ejection fraction less than 45% by echocardiogram  
Creatinine greater than 2-fold higher than the most recent level prior to CAR T-cell infusion Norepinephrine requirement at a dose greater than 3 g/minute for 36 hours since the first administration of norepinephrine.
Requirement of 5 mcg/minute or more of norepinephrine to maintain systolic blood pressure greater than 90 mm Hg.  
Oxygen requirement of 40% or greater fraction of inspired oxygen (FIO2) to maintain oxygen saturation of >92%.  
Subjective significant dyspnea and respiratory rate greater than 25 for 2 hours or more.  
PTT or INR>2x upper limit of normal Bleeding possibly related to cytokine-release syndrome Creatine kinase greater than 5x upper limit of normal
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intermediate-dose methylprednisolone for toxicities not

1. Give methylprednisolone 50 mg every 6 hours for any of the toxicities under \#19 above that don't improve after tocilizumab administration.
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high-dose methylprednisolone should be given

1. Give methylprednisolone 200 mg every 6 hours for systolic blood pressure that is less than 90 mm Hg while the patient is on 15 mcg/minute or higher doses of norepinephrine. If the patient has not had tocilizumab, give 8 mg/kg of tocilizumab along with the methylprednisolone.  
2. Give methylprednisolone 200 mg every 6 hours for hypotension requiring 15 mcg/minute or more of norepinephrine continuously for 8 hours or more. If the patient has not already had tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone.  
3. Give methylprednisolone 200 mg every 6 hours for any left ventricular ejection fraction 30% or less. If the patient has not already had tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone.  
4. Give methylprednisolone 200 mg every 6 hours for any situation in which pulmonary toxicity makes mechanical ventilation likely to be required within 4 hours. If the patient has not had tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone.  
5. In life-threating toxicity not improving after 200 mg of methylprednisolone, 1000 mg of methylprednisolone can be administered.  
In general, stop corticosteroid use when toxicity improves to a tolerable level. For example, in patients with hypotension, stop methylprednisolone 6 to 12 hours after vasopressors are no longer needed.
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neurological toxicity

1. All patients with neurological toxicities other than somnolence and delirium should get a neurology consult.  
2. All patients with significant neurological toxicity should get an MRI of the brain. 3. All patients with significant neurological toxicity should get a lumbar puncture after MRI if it is safe to perform a lumbar puncture.  
4. The following patients should receive dexamethasone 10 mg intravenously every 6 hours until the toxicities improve. Note: for seizures administer standard seizure therapies in addition to dexamethasone. For patients already getting higher doses of corticosteroids for CAR-related toxicity, it is not necessary to add dexamethasone 10 mg every 6 hours. Stop dexamethasone as soon as toxicity improves to a tolerable level; the duration of dexamethasone use will need to be determined on a patient to patient basis. Tocilizumab is possibly not effective for neurological toxicity, so it should not be given when patients have isolated neurological toxicity.  
1. Inability of patient to follow simple commands such as "squeeze my fingers".  
2. Any generalized seizure 3. Somnolence that is different than normal sleep such as constant sleep or difficult to arouse or any difficulty with airway protection 4. Ataxia severe enough to preclude ambulation 5. Disorientation to person or place that persists continuously longer than 24 hours 6. Neurologic toxicity lasting more than 2 hours that is severe enough to interfere with self-care activities of daily living (ADLs)
7. Severe agitation or confusion that limit the ability to care for the patient without restraints  
Version Date: April 26, 2021
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15.4 appendix d infusion instructions

Primary IV tubing (2) Secondary IV tubing (1) NS (sodium chloride 0.9%) 250cc bags (2) IV infusion pump Gloves  
| Steps:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Key Points:                                                                       |    |                                                                      |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------|----|----------------------------------------------------------------------|
| 1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | The RN will be informed of the  approximate time of cell arrival at  the bedside. |   | Premeds are acetaminophen 650 mg PO  and diphenhydramine 12.5 mg IV. |
| 2. Verify the physician orders: - to administer the cells - for the date of administration - for premedication orders  - protocol number 3. Verify that the protocol consent  4. Ensure that emergency and monitoring  equipment are available in the patient's  room: - oxygen - suction - vital sign monitor with pulse oximeter  and thermometer  5. Provide patient education covering  infusion procedure, potential complications  and associated symptoms to report.  7. Measure and record baseline vital signs,  respiratory and circulatory assessments. 8. Verify the patency of the patient's IV | A central venous access device such as a                                          |    |                                                                      |
| access.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | non-valved PICC line should be used.                                              |    |                                                                      |  
| Version Date: April 26, 2021 9. Hang a primary line of 250cc NS at a  kvo rate - NEW bag and NEW tubing.                                                                                                                                                                                                                            | This will be the dedicated NS line for  infusing the cells. Under no circumstances  are any other substances to be infused into  the line.                                                                                                                                                  |       |      |     |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------|------|-----|
| This MUST be ready and infusing prior to  the cells being delivered to the unit.                                                                                                                                                                                                                                                    | Cell death occurs quickly - the infusion  must be initiated immediately.                                                                                                                                                                                                                    |       |      |     |
| The patient's primary IV hydration can  infuse via a separate lumen while the cells  are infusing, but NO MEDs should be administered during this time.                                                                                                                                                                             | Do not infuse medication during the cell  infusion. If emergency meds must be  administered, use the hydration or  emergency NS IV line.                                                                                                                                                    |       |      |     |
| Have a second bag of 250cc NS and tubing  ready as an emergency line.                                                                                                                                                                                                                                                               | This will be the emergency IV solution  and can be used for medication  administration. Do not use an inline filter for cells.                                                                                                                                                              |       |      |     |
| 10.                                                                                                                                                                                                                                                                                                                                 | The primary RN will be notified                                                                                                                                                                                                                                                             |       |      |     |
| approximately 10 minutes before the cells  arrive on the unit. The cells will be hand  delivered to the bedside.                                                                                                                                                                                                                    | It is critical to be at the bedside awaiting  the arrival of the cells for infusion; have  baseline VS, assessment, and IV lines  hooked up when the cells arrive. Cell  death occurs as soon as the cells are  removed from the laboratory. Initiate the  infusion as quickly as possible. |       |      |     |
| It is critical to be at the bedside awaiting  the arrival of the cells for infusion.  12. Prior to spiking the cell bag, two RNs  will perform the identification procedure.  Both RNs must have their names charted in  the CRIS cellular therapy flow sheet 13. Infuse the cells by INFUSION  PUMP or syringe over 20-30 minutes. | This prevents the cells from clumping in  the bag.                                                                                                                                                                                                                                          |       |      |     |
| a. Piggyback                                                                                                                                                                                                                                                                                                                        | the                                                                                                                                                                                                                                                                                         | cells | into | the |
| dedicated                                                                                                                                                                                                                                                                                                                           | NS                                                                                                                                                                                                                                                                                          | line; | use  | the |
| backflush technique to prime the  line.                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                             |       |      |     |
| b. While the cells are infusing, gently agitate the bag of cells every few  minutes. When the cell bag is  empty, backflush NS to rinse the  bag and infuse this at the same rate                                                                                                                                                   |                                                                                                                                                                                                                                                                                             |       |      |     |  
Version Date: April 26, 2021  
| as the cells; rinse bag until NS runs  clear.                                                                                                                                                                                                                                                                                                                                                                                                   |                                  |                                |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------|--------------------------------|
|                                                                                                                                                                                                                                                                                                                                                                                                                                                 | c.                               | Note: in some cases cells will |
| arrive from DTM in a syringe. In this  case infuse the cells via syringe over  20-30 minutes in the dedicated NS line  proximal port, see nursing cellular  infusion SOP for further details.                                                                                                                                                                                                                                                   |                                  |                                |
| 14.                                                                                                                                                                                                                                                                                                                                                                                                                                             | Measure and record VS before and |                                |
| after the cell infusion, q1h x 4, and then  q4h after completion of the infusion.  a.Assess and document the patient's  respiratory and circulatory status  post cell infusion.  15. Documentation: a. After the cells have infused, remove  the adhesive backed "cell therapy  product" tag from the cell bag and  place it on a progress note in the  patient's chart.  b. Document the cell infusion in  CRIS using the appropriate screens. |                                  |                                |