This is a multi-center prospective rater-masked (blinded) randomized controlled trial of 156 participants, comparing the treatment strategy of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) to the treatment strategy of Best Available Therapy (BAT) for treatment-resistant relapsing multiple sclerosis (MS). Participants will be randomized at a 1 to 1 (1:1) ratio.

All participants will be followed for 72 months after randomization (Day 0, Visit 0).

Participant recruitment for this six-year research study focuses on multiple sclerosis (MS) that has remained active despite treatment. This study will compare high dose immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) to best available therapy (BAT) in the treatment of relapsing MS.

MS is a disease caused by one's own immune cells. Normally, immune cells fight infection. In MS, immune cells called T cells, or chemical products made by immune cells, react against the covering or coat (myelin) of nerve fibers in the brain and spinal cord. This leads to stripping the coat from certain nerve fibers (demyelination), and this causes neurologic problems. MS can cause loss of vision, weakness or incoordination, loss or changes in sensation, problems with thinking or memory, problems controlling urination, and other disabilities.

Most individuals with MS first have immune attacks (called relapses) followed by periods of stability. Over time, MS can have episodes of new and worsening symptoms, ranging from mild to disabling. This is called relapsing MS. Relapsing MS includes relapsing remitting MS (RRMS) and secondary progressive MS (SPMS). There are medicines (drugs) to decrease relapses, but these are neither considered to be curative nor, to induce prolonged remissions without continuing therapy.

More than a dozen medicines have been approved for the treatment of relapsing forms of MS. These medicines differ in how safe they are and how well they work. Despite availability of an increasing number of effective medicines, some individuals with relapsing MS do not respond to treatment. Research is being conducted to find other treatments.

High dose immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) has been shown to help relapsing MS in cases where medicines did not work. AHSCT involves collecting stem cells, which are produced in the bone marrow. These stem cells are "mobilized" to leave the bone marrow and move into the blood where they can be collected and stored. Participants will then receive chemotherapy intended to kill immune cells. One's own stored (frozen) stem cells are then given back, through an infusion. This "transplant" of one's stem cells allows the body to form new immune cells in order to restore their immune system. New research suggest that MS might be better controlled with AHSCT than with medicines.

Measured by the Kurtzke Expanded Disability Status Scale performed by the masked (blinded) rater.

EDSS, defined by:

• A decrease in EDSS of ≥ 1.0 step(s) compared to the EDSS at randomization (Day 0) and
• Confirmation of disability improvement ≥ 6 months later. The time of confirmed disability worsening measured by EDSS will be the time of first increase in EDSS ≥ 1.0 step(s).

Measured by the Kurtzke Expanded Disability Status Scale performed by the masked (blinded) rater.

Confirmed disability improvement defined by:

• A decrease in EDSS of ≥ 1.0 step(s) compared to the EDSS at randomization (Day 0) and
• Confirmation of disability improvement ≥ 6 months later. The time of confirmed disability improvement measured by EDSS will be the time of first decrease in EDSS ≥ 1.0 step(s).

An event that results in any of the following outcomes:

• Death,
• A life-threatening event that places the participant at immediate risk of death,
• Inpatient hospitalization or prolongation of existing hospitalization,
• Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or
• A congenital anomaly or birth defect.
  • Note: Important medical events that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

Reference: 21 CFR 312.32(a)

The occurrence of PML during the course of participation in this study.

A disease of the white matter of the brain, caused by a virus infection, Polyomavirus JC (JC virus), that targets cells that make myelin--the material that insulates nerve cells (neurons).

Graft failure can either be primary (graft never established) or secondary (loss of an established graft).

Primary graft failure is the absence of adequate hematopoiesis by Day T28, defined as meeting all of the following conditions:

• Bone marrow cellularity <5%,
• Peripheral WBC < 500/µl,
• Peripheral ANC < 100/ µl, and
• Platelets < 10,000/ µl.

Inclusion Criteria:

Participant(s) must meet all of the following criteria to be eligible for this study:

1. Diagnosis of Multiple Sclerosis (MS) according to the 2017 McDonald Criteria
2. (Kurtzke) Expanded Disability Status Scale (EDSS) ≥ 2.0 and ≤ 5.5 at the time of randomization (Day 0)
3. T2 abnormalities on brain Magnetic Resonance Imaging (MRI) that fulfill the 2017 McDonald MRI criteria for dissemination in space

   --A detailed MRI report or MRI images must be available for review by the site neurology investigator.

4. Highly active treatment-resistant relapsing MS, defined as ≥ 2 episodes of treatment failure in the 24 months prior to the screening visit (Visit -2). as described below:
   1. Each episode of treatment failure must occur following ≥ 3 months of treatment with an FDA-approved Disease-modifying Therapy (DMT) for relapsing forms of MS, or with rituximab, and
   2. At least one episode of treatment failure must occur with an oral agent or a monoclonal antibody, specifically: dimethyl fumarate, teriflunomide, cladribine, daclizumab, siponimod, fingolimod, rituximab, ocrelizumab, natalizumab, or alemtuzumab, and
   3. At least one episode of treatment failure must have occurred within the 12 months prior to the screening visit (Visit -2), and
   4. At least one episode of treatment failure must be a clinical MS relapse (see item d.i. below). The other episode(s) must occur at least one month before or after the onset of the clinical MS relapse, and must be either another clinical

   MS relapse or MRI evidence of disease activity (see item d.ii. below):

   i. Clinical MS relapse must be confirmed by a neurologist's assessment and documented contemporaneously in the medical record. If the clinical MS relapse is not documented in the medical record, it must be approved by the study adjudication committee, and

   ii. MRI evidence of disease activity must include ≥ 2 unique active lesions on a brain or spinal cord MRI. A detailed MRI report or MRI images must be available for review by the site neurology investigator. A unique active lesion is defined as either of the following:

   • A gadolinium-enhancing lesion, or
   • A new non-enhancing T2 lesion compared to a reference scan obtained not more than 24 months prior to the screening visit (Visit -2).
5. Candidacy for treatment with at least one of the following high efficacy DMTs: natalizumab, alemtuzumab, ocrelizumab, and/or rituximab.

   --Note: Rituximab and ocrelizumab are considered equivalent for candidacy.Candidacy for treatment for each DMT is defined as meeting all of the following:

   • No prior treatment failure with the candidate DMT, and
   • No contraindication to the candidate DMT, and
   • No treatment with the candidate DMT in the 12 months prior to screening.
6. Insurance or public funding approval for MS treatment with at least one candidate DMT, and
7. Ability to comply with study procedures and provide informed consent, in the opinion of the investigator.

Exclusion Criteria:

Subject(s) who meet any of the following criteria will not be eligible for this study:

1. Diagnosis of primary progressive Multiple Sclerosis (MS) according to the 2017 McDonald criteria
2. History of neuromyelitis optica or anti-MOG associated encephalomyelitis
3. Prior treatment with an investigational agent within 3 months or 5 half-lives, whichever is longer
4. Either of the following within one month prior to randomization (Day 0):
   1. Onset of acute MS relapse, or
   2. Treatment with intravenous methylprednisolone 1000 mg/day for 3 days or equivalent.
5. Initiation of natalizumab, alemtuzumab, ocrelizumab, or rituximab between screening visit (Visit -2) and randomization (Day 0)
6. Brain MRI or Cerebrospinal fluid (CSF) examination indicating a diagnosis of progressive multifocal leukoencephalopathy (PML)
7. History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS)
8. Presence of unexplained cytopenia, polycythemia, thrombocythemia or leukocytosis
9. History of sickle cell anemia or other hemoglobinopathy
10. Evidence of past or current hepatitis B or hepatitis C infection, including treated hepatitis B or hepatitis C

    -Note: Hepatitis B surface antibody following hepatitis B immunization is not considered to be evidence of past infection.

11. Presence or history of mild to severe cirrhosis
12. Hepatic disease with the presence of either of the following:
    1. Total bilirubin ≥ 1.5 times the upper limit of normal (ULN) or total bilirubin
       • 3.0 times the ULN in the presence of Gilbert's syndrome, or
    2. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥ 2.0 times the ULN.
13. Evidence of HIV infection
14. Positive QuantiFERON - TB Gold or TB Gold Plus test results. PPD tuberculin test may be substituted for QuantiFERON - TB Gold or TB Gold Plus test
15. Active viral, bacterial, endoparasitic, or opportunistic infections
16. Active invasive fungal infection
17. Hospitalization for treatment of infections or parenteral (IV or IM) antibacterials, antivirals, antifungals, or antiparasitic agents within the 30 days prior to randomization (Day 0) unless clearance is obtained from an Infectious Disease specialist
18. Receipt of live or live-attenuated vaccines within 6 weeks of randomization (Day 0)
19. Presence or history of clinically significant cardiac disease including:
    1. Arrhythmia requiring treatment with any antiarrhythmia therapy, with the exception of low dose beta blocker for intermittent premature ventricular contractions
    2. Coronary artery disease with a documented diagnosis of either:
       • Chronic exertional angina, or
       • Signs or symptoms of congestive heart failure.
    3. Evidence of heart valve disease, including any of the following:
       • Moderate to severe valve stenosis or insufficiency,
       • Symptomatic mitral valve prolapse, or
       • Presence of prosthetic mitral or aortic valve.
20. Left ventricular ejection fraction (LVEF) < 50%
21. Impaired renal function defined as Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m^2 according to the CKD-EPI formula
22. Forced expiratory volume in one second (FEV1) < 70% predicted (no bronchodilator)
23. Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) < 70% predicted
24. Poorly controlled diabetes mellitus, defined as HbA1c >8%
25. History of malignancy, with the exception of adequately treated localized basal cell or squamous skin cancer, or carcinoma in situ of the cervix.

    -Note:Malignancies for which the participant is judged to be cured by therapy completed at least 5 years prior to randomization (Day 0) will be considered on an individual basis by the study adjudication committee.

26. Presence or history of any moderate to severe rheumatologic autoimmune disease requiring treatment, including but not limited to the following:
    • systemic lupus erythematous
    • systemic sclerosis
    • rheumatoid arthritis
    • Sjögren's syndrome
    • polymyositis
    • dermatomyositis
    • mixed connective tissue disease
    • polymyalgia rheumatica
    • polychondritis
    • sarcoidosis
    • vasculitis syndromes, or
    • unspecified collagen vascular disease.
27. Presence of active peptic ulcer disease, defined as endoscopic or radiologic diagnosis of gastric or duodenal ulcer
28. Prior history of AHSCT
29. Prior history of solid organ transplantation
30. Positive pregnancy test or breast-feeding
31. Inability or unwillingness to use effective means of birth control
32. Failure to willingly accept or comprehend irreversible sterility as a side effect of therapy
33. Psychiatric illness, mental deficiency, or cognitive dysfunction severe enough to interfere with compliance or informed consent
34. History of hypersensitivity to mouse, rabbit, or Escherichia coli-derived proteins
35. Any metallic material or electronic device in the body, or condition that precludes the participant from undergoing MRI with gadolinium administration
36. Presence or history of ischemic cerebrovascular disorders, including but not limited to transient ischemic attack, subarachnoid hemorrhage, cerebral thrombosis, cerebral embolism, or cerebral hemorrhage
37. Presence or history of other neurological disorders, including but not limited to:
    • central nervous system (CNS) or spinal cord tumor
    • metabolic or infectious cause of myelopathy
    • genetically-inherited progressive CNS disorder
    • CNS sarcoidosis, or
    • systemic autoimmune disorders potentially causing progressive neurologic disease or affecting ability to perform the study assessments.
38. Presence of any medical comorbidity that the investigator determines will significantly increase the risk of treatment mortality, or
39. Presence of any other concomitant medical condition that the investigator deems incompatible with trial participation.