Inclusion Criteria:

1. Age between ≥18 to ≤50, both genders. 2. Women of childbearing potential* (WOCBP) and men in a sexual relation with WOCBP must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. 3. Diagnosis of RRMS using revised McDonald criteria of clinically definite MS1. 4. An EDSS score of 0 to 5.5. 5. Significant inflammatory disease activity in the last year despite treatment with standard disease modifying therapy (interferon beta, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, natalizumab) a. Significant inflammatory disease activity is defined by: i. One or more clinically reported multiple sclerosis (MS) relapse(s), ii. AND 1 or more T1 Gd-enhanced lesion(s), iii. OR three or more new or enlarging T2 lesions on magnetic resonance imaging (MRI) The relapse(s) must have been treated with iv or oral high dose corticosteroids prescribed by a neurologist, and must have occurred 3 or more months after the onset of an immunomodulatory treatment, as MS immunomodulatory treatment may reach full effect after 3 months or more2. 6. The patient is a RRMS-patient referred from neurological departments in Norway, Denmark, Sweden or possibly other European countries to an assigned study site. 7. Signed informed consent and expected patient cooperation regarding the treatment schemes and procedures planned in the treatment and follow-up periods must be obtained and documented according to ICH GCP and national/local regulations.

Exclusion Criteria:

1. Known hypersensitivity or other known serious side effects for any of the study medications, including co-medications such as high-dose glucocorticosteroids. 2. Any illness or prior treatment that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemotherapy or high-dose glucocorticosteroids. 3. Any ongoing infection, including Tbc, CMV, EBV, HSV, VZV, hepatitis virus, toxoplasmosis, HIV or syphilis infections, as well as heaptitis B surface antigen positivity and/or hepatitis C PCR positivity verified at Visit 1. 4. Patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV), unless tested for antibodies to VZV. VZV negative patients can only be included if they receive vaccination against VZV at least 6 weeks prior to inclusion. 5. Current or previous treatments with long-term effects that may influence the treatment effects or potential toxicities/side effects of the treatment arms. This includes, but is not restricted to previous treatment with rituximab, mitoxantrone, alemtuzumab, cladribin and ocrelizumab. 6. Immunocompromised patients, or patients currently reveiving immunosuppressive or myelosuppressive therapy. 7. Treatment with glucocorticoids or ACTH within one month prior to start of study treatment. 8. Having experienced an MS relapse within one month prior to study inclusion. 9. Prior or current major depression. 10. Prior or current psychiatric illness, mental deficiency or cognitive dysfunction influencing the patient ability to make an informed consent or comply with the treatment and follow-up phases of this protocol. 11. Prior or current alcohol or drug dependencies. 12. Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhytmia, unstable or advanced ischemic heart disease (NYHA III or IV) 13. Significant hypertension: BP > 180/110. 14. Active malignancy, or prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix. 15. Known untreated or unregulated thyroid disease. 16. Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy. 17. WBC < 1,5 x 109/L if not caused by a reversible effect of documented ongoing medication. If WBC < 1,5 x 109/L is caused by a reversible effect of documented ongoing medication the WBC count must be > 1,5 x 109/L before start of study treatment. 18. Platelet (thrombocyte) count < 100 x 109/L. 19. ALAT and/or ASAT more than 2 times the upper normal reference limit (UNL) 20. Serum creatinine > 200 µmol/L. 21. Serum bilirubin > ULN. 22. Moderate or severely impaired kidney function (creatinine-clearance below 60 ml/min) 23. Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams. 24. Diagnosis of primary progressive MS. 25. Diagnosis of secondary progressive MS. 26. Treatment with natalizumab and fingolimod within the last 2 months, and treatment with dimetylfumurat within the last month (washout must be performed as specified in section 5.1) prior to start of study medication. 27. Use of teriflunomide (Aubagio®) within the previous 2 years unless cleared from the body (plasma concentration < 0.02 mcg/ml following elimination from the body with cholestyramine or activated powdered charcoal) as specified in section 5.1 prior to start of study medication. 28. Any hereditary neurological disease such as Charcot-Marie-Tooth disease or Spinocerebellar ataxia. 29. Any disease that can influence the patient safety and compliance, or the evaluation of disability. 30. History of hypersensitivity reaction to rabbit. 31. Women who are pregnant, breast-feeding, or who plan to become pregnant within the timeframe of this study. 32. Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational treatment(s). Patients participating in a purely observational trial will not be excluded.

This is a randomized study of autologous HSCT using a low intensity, non-ablative conditioning regimen with cyclophosphamide and ATG versus treatment with the currently presumed best available immunomodulatory medication (alemtuzumab, cladribine or ocrelizumab) in RRMS patients with significant inflammatory disease activity in spite of ongoing immunomodulatory MS treatment. Significant disease activity is defined as having one or more clinically reported multiple sclerosis (MS) relapse(s), AND 1 or more T1 Gd-enhanced lesion(s), OR three or more new or enlarging T2 lesions on magnetic resonance imaging (MRI) over the last year while being treated on immunomodulatory medication by standard national guidelines. The relapse(s) must have occurred 3 or more months after the onset of an immunomodulatory treatment, as immunomodulatory treatment in MS may reach full effect after 3 months or more. Both the knowledge of the treatment effect of registered immunomodulatory therapies for RRMS, and the number of treatments approved for RRMS by the European Medicines Agency (EMA) are rapidly increasing. During the study period, there may thus appear new supplementing information on other MS immunomodulatory treatments that favour the use of a new comparator (replacing or supplementing the comparators). This will be evaluated by the PMC if applicable during the study period and the planned extension period. If the treatment efficacy obtained by HSCT is better than the currently most efficacious standard, immunomodulatory treatment in randomized treatment trials, HSCT will likely be approved as a part of the standard treatment recommendations for a significant proportion of RRMS patients. A randomized study regarding with statistical power to evaluate the clinical outcome of autologous HSCT compared to a standard immunomodulatory treatment in MS has not yet been published. Except for Sweden, HSCT is currently not registered as a part of standard MS treatment in the public health services of Europe. The HSCT regimen for the study will be identical to the regimen used in similar patient populations in Sweden, Norway and Denmark. Alemtuzumab, cladribine or ocrelizumab have been chosen as the primary comparators, because they are the immunomodulatory medication currently authorised by the EMA for treatment of RRMS with the most favourable therapeutic effects. In a meta-analysis of immunomodulatory treatment effects in RRMS, thse medications had the most eminent reduction of annualized relapse rate and 3 month confirmed disability progression. In this study, a health economic evaluation will be included. Accordingly, the proposed study should provide a robust basis for future official decisions regarding the role of HSCT in RRMS treatment.

Arms

Experimental: HSCT (Cyclophosphamide and ATG)

Day 1: Cyclophosphamide 2.0 g/m2 body surface area Days 5-10: Granulocyte colony stimulating factor (filgrastim) 5 mcg/kg body weight/day sc. Day 11 and until apheresis is discontinued: Granulocyte colony stimulating factor (filgrastim) 5 mcg/kg body weight x 2 sc/day. HSCT days -5 to -2: Cyclophosphamide 50 mg/kg/day. HSCT days -5 to -1: Anti-thymocyte globulin (ATG-rabbit, Thymoglobuline®) 0.5 mg/kg body weight iv on day -5, 1.0 mg ATG-rabbit/kg will be given iv on day -4, and 1.5 mg ATG-rabbit /kg will be given iv on days -3,-2 and -1 over 10 hours. HSCT day 0: Reinfusion of a minimum of 3,0 x 106 CD 34+ cells/kg body weight.

Active Comparator: Alemtuzumab, Cladribine or Ocrelizumab

Alemtuzumab, Cladribine or Ocrelizumab administered after the label of the study drug.

Interventions

Drug: - Cyclophosphamide and ATG

Hematopoetic stem cell transplantation

Drug: - Alemtuzumab

Alemtuzumab (Lemtrada)

Drug: - Cladribine Pill

Cladribine (Mavenclad)

Drug: - Ocrelizumab

Ocrelizumab (Ocrevus)