Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)

* INCLUSION CRITERIA: * Enrolled in 09-I-0032 protocol. * Clinically definite MS. * Age \>=18 years at time of study enrollment. * Expanded Disability Status Scale (EDSS) 1.0-7.5. * For progressive MS cohort enrollment: * Documented sustained clinical progression of at least 0.5 CombiWISE points/year on stable therapy (or untreated) * If follow-up is \<3 years, CombiWISE progression slopes are measured by \>= 4 time points regression analysis of CombiWISE values spanning at least 18 months (1.5 years) * If follow-up is \>=3 years, CombiWISE progression slopes are measured by \>= 2 time-points regression analysis of CombiWISE values spanning at least 36 months (3 years) * Because currently only NDS utilizes CombiWISE scale, the progression slopes will be determined via 09-I-0032 natural history protocol that contains completely overlapping procedures. * It is possible that after other MS centers start using CombiWISE scale, this progression criterion may be derived from outside data, as long as they are adequately documented. * For non-progressing MS with residual disability cohort enrollment: * CombiWISE slope on stable therapy (derived identically as in progressive MS cohort) \>0 and \<0.5 CombiWISE units/year (i.e., neurological deficit that is no longer improving) * CombiWISE at the end of screening period \>10 (i.e., sustained residual disability) * Women who can become pregnant must be willing to use a medically acceptable form of birth control, while being treated on this study. * Patients on current FDA-approved DMTs will be enrolled with the understanding that the underlying FDA-approved therapy must remain stable during this protocol. If patient desires and/or his/her medical condition requires changing FDA-approved DMT during the duration of this protocol, the drugs administered under this protocol will be withdrawn, to establish new baseline of CSF biomarkers under changed therapy, and, if necessary, to establish new progression rate. New baseline of CSF biomarkers on changed therapy can be established after 6 months of new therapy. * Because the efficacy of current DMTs decreases with patient s age so that on average, zero percent efficacy on disability progression occurs after age 53, only those patients who change to higher potency therapy (i.e., treatment escalation) before age 53 will need to repeat the entire process of establishing baseline progression rate: go back to \>= 1.5 year baseline period on new DMT to verify that the rate of progression remains \>=0.5 CombiWISE points/year. * Following therapeutic change that occurs before age 53 will be considered treatment escalation: 1. Initiation of any FDA-approved DMT in previously untreated subject or 2. Change from any low potency (i.e., copaxone, teriflunomide, interferon beta preparations, dimethyl or monomethyl fumarate and fingolimod) to any high potency drugs (i.e., any B-cell depleting agents, natalizumab, alemtuzumab, siponimod, ozanimod and cladribine). All other therapy changes (i.e., parallel change from low efficacy to low efficacy or from high efficacy to high efficacy, as well as discontinuation of treatment after age 53) will require new CSF baseline (6 months after such therapy change), but will not require 18 months to calculate new CombiWISE slope. * After new CSF baseline, and, if necessary, new CombiWISE progression slopes are established, patient can be matched to the same monotherapy or combination therapy regimen they were on before the immunomodulatory DMT change. * Willing and able to participate in all aspects of the protocol. * Able and willing to provide informed consent. EXCLUSION CRITERIA: * Clinically significant medical disorders that, in the judgment of the investigators, could expose the patient to undue risk of harm or prevent the patient from safely completing all required elements of the study (such as, but not limited to significant cerebrovascular disease, ischemic cardiomyopathy, clotting disorder, other neurodegenerative disorder, substance abuse or significant psychiatric disorder such as depression with suicidal ideations, unable to perform or tolerate MRI examinations). * Clinically significant medical disorders, other than MS that require chronic treatment with immunosuppressive or immunomodulatory agents. * Pregnancy or breastfeeding. * Abnormal screening/baseline blood tests exceeding any of the limits defined below: * Serum alanine transaminase or aspartate transaminase levels which are greater than three times the upper limit of normal values. * Total white blood cell count \< 3 000/mm\^3. * Platelet count \< 85 000/mm\^3. * Serum creatinine level \> 2.0 mg/dL and eGFR (glomerular filtration rate) \< 60. * Serological evidence of HIV, HTLV-1 or active hepatitis A, B or C. * Positive pregnancy test. Following drug-specific exclusion criteria will be applied when assigning specific agent (these are not exclusions from the trial): * Pioglitazone * Congestive heart failure. * History of bladder carcinoma. * Type 1 diabetes. * Hypersensitivity to the drug. * Taking teriflunomide (Aubagio) because of risk of hypoglycemia on this combination. * Dantrolene * Hypersensitivity to the drug. * Hepatic impairment/active hepatic disease (cannot be paired with pirfenidone due to risk of cumulative hepatoxicity). * Persistent elevation of LFTs. * History of previous drug/medication or alcohol-related liver toxicities. * Pirfenidone * Hypersensitivity to the drug. * Hepatic impairment/active hepatic disease (cannot be paired with dantrolene due to risk of cumulative hepatoxicity). * Persistent elevation of LFTs. * Smoking. * Cilostazol * Hypersensitivity to the drug. * Congestive heart failure. * Hemostatic disorder/active bleeding. * Taking any S1P inhibitor (i.e., fingolimod, ozanimod, Siponimod or ponesimod) due to additive risk for QTc interval prolongation and thus increasing risk of arrythmia. * Leucovorin * Hypersensitivity to the drug. * Colorectal cancer (active). * Vitamin B12 deficiency