This is a Phase IB/II trial that will investigate the safety, tolerability and efficacy of combination therapy using All-Trans Retinoic Acid (ATRA) with Carfilzomib based therapies in plasma cell myeloma also commonly referred as Multiple Myeloma (MM), in patients considered refractory to proteasome inhibitors (PIs). Multiple myeloma is an incurable clonal plasma cell disorder that comprises 10% of all hematologic malignancies. Over the past 30 years the global prevalence of multiple myeloma has risen to 126%, with 85% of diagnoses occurring in patients >55 years of age. In the past 15 years, survival has improved considerably, which is attributed to the development of multiple different classes of medications, including proteasome inhibitors. Proteasome inhibitors are the foundation of many multiple myeloma treatments in both transplant eligible and ineligible patients for the past 2 decades. While proteasome inhibitors have improved both progression free survival (PFS) and overall survival (OS), many patients eventually develop disease progression arising from resistance to therapies. As a result, there is an unmet need to overcome resistance and find ways to enhance multiple myeloma sensitivity to proteasome inhibitor toxicity. Carfilzomib, a modified peptide epoxyketone that selectively targets intracellular proteasome enzymes, is approved in combination with dexamethasone in patients that have received ≥1 line of therapy or in combination. There are few studies assessing ways to enhance carfilzomib-mediated multiple myeloma toxicity. All-Trans Retinoic Acid (ATRA) is an oxidative metabolite of retinol (vitamin A) and plays an important role in the regulation of cellular proliferation and differentiation. In a recent pre-clinical study, ATRA was found to enhance sensitivity of carfilzomib-mediated apoptosis in vitro via an interferon beta (IFN-β) response pathway. In the clinical setting, ATRA is a well-tolerated drug that has shown little change in the rate of adverse events in early clinical trials with multiple myeloma. The investigators hypothesize that ATRA enhances sensitivity of multiple myeloma to carfilzomib therapy.

Inclusion Criteria:

1. Age ≥ 18 years with relapsed/refractory multiple myeloma documented according to International Myeloma Working Group (IMWG) criteria.

2. Previously treated with at least three lines of therapy which would include Immunomodulatory drugs (IMiDs), Proteosome inhibitors (including carfilzomib), anti-CD 38 antibodies and failed to achieve a minor response after completing at least 2 cycles of carfilzomib-based therapy or are relapsed while on therapy.

3. Patient or legal guardian voluntarily can sign informed consent.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2

5. Adequate organ function defined as:

   1. Hemoglobin ≥8 g/dL (baseline or after Peripheral Red Blood Cell transfusion), Platelet count >75,000 and Absolute Neutrophil Count >1000/ micro liter.
   2. Left Ventricular Ejection fraction ≥50%
   3. Creatinine Clearance ≥ 30 ml/min
   4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN)
   5. Total bilirubin ≤ 1.5 × ULN

6. Measurable disease requiring treatment defined as patients having one or more of the criteria below:

   1. Serum M protein ≥ 0.5 g/dL or
   2. Urine M-protein ≥ 200 mg/24 hours or
   3. Serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum
   4. kappa lambda ratio.

7. If previous autologous stem cell transplantation, must have fully recovered from transplant related toxicities and be >60 days from transplant and have had hematologic recovery independent of growth factor support.

8. Willingness to undergo interim bone marrow biopsy as scheduled or if felt to be medically indicated.

9. Life Expectancy ≥ 6 months

10. Women with childbearing potential and men should practice at least one of the following methods of birth control:

    1. Total abstinence from sexual intercourse (periodic abstinence not acceptable);
    2. Surgically sterile partner(s) including vasectomy, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy;
    3. Intrauterine device with an additional method of contraception to make two effective methods of contraception during treatment with Vesanoid;
    4. Double-barrier method (condom + diaphragm or cervical cap with spermicide, contraceptive sponge, jellies, or cream);
    5. Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at least 3 months prior to study drug administration. If hormonal contraceptives are used, the specific contraceptive must have been used for at least 3 months prior to study drug administration. If the patient is currently using a hormonal contraceptive, she should also use a barrier method during this study Women of child-bearing potential must have a negative results of a pregnancy test performed at initial screening on a serum sample obtained within 21 days prior to C1D1, and prior to dosing on a urine sample obtained within 72 hours of the first study drug administration. Males must refrain from sperm donations from date of C1D1 to 90 days after the last date of the study drug.

Exclusion Criteria:

1. Non-secretory or hyposecretory multiple myeloma, defined as <0.5 g/dL M-protein in serum, <200 mg/24-hour urine M-protein, or disease only measured by serum free light chain.
2. Plasma Cell Leukemia (Previously treated Plasma Cell Leukemia can be included per PI discretion)
3. Concurrent light chain amyloidosis
4. Central nervous system involvement (patients with known brain metastases have poor prognosis and often develop progressive neurologic dysfunction that may confound the evaluation of neurologic and other Adverse Events while on ATRA).
5. Pregnant or breast feeding
6. Severe, active, recurrent, or intercurrent infection (viral, bacterial, fungal), or diagnosis of neutropenia and fever within one week of C1D1.
7. History of Allogeneic hematopoietic cell transplantation or solid organ transplantation.
8. Unstable angina pectoris, cardiac arrhythmia or > New York Heart Failure association class II cardiac failure, defined as comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
9. Patient has a significant history of renal, neurologic (peripheral neuropathy), psychiatric, endocrinologic (diabetes mellitus), metabolic, immunologic, cardiovascular, pulmonary, hepatic disease, or significant social situation within the past 6 months that, in the opinion of the investigator, would impede his/her ability to fully participate in the study. For patients who have required an intervention for the above diseases within the past 6 months, a case-by-case discussion with the investigator must occur.
10. On investigational therapies within 12 weeks of enrollment.
11. Previous allergic reaction or intolerance to a proteasome inhibitor, including carfilzomib, bortezomib, or ixazomib.
12. Or deemed unfit for the study on evaluation by Investigator.