Multiple MyelomaPhase 1/2ATRANCT06536413

ATRA and Carfilzomib in Plasma Cell Myeloma Patients

A Phase 1/2 study testing All-Trans Retinoic Acid (ATRA) Dose 0, All-Trans Retinoic Acid (ATRA) Dose -1 and All-Trans Retinoic Acid (ATRA) Dose 1 in people with Multiple Myeloma, run by The Methodist Hospital Research Institute at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Multiple Myeloma
What is being tested?: All-Trans Retinoic Acid (ATRA) Dose 0, All-Trans Retinoic Acid (ATRA) Dose -1 and All-Trans Retinoic Acid (ATRA) Dose 1
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 42 participants
Where: 1 siteUnited States
Study dates: 29 Jul 2024to Jul 2030
Phase: Phase 1/2
Are there results?: Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Age ≥ 18 years with relapsed/refractory multiple myeloma documented according to International Myeloma Working Group (IMWG) criteria.
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.
Patient or legal guardian voluntarily can sign informed consent.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
Adequate organ function defined as:
Hemoglobin ≥8 g/dL (baseline or after Peripheral Red Blood Cell transfusion), Platelet count >75,000 and Absolute Neutrophil Count >1000/ micro liter.

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Left Ventricular Ejection fraction ≥50%
Creatinine Clearance ≥ 30 ml/min
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN)
Total bilirubin ≤ 1.5 × ULN
Measurable disease requiring treatment defined as patients having one or more of the criteria below:
Serum M protein ≥ 0.5 g/dL or
Urine M-protein ≥ 200 mg/24 hours or
Serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum
kappa lambda ratio.
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.
Willingness to undergo interim bone marrow biopsy as scheduled or if felt to be medically indicated.
Life Expectancy ≥ 6 months
Women with childbearing potential and men should practice at least one of the following methods of birth control:
Total abstinence from sexual intercourse (periodic abstinence not acceptable);
Surgically sterile partner(s) including vasectomy, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy;
Intrauterine device with an additional method of contraception to make two effective methods of contraception during treatment with Vesanoid;
Double-barrier method (condom + diaphragm or cervical cap with spermicide, contraceptive sponge, jellies, or cream);
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.

Who cannot join

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.
Plasma Cell Leukemia (Previously treated Plasma Cell Leukemia can be included per PI discretion)
Concurrent light chain amyloidosis
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).
Pregnant or breast feeding
Severe, active, recurrent, or intercurrent infection (viral, bacterial, fungal), or diagnosis of neutropenia and fever within one week of C1D1.

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History of Allogeneic hematopoietic cell transplantation or solid organ transplantation.
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.
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.
On investigational therapies within 12 weeks of enrollment.
Previous allergic reaction or intolerance to a proteasome inhibitor, including carfilzomib, bortezomib, or ixazomib.
Or deemed unfit for the study on evaluation by Investigator.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Sai Ravi Pingali, MD contact

713-441-0566

spingali@houstonmethodist.org

United States1 site, 1 recruiting

Houston Methodist Neal Cancer Center
Houston, Texas, 77030
Sai Ravi Pingali, MD
Recruiting

Other trials in United States

About this study

Official title: Phase IB/II Study Combining All-Trans Retinoic Acid (ATRA) With Carfilzomib Based Therapy in Plasma Cell Myeloma Patients Refractory to Carfilzomib

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.

Conditions: Multiple Myeloma
Being tested: All-Trans Retinoic Acid (ATRA) Dose 0, All-Trans Retinoic Acid (ATRA) Dose -1, All-Trans Retinoic Acid (ATRA) Dose 1
Medical subject headings: Multiple Myeloma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

All-Trans Retinoic Acid (ATRA) Dose 0Drug
Patients will receive oral ATRA 25 mg/m2 per day in two divided doses with carfilzomib-based regimens.
Eligible patients will enter the study in cohorts of two with the first cohort treated at Dose 0. To assign a dose to the next cohort of patients, dose escalation/de-escalation according to the the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients who respond and do not have any dose limiting toxicity (DLT), treatment will continue for a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to standard -of-care options. Each cycle will be 28 days. In phase 1b, a minimum of 16 evaluable patients will be recruited and in the second phase a minimum of 26 evaluable patients will be recruited. A minimum of 42 evaluable patients will be recruited in the study.
If a dose limiting toxicity occurs at 25 mg/m2, then the dose will be reduced by 50% to 15 mg/sq m daily in two divided doses.
All-Trans Retinoic Acid (ATRA) Dose -1Drug
Patients will receive oral ATRA 15 mg/m2 per day in two divided doses with carfilzomib-based regimens.
Eligible patients will enter the study in cohorts of two with the first cohort treated at Dose 0. To assign a dose to the next cohort of patients, dose escalation/de-escalation according to the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients who respond and do not have any dose limiting toxicity (DLT), treatment will continue for a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to standard -of-care options. Each cycle will be 28 days. In phase 1b, a minimum of 16 evaluable patients will be recruited and in the second phase a minimum of 26 evaluable patients will be recruited. A minimum of 42 evaluable patients will be recruited in the study.
All-Trans Retinoic Acid (ATRA) Dose 1Drug
Patients will receive oral ATRA 45 mg/m2 per day in two divided doses with carfilzomib-based regimens.
Eligible patients will enter the study in cohorts of two with the first cohort treated at Dose 0. To assign a dose to the next cohort of patients, dose escalation/de-escalation according to the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients who respond and do not have any dose limiting toxicity (DLT), treatment will continue for a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to standard -of-care options. Each cycle will be 28 days. In phase 1b, a minimum of 16 evaluable patients will be recruited and in the second phase a minimum of 26 evaluable patients will be recruited. A minimum of 42 evaluable patients will be recruited in the study.

Study groups in NCT06536413
Study group	Role	What they receive
All-Trans Retinoic Acid (ATRA), Carfilzomib, and Dexamethasone	Experimental	Carfilzomib will be given at Cycle 1 (20 mg/m2 on Days 1, 70 mg/m2 on Days 8 and 15) and Cycles 2 - onward (70 mg/m2 on Days 1, 8, and 15) as a 30-minute intravenous (IV) infusion to evaluate tolerability to treatment. Dexamethasone will be given [20 mg, PO/IV] on the days of carfilzomib treatment. ATRA will be given for 3 weeks (21 days) out of every 4 weeks (28 days) up to a maximum of 24 weeks (6 cycles). Only for Cycle 1, patients will start oral ATRA 25 mg/m2 7 days prior to Cycle 1 Day 1 through Cycle 1 Day 21 for a total of 28 days of dosing. To assign a dose to the next cohort of patients, dose escalation/de-escalation according to the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients who respond and do not have any dose limiting toxicity (DLT), treatment will continue for a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to standard -of-care options. Receives: Drug: All-Trans Retinoic Acid (ATRA) Dose 0; Drug: All-Trans Retinoic Acid (ATRA) Dose -1; Drug: All-Trans Retinoic Acid (ATRA) Dose 1

What is being measured

The primary outcome is the main question the study is designed to answer.

Safety and Tolerability of ATRA in combination with Carfilzomib/ Dexamethazone and RP2D
To determine safety and tolerability of ATRA in combination with carfilzomib/dexamethasone and determine the recommended phase II dose (RP2D). The RP2D will be defined as the highest dose administered at which 6 patients are treated with with no more than 2 experiencing dose limiting toxicity (DLT) (determined by diseases progression, unacceptable toxicity, physician's discretion).
Measured: From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study, whichever came first, assessed up to 7 months.

Secondary outcomes (4)

Efficacy of combination therapy of ATRA, Carfilzomib, and Dexamethasone in resistant Multiple Myeloma
Overall Response Rate (percentage of patients with complete response [CR] or partial response [PR]), as defined by International Myeloma Working Group (IMWG) criteria.
Measured: From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever came first, assessed up to 7 months.
Duration of Response of combination therapy of ATRA, Carfilzomib, and Dexamethasone in resistant Multiple Myeloma
Duration of response rate as defined by the duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease.
Measured: From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease, whichever came first, assessed up to 7 months after initial treatment date.
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Toxicity and safety, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
Measured: The dose limiting toxicity period begins from date of initial treatment until 21 days after.
Disease response as measured by serum, viable cryopreserved peripheral blood mononuclear cells, and bone marrow myeloma plasma cells.
To characterize the disease response of the ATRA and carfilzomib/dexamethasone combination as measured by serum, viable cryopreserved peripheral blood mononuclear cells, and bone marrow myeloma plasma cells.
Measured: Correlative samples will be collected at Baseline, Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1. Cycles are 28 days in length.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

29 Jul 2024Jul 2030

First posted5 Aug 2024
Study start29 Jul 2024
Primary completionJul 2029 (estimated)
Study completionJul 2030 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (44)Papers the sponsor has linked to this study.
Other trials for Multiple MyelomaStudies of the same condition, open and under way.
More trials run by The Methodist Hospital Research InstituteThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Sequential
Masking: None (open label)
Enrolment: 42 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT06536413
Sponsor's protocol ID: PRO00037762 (HMCC-HM22-001)
Acronym: ATRA
Status last verified: Mar 2026
First submitted: 27 Jun 2024
Last updated: 3 Apr 2026
Results posted: No
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

Publications

Otsuki T, Sakaguchi H, Hatayama T, Wu P, Takata A, Hyodoh F. Effects of all-trans retinoic acid (ATRA) on human myeloma cells. Leuk Lymphoma. 2003 Oct;44(10):1651-6. doi: 10.1080/1042819031000099652.
PubMed 14692515
Nijhof IS, Groen RW, Lokhorst HM, van Kessel B, Bloem AC, van Velzen J, de Jong-Korlaar R, Yuan H, Noort WA, Klein SK, Martens AC, Doshi P, Sasser K, Mutis T, van de Donk NW. Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Leukemia. 2015 Oct;29(10):2039-49. doi: 10.1038/leu.2015.123. Epub 2015 May 15.
PubMed 25975191
Frerichs KA, Minnema MC, Levin MD, Broijl A, Bos GMJ, Kersten MJ, Mutis T, Verkleij CPM, Nijhof IS, Maas-Bosman PWC, Klein SK, Zweegman S, Sonneveld P, van de Donk NWCJ. Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma. Blood Adv. 2021 Dec 14;5(23):5128-5139. doi: 10.1182/bloodadvances.2021005220.
PubMed 34625791
Garcia-Guerrero E, Rodriguez-Lobato LG, Sierro-Martinez B, Danhof S, Bates S, Frenz S, Haertle L, Gotz R, Sauer M, Rasche L, Kortum KM, Perez-Simon JA, Einsele H, Hudecek M, Prommersberger SR. All-trans retinoic acid works synergistically with the gamma-secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells. Haematologica. 2023 Feb 1;108(2):568-580. doi: 10.3324/haematol.2022.281339.
PubMed 36722406
Wang Q, Lin Z, Wang Z, Ye L, Xian M, Xiao L, Su P, Bi E, Huang YH, Qian J, Liu L, Ma X, Yang M, Xiong W, Zu Y, Pingali SR, Xu B, Yi Q. RARgamma activation sensitizes human myeloma cells to carfilzomib treatment through the OAS-RNase L innate immune pathway. Blood. 2022 Jan 6;139(1):59-72. doi: 10.1182/blood.2020009856.
PubMed 34411225
Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, Dispenzieri A, Kumar S, Clark RJ, Baris D, Hoover R, Rajkumar SV. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009 May 28;113(22):5412-7. doi: 10.1182/blood-2008-12-194241. Epub 2009 Jan 29.
PubMed 19179464
Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ 3rd. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006 Mar 30;354(13):1362-9. doi: 10.1056/NEJMoa054494.
PubMed 16571879
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014 Nov;15(12):e538-48. doi: 10.1016/S1470-2045(14)70442-5. Epub 2014 Oct 26.
PubMed 25439696
Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, Larson DR, Plevak MF, Jelinek DF, Fonseca R, Melton LJ 3rd, Rajkumar SV. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007 Jun 21;356(25):2582-90. doi: 10.1056/NEJMoa070389.
PubMed 17582068
Cowan AJ, Allen C, Barac A, Basaleem H, Bensenor I, Curado MP, Foreman K, Gupta R, Harvey J, Hosgood HD, Jakovljevic M, Khader Y, Linn S, Lad D, Mantovani L, Nong VM, Mokdad A, Naghavi M, Postma M, Roshandel G, Shackelford K, Sisay M, Nguyen CT, Tran TT, Xuan BT, Ukwaja KN, Vollset SE, Weiderpass E, Libby EN, Fitzmaurice C. Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018 Sep 1;4(9):1221-1227. doi: 10.1001/jamaoncol.2018.2128.
PubMed 29800065
Minnie SA, Hill GR. Immunotherapy of multiple myeloma. J Clin Invest. 2020 Apr 1;130(4):1565-1575. doi: 10.1172/JCI129205.
PubMed 32149732
Ito S. Proteasome Inhibitors for the Treatment of Multiple Myeloma. Cancers (Basel). 2020 Jan 22;12(2):265. doi: 10.3390/cancers12020265.
PubMed 31979059
Herndon TM, Deisseroth A, Kaminskas E, Kane RC, Koti KM, Rothmann MD, Habtemariam B, Bullock J, Bray JD, Hawes J, Palmby TR, Jee J, Adams W, Mahayni H, Brown J, Dorantes A, Sridhara R, Farrell AT, Pazdur R. U.s. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma. Clin Cancer Res. 2013 Sep 1;19(17):4559-63. doi: 10.1158/1078-0432.CCR-13-0755. Epub 2013 Jun 17.
PubMed 23775332
Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hajek R, Rosinol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. doi: 10.1056/NEJMoa1411321. Epub 2014 Dec 6.
PubMed 25482145
Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hajek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosinol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR Investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. doi: 10.1016/S1470-2045(15)00464-7. Epub 2015 Dec 5.
PubMed 26671818

Interested in taking part?

Sai Ravi Pingali, MD

713-441-0566

spingali@houstonmethodist.org

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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All Multiple Myeloma trials

Study at a glance

From the registry record, last updated by the sponsor on 3 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Phase IB/II Study Combining All-Trans Retinoic Acid (ATRA) With Carfilzomib Based Therapy in Plasma Cell Myeloma Patients Refractory to Carfilzomib
ClinicalTrials.gov ID: NCT06536413
Acronym / sponsor ID: ATRA / PRO00037762 (HMCC-HM22-001)
Conditions: Multiple Myeloma
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Recruiting
Enrolment: 42 participants (estimated)
Lead sponsor: The Methodist Hospital Research InstituteUniversity, hospital or other
Collaborators: Cancer Prevention Research Institute of Texas
Study start: 29 Jul 2024 (actual)
Primary completion: Jul 2029 (estimated)
Study completion: Jul 2030 (estimated)
First posted: 5 Aug 2024 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Sequential
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
All-Trans Retinoic Acid (ATRA), Carfilzomib, and Dexamethasone	Experimental	Drug: All-Trans Retinoic Acid (ATRA) Dose 0, Drug: All-Trans Retinoic Acid (ATRA) Dose -1, Drug: All-Trans Retinoic Acid (ATRA) Dose 1Carfilzomib will be given at Cycle 1 (20 mg/m2 on Days 1, 70 mg/m2 on Days 8 and 15) and Cycles 2 - onward (70 mg/m2 on Days 1, 8, and 15) as a 30-minute intravenous (IV) infusion to evaluate tolerability to treatment. Dexamethasone will be given [20 mg, PO/IV] on the days of carfilzomib treatment. ATRA will be given for 3 weeks (21 days) out of every 4 weeks (28 days) up to a maximum of 24 weeks (6 cycles). Only for Cycle 1, patients will start oral ATRA 25 mg/m2 7 days prior to Cycle 1 Day 1 through Cycle 1 Day 21 for a total of 28 days of dosing. To assign a dose to the next cohort of patients, dose escalation/de-escalation according to the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients who respond and do not have any dose limiting toxicity (DLT), treatment will continue for a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to standard -of-care options.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (24 listed)

Age ≥ 18 years with relapsed/refractory multiple myeloma documented according to International Myeloma Working Group (IMWG) criteria.
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.
Patient or legal guardian voluntarily can sign informed consent.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
Adequate organ function defined as:

Key exclusion criteria (12 listed)

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.
Plasma Cell Leukemia (Previously treated Plasma Cell Leukemia can be included per PI discretion)
Concurrent light chain amyloidosis
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).
Pregnant or breast feeding

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
All-Trans Retinoic Acid (ATRA) Dose 0Patients will receive oral ATRA 25 mg/m2 per day in two divided doses with carfilzomib-based regimens. Eligible patients will enter the study in cohorts of two with the first cohort treated at Dose 0. To assign a dose to the next cohort of patients, dose escalation/de-escalation according to the the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients who respond and do not have any dose limiting toxicity (DLT), treatment will continue for a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to standard -of-care options. Each cycle will be 28 days. In phase 1b, a minimum of 16 evaluable patients will be recruited and in the second phase a minimum of 26 evaluable patients will be recruited. A minimum of 42 evaluable patients will be recruited in the study. If a dose limiting toxicity occurs at 25 mg/m2, then the dose will be reduced by 50% to 15 mg/sq m daily in two divided doses.	Drug	All-Trans Retinoic Acid (ATRA), Carfilzomib, and Dexamethasone
All-Trans Retinoic Acid (ATRA) Dose -1Patients will receive oral ATRA 15 mg/m2 per day in two divided doses with carfilzomib-based regimens. Eligible patients will enter the study in cohorts of two with the first cohort treated at Dose 0. To assign a dose to the next cohort of patients, dose escalation/de-escalation according to the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients who respond and do not have any dose limiting toxicity (DLT), treatment will continue for a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to standard -of-care options. Each cycle will be 28 days. In phase 1b, a minimum of 16 evaluable patients will be recruited and in the second phase a minimum of 26 evaluable patients will be recruited. A minimum of 42 evaluable patients will be recruited in the study.	Drug	All-Trans Retinoic Acid (ATRA), Carfilzomib, and Dexamethasone
All-Trans Retinoic Acid (ATRA) Dose 1Patients will receive oral ATRA 45 mg/m2 per day in two divided doses with carfilzomib-based regimens. Eligible patients will enter the study in cohorts of two with the first cohort treated at Dose 0. To assign a dose to the next cohort of patients, dose escalation/de-escalation according to the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients who respond and do not have any dose limiting toxicity (DLT), treatment will continue for a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to standard -of-care options. Each cycle will be 28 days. In phase 1b, a minimum of 16 evaluable patients will be recruited and in the second phase a minimum of 26 evaluable patients will be recruited. A minimum of 42 evaluable patients will be recruited in the study.	Drug	All-Trans Retinoic Acid (ATRA), Carfilzomib, and Dexamethasone

Primary outcome

Safety and Tolerability of ATRA in combination with Carfilzomib/ Dexamethazone and RP2D
Time frame: From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study, whichever came first, assessed up to 7 months.
To determine safety and tolerability of ATRA in combination with carfilzomib/dexamethasone and determine the recommended phase II dose (RP2D). The RP2D will be defined as the highest dose administered at which 6 patients are treated with with no more than 2 experiencing dose limiting toxicity (DLT) (determined by diseases progression, unacceptable toxicity, physician's discretion).

4 secondary outcomes

Efficacy of combination therapy of ATRA, Carfilzomib, and Dexamethasone in resistant Multiple Myeloma
Time frame: From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever came first, assessed up to 7 months.
Duration of Response of combination therapy of ATRA, Carfilzomib, and Dexamethasone in resistant Multiple Myeloma
Time frame: From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease, whichever came first, assessed up to 7 months after initial treatment date.
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Time frame: The dose limiting toxicity period begins from date of initial treatment until 21 days after.
Disease response as measured by serum, viable cryopreserved peripheral blood mononuclear cells, and bone marrow myeloma plasma cells.
Time frame: Correlative samples will be collected at Baseline, Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1. Cycles are 28 days in length.

Results and safety

This study is still under way. Results are not available in the source record yet.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 3 Apr 2026.
Background: PubMed 14692515Otsuki T, Sakaguchi H, Hatayama T, Wu P, Takata A, Hyodoh F. Effects of all-trans retinoic acid (ATRA) on human myeloma cells. Leuk Lymphoma. 2003 Oct;44(10):1651-6. doi: 10.1080/1042819031000099652.
Background: PubMed 25975191Nijhof IS, Groen RW, Lokhorst HM, van Kessel B, Bloem AC, van Velzen J, de Jong-Korlaar R, Yuan H, Noort WA, Klein SK, Martens AC, Doshi P, Sasser K, Mutis T, van de Donk NW. Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Leukemia. 2015 Oct;29(10):2039-49. doi: 10.1038/leu.2015.123. Epub 2015 May 15.
Background: PubMed 34625791Frerichs KA, Minnema MC, Levin MD, Broijl A, Bos GMJ, Kersten MJ, Mutis T, Verkleij CPM, Nijhof IS, Maas-Bosman PWC, Klein SK, Zweegman S, Sonneveld P, van de Donk NWCJ. Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma. Blood Adv. 2021 Dec 14;5(23):5128-5139. doi: 10.1182/bloodadvances.2021005220.
Background: PubMed 36722406Garcia-Guerrero E, Rodriguez-Lobato LG, Sierro-Martinez B, Danhof S, Bates S, Frenz S, Haertle L, Gotz R, Sauer M, Rasche L, Kortum KM, Perez-Simon JA, Einsele H, Hudecek M, Prommersberger SR. All-trans retinoic acid works synergistically with the gamma-secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells. Haematologica. 2023 Feb 1;108(2):568-580. doi: 10.3324/haematol.2022.281339.
Background: PubMed 34411225Wang Q, Lin Z, Wang Z, Ye L, Xian M, Xiao L, Su P, Bi E, Huang YH, Qian J, Liu L, Ma X, Yang M, Xiong W, Zu Y, Pingali SR, Xu B, Yi Q. RARgamma activation sensitizes human myeloma cells to carfilzomib treatment through the OAS-RNase L innate immune pathway. Blood. 2022 Jan 6;139(1):59-72. doi: 10.1182/blood.2020009856.
Background: PubMed 19179464Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, Dispenzieri A, Kumar S, Clark RJ, Baris D, Hoover R, Rajkumar SV. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009 May 28;113(22):5412-7. doi: 10.1182/blood-2008-12-194241. Epub 2009 Jan 29.
Background: PubMed 16571879Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ 3rd. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006 Mar 30;354(13):1362-9. doi: 10.1056/NEJMoa054494.
Background: PubMed 25439696Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014 Nov;15(12):e538-48. doi: 10.1016/S1470-2045(14)70442-5. Epub 2014 Oct 26.
Background: PubMed 17582068Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, Larson DR, Plevak MF, Jelinek DF, Fonseca R, Melton LJ 3rd, Rajkumar SV. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007 Jun 21;356(25):2582-90. doi: 10.1056/NEJMoa070389.
Background: PubMed 29800065Cowan AJ, Allen C, Barac A, Basaleem H, Bensenor I, Curado MP, Foreman K, Gupta R, Harvey J, Hosgood HD, Jakovljevic M, Khader Y, Linn S, Lad D, Mantovani L, Nong VM, Mokdad A, Naghavi M, Postma M, Roshandel G, Shackelford K, Sisay M, Nguyen CT, Tran TT, Xuan BT, Ukwaja KN, Vollset SE, Weiderpass E, Libby EN, Fitzmaurice C. Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018 Sep 1;4(9):1221-1227. doi: 10.1001/jamaoncol.2018.2128.
Background: PubMed 32149732Minnie SA, Hill GR. Immunotherapy of multiple myeloma. J Clin Invest. 2020 Apr 1;130(4):1565-1575. doi: 10.1172/JCI129205.
Background: PubMed 31979059Ito S. Proteasome Inhibitors for the Treatment of Multiple Myeloma. Cancers (Basel). 2020 Jan 22;12(2):265. doi: 10.3390/cancers12020265.
Bayesian Optimal Interval Designs for Phase I Clinical TrialsLink provided by the sponsor.
Continued Improvement in Survival of Patients with Newly Diagnosed Multiple Myeloma (MM)Link provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.

Sai Ravi Pingali, MD contact

713-441-0566

spingali@houstonmethodist.org

Sai Ravi Pingali, MD principal investigator

Houston Methodist Neal Cancer Center

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 3 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Sai Ravi Pingali, MD (713-441-0566, spingali@houstonmethodist.org), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Safety and Tolerability of ATRA in combination with Carfilzomib/ Dexamethazone and RP2D (time frame: From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study, whichever came first, assessed up to 7 months.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06536413, which also lists 44 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Apr 2026.