Study of Pomalidomide and Low Dose Dexamethasone With or Without Pembrolizumab (MK-3475) in Refractory or Relapsed and Refractory Multiple Myeloma (rrMM) (MK-3475-183/KEYNOTE-183)

• ClinicalTrials.gov Identifier: NCT02576977
• Recruitment Status: Terminated
• First Posted: October 15, 2015
• Results First Posted: August 2, 2019
• Last Update Posted: October 8, 2021
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

Brief Summary:

The purpose of this study is to compare the efficacy of pomalidomide and low dose dexamethasone with pembrolizumab (MK-3475) to that of pomalidomide and low dose dexamethasone without pembrolizumab in terms of Progression-Free Survival (PFS) in participants with refractory or relapsed and refractory multiple myeloma (rrMM) who have undergone at least 2 lines of prior treatment. The study's 2 primary hypotheses are: 1. Pembrolizumab in combination with pomalidomide and low dose dexamethasone prolongs PFS as assessed by Clinical Adjudication Committee (CAC) blinded central review using International Myeloma Working Group Criteria for Response Assessment in Multiple Myeloma (IMWG) criteria compared to treatment with pomalidomide and low dose dexamethasone standard of care (SOC) alone. 2. Pembrolizumab in combination with pomalidomide and low dose dexamethasone prolongs OS compared to treatment with pomalidomide and low dose dexamethasone (SOC) alone.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma	Biological: Pembrolizumab; Drug: Pomalidomide; Drug: Dexamethasone	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 251 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Study of Pomalidomide and Low Dose Dexamethasone With or Without Pembrolizumab (MK3475) in Refractory or Relapsed and Refractory Multiple Myeloma (rrMM) (KEYNOTE 183)
• Actual Study Start Date: October 19, 2015
• Actual Primary Completion Date: July 9, 2018
• Actual Study Completion Date: July 16, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pembrolizumab+Pomalidomide+Dexamethasone; Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 every 3 weeks (Q3W) PLUS pomalidomide 4 mg orally (PO) on Days 1 to 21 of each 28-day cycle PLUS dexamethasone 40 mg PO on Days 1, 8, 15 and 22 of each 28-day cycle.	Biological: Pembrolizumab; pembrolizumab 200 mg IV infusion; Other Names: KEYTRUDA®; MK-3475; SCH 9000475; Drug: Pomalidomide; pomalidomide 4 mg capsules; Other Name: POMALYST®; Drug: Dexamethasone; dexamethasone 40 mg tablets
Active Comparator: Pomalidomide+Dexamethasone; Participants receive pomalidomide 4 mg PO on Days 1 to 21 of each 28-day cycle PLUS dexamethasone 40 mg PO on Days 1, 8, 15 and 22 of each 28-day cycle.	Drug: Pomalidomide; pomalidomide 4 mg capsules; Other Name: POMALYST®; Drug: Dexamethasone; dexamethasone 40 mg tablets

Outcome Measures

Primary Outcome Measures :

1. Progression Free Survival (PFS) Assessed by Clinical Adjudication Committee (CAC) Blinded Central Review According to the International Myeloma Working Group (IMWG) Response Criteria [ Time Frame: Up to approximately 30 months ]
   Progression free survival was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. PFS was assessed by CAC blinded central review according to the IMWG criteria based on the development of new bone lesions or soft tissue plasmacytomas or on a definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Median PFS was calculated from the product-limit (Kaplan-Meier) method for censored data. The database cutoff date was July 9, 2018.
2. Overall Survival (OS) [ Time Frame: Up to approximately 54 months ]
   Overall survival is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Median overall survival was calculated from the product-limit (Kaplan-Meier) method for censored data. The database cutoff date was August 3, 2020.

Secondary Outcome Measures :

1. Overall Response Rate (ORR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review [ Time Frame: Up to approximately 30 months ]
   ORR was defined as the percentage of the participants in the analysis population who achieved at least a partial response (stringent complete response [sCR]+complete response [CR]+very good partial response [VGPR]+partial response [PR]) according to the IMWG. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND <5% plasmacytomas in the bone marrow; sCR=stringent complete response, CR as above PLUS normal serum free light-chain (FLC) assay ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; VGPR = serum and urine M-component detectable by immunofixation but not on electrophoresis OR ≥ 90% reduction in serum M-component plus urine M-component <100 mg/24 hr; PR = ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours. The database cutoff date was July 9, 2018.
2. Participants Experiencing One or More Adverse Events (AEs) [ Time Frame: Up to approximately 54 months ]
   An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. Database cutoff was August 3, 2020.
3. Participants Discontinuing Study Investigational Product Due to an AE [ Time Frame: Up to approximately 54 months ]
   An adverse event was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. Database cutoff was August 3, 2020.
4. Disease Control Rate (DCR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review [ Time Frame: Up to approximately 30 months ]
   Disease control rate was the percentage of participants who achieved confirmed sCR, CR, VGPR, PR, minimal response (MR) or have demonstrated stable disease (SD) for at least 12 weeks prior to any evidence of progression. PD was development of or an increase in the size of bone lesions or soft tissue plasmacytomas. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND <5% plasmacytomas in the bone marrow; sCR=stringent complete response, CR as above PLUS normal serum FLC assay ratio and absence of clonal cells in bone marrow by immunohistochemistry/fluorescence; VGPR = serum and urine M-component detectable by immunofixation but not on electrophoresis OR ≥ 90% reduction in serum M-component plus urine M-component <100 mg/24 hr; PR = ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours. The data cutoff date was July 9, 2018.
5. Second Progression Free Survival (PFS2) [ Time Frame: Up to approximately 30 months ]
   PFS2 was defined as the time from randomization to subsequent disease progression after initiation of new anti-cancer therapy, or death from any cause, whichever occurred first, by investigator assessment. As a result of a full clinical hold by FDA that led to discontinuation of study enrollment, no data was collected for analysis of PFS2.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Has a confirmed diagnosis of active multiple myeloma and measurable disease
• Must have undergone prior treatment with ≥2 treatment lines of anti-myeloma therapy and must have failed last line of treatment (refractory to last line of treatment)
• Prior anti-myeloma treatments must have included an immunomodulatory drug (IMiD) AND proteasome inhibitor alone or in combination and participant must have failed therapy with an IMiD OR proteasome inhibitor
• Has performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
• Female participants of childbearing potential must have 2 negative urine human chorionic gonadotropin tests within 10 to 14 days and within 24 hours prior to receiving study medication
• Female participants of childbearing potential and male participants must agree to use adequate contraception 28 days prior to study start and continuing for up to 28 days after the last dose of pomalidomide (or 120 days after the last dose of pembrolizumab)

Exclusion Criteria:

• Has had prior anti-myeloma therapy within 2 weeks prior to study start and has not recovered (i.e., ≤ Grade 1 or at Baseline) from adverse events due to a previously administered agent
• Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Participants who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of Graft versus Host Disease [GVHD]).
• Has received autologous stem cell transplant (auto-SCT) within 12 weeks before the first infusion or is planning for or is eligible for auto-SCT
• Has received previous therapy with pomalidomide
• Has peripheral neuropathy ≥ Grade 2
• Has a known additional malignancy that is progressing or requires active treatment within the last 5 years (except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy)
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Has received prior therapy with an anti-programmed cell death 1 receptor (anti-PD-1), antiprogrammed death-ligand 1 (anti-PD-L1), anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways)
• Is pregnant or breast-feeding

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme LLC:

Study Protocol and Statistical Analysis Plan  [PDF] June 4, 2020

More Information

Additional Information:

Merck Oncology Clinical Trials Information 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Liao JJZ, Farooqui MZH, Marinello P, Hartzel J, Anderson K, Ma J, Gause CK. Using artificial intelligence tools in answering important clinical questions: The KEYNOTE-183 multiple myeloma experience. Contemp Clin Trials. 2020 Dec;99:106179. doi: 10.1016/j.cct.2020.106179. Epub 2020 Oct 18.

Mateos MV, Blacklock H, Schjesvold F, Oriol A, Simpson D, George A, Goldschmidt H, Larocca A, Chanan-Khan A, Sherbenou D, Avivi I, Benyamini N, Iida S, Matsumoto M, Suzuki K, Ribrag V, Usmani SZ, Jagannath S, Ocio EM, Rodriguez-Otero P, San Miguel J, Kher U, Farooqui M, Liao J, Marinello P, Lonial S; KEYNOTE-183 Investigators. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019 Sep;6(9):e459-e469. doi: 10.1016/S2352-3026(19)30110-3. Epub 2019 Jul 18.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02576977
• Other Study ID Numbers: 3475-183; 2015-002509-13 ( EudraCT Number ); 163146 ( Registry Identifier: JAPAN-CTI ); MK-3475-183 ( Other Identifier: Merck Protocol Number ); KEYNOTE-183 ( Other Identifier: Merck )
• First Posted: October 15, 2015
• Results First Posted: August 2, 2019
• Last Update Posted: October 8, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme LLC:

PDL1; PD1; Multiple Myeloma

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Dexamethasone; Pembrolizumab; Pomalidomide; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immunologic Factors