Pembrolizumab in Treating Patients With Intermediate or High-Risk Smoldering Multiple Myeloma

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02603887
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 20
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 77.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This pilot early phase I trial studies pembrolizumab in treating patients with slow growing (smoldering) multiple myeloma with intermediate or high-risk of spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Condition or Disease	Intervention/Treatment	Phase
Smoldering Plasma Cell Myeloma	Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab	Early Phase 1

Detailed Description

PRIMARY OBJECTIVE:

1. To determine the overall response rate after 8 cycles of treatment according to the International Myeloma Working Group Criteria (IMWG).

SECONDARY OBJECTIVES:

1. To determine time to progression to multiple myeloma (TTP) at 30 months from study entry.

2. To determine overall survival (OS). III. To determine duration of response (DOR). IV. To determine the clinical benefit rate (CBR) after 8 cycles of treatment according to the modified IMWG Criteria for multiple myeloma (MM).

3. To evaluate safety and tolerability of single agent treatment in this population.

EXPLORATORY OBJECTIVES:

1. Rate of minimal residual disease (MRD) negativity at complete remission (CR).

2. Molecular profiling (including whole exome sequencing and gene expression profiling) and cellular (including flow cytometry) profiling at baseline and/or at progression using bone marrow aspirate samples and peripheral blood.

3. Immunophenotypic characterization of dendritic, T-, B-, natural killer (NK)- and natural killer T (NKT)-cells, and inhibitory/activation markers on tumor cells at baseline and at completion of 8 cycles of therapy in bone marrow aspirate samples and/or peripheral blood.

4. Evaluation of changes in PD-L1 and PD-1 expression at baseline/end of 8 cycles of treatment and correlate with clinical response.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6-12 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Single Arm, Single Center, Open Label Trial of Pembrolizumab in Patients With Intermediate and High Risk Smoldering Multiple Myeloma
• Actual Study Start Date: Jul 20, 2016
• Anticipated Primary Completion Date: Dec 31, 2022
• Anticipated Study Completion Date: Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (pembrolizumab) Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Pembrolizumab; Given IV; Other Names: Keytruda Lambrolizumab MK-3475 SCH 900475

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [From cycle 1 to cycle 8, up to 168 days]

   Overall response rate is defined as patients who have achieved partial response or higher as described per IMWG criteria for multiple myeloma after 8 cycles of therapy with pembrolizumab. Will be measured according to International Myeloma Working Group Criteria (IMWG) criteria. Response rate will be estimated accordingly. Each cycle has a duration of 21 days.

Secondary Outcome Measures

1. Number of Participants That Had Progression to Multiple Myeloma [At 30 months from study entry]

   Progressive disease assessed by IMWG criteria for multiple myeloma after 8 cycles of therapy with pembrolizumab.

2. Clinical Benefit Rate [From cycle 1 to cycle 8, up to 168 days]

   Minor response or better assessed by IMWG criteria for multiple myeloma after 8 cycles of therapy with pembrolizumab

3. Overall Survival [Time of start of treatment to death from any cause up to 2 years and 6 months]

   Participants in a study or treatment group who are still alive for a certain period of time after they were diagnosed with or started treatment for a disease

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult patients with intermediate or high-risk smoldering multiple myeloma (SMM) are eligible; patients need to have clonal bone marrow plasma cells >= 10% and/or monoclonal spike in blood of >= 3 g/dL and/or monoclonal urine component (Bence jones proteinuria) >= 500 mg/24 hours and need to meet subject inclusion criteria and exclusion criteria as per below

• Patients must have histologically confirmed SMM based on the following criteria:

• (A) Mayo clinic criteria (patient must have at least 2 risk factors present):

• 1. Bone marrow core biopsy plasma cell involvement by cluster of differentiation (CD)138 immunohistochemistry >= 10%
• 1. Monoclonal spike >= 3 g/dL
• 1. Free light chain ratio in serum < 0.125 or > 8; *2 of 3 risk factors: intermediate risk for progression at a rate of 51% at 5 years, *3 of 3 risk factors: high risk for progression at a rate of 76% at 5 years

• OR (B) Programa para el Tratamiento de Hemopatias Malignas (PETHEMA) criteria (patient must have at least 1 risk factor present)

• 1. = 95% abnormal plasma cells/total plasma cells in bone marrow compartment

• 1. Immunoparesis *1 of 2 risk factors: intermediate risk for progression at a rate of 46% at 5 years, *2 of 2 risk factors: high risk for progression at a rate of 72% at 5 years

• OR (C) Southwestern Oncology Group (SWOG) criteria (patient must have 2 risk factors present or one risk factor if this risk factor is a 70-gene signature (GEP70) score of > 37.2)

• 1. Monoclonal spike >= 3 g/dL
• 1. Involved free light chain >= 25 mg/dL
• 1. GEP70 risk score > 37.2 >= 2 risk factors: high risk of progression at a rate of 70% at 2 years; we would also include patients with 1 risk factor as long as this risk factor is GEP70 risk score > 37.2 since patients with this risk factor have an intermediate risk of progression at a rate of 50% at 2 years

• Creatinine clearance >= 50 ml/min; creatinine clearance (CrCl) will be calculated by Cockcroft-Gault method

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Absolute neutrophil count (ANC) >= 1.0 x 10^9 /L

• Hemoglobin >= 10 g/dL

• Platelet count >= 50 x 10^9/L

• Bilirubin < 1.5 x the upper limit of normal (ULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN

• Subjects must be able to give informed consent

• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year

• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria:

• Evidence of myeloma defining events or biomarkers of malignancy due to underlying plasma cell proliferative disorder meeting at least one of the following

• 1. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL)
• 1. Renal insufficiency: creatinine clearance < 40 ml/min or serum creatinine > 2 mg/dL
• 1. Anemia: hemoglobin value < 10 g/dL or 2 g/dL < normal reference
• 1. Bone lesions: one or more osteolytic lesions on skeletal radiography, computerized tomography (CT) or 2-deoxy-2[F-18] fluoro-D-glucose positron emission tomography CT (PET-CT)
• 1. Clonal bone marrow plasma cell percentage >= 60%
• 1. Involved: uninvolved serum free light chain ratio >= 100 measured by Freelite assay (The Binding Site Group, Birmingham, United Kingdom [UK])

• 1. 1 focal lesions on magnetic resonance imaging (MRI) studies (each focal lesion must be 5 mm or more in size), if clinically indicated

• Prior or concurrent systemic treatment for SMM; a) bisphosphonates are permitted; b) treatment with corticosteroids is not permitted; c) radiotherapy is not permitted; d) prior treatment for smoldering multiple myeloma with chemotherapy agents approved for the treatment of multiple myeloma is not permitted

• Plasma cell leukemia

• Pregnant or lactating females; breastfeeding should be discontinued if the mother is treated with pembrolizumab

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment

• Has a known history of active TB (bacillus tuberculosis)

• Hypersensitivity to pembrolizumab or any of its excipients

• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier

• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer

• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment

• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis

• Has an active infection requiring systemic therapy

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment

• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-programmed death ligand 2 (PD-L2) agent

• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)

• Has received a live vaccine within 30 days of planned start of study therapy; Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

• Evidence of interstitial lung disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Elisabet E Manasanch, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 8, 2016

More Information

Additional Information:

• MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT02603887
• Other Study ID Numbers: 2015-0371; NCI-2015-02135; 2015-0371; P30CA016672
• First Posted: Nov 13, 2015
• Last Update Posted: Mar 24, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Smoldering Multiple Myeloma; Pembrolizumab

Study Results

Participant Flow

Recruitment Details	Enrollment period was between July 2016 and August 2017
Pre-assignment Detail	20 participants were consented. 13 participants were treated at MD Anderson Cancer Center. An additional participant started stage 2 that did not participate in Stage 1"

Arm/Group Title	Treatment (Pembrolizumab)
Arm/Group Description	Pembrolizumab 200 mg, 30 minute IV infusion every 21 days up to 24 cycles if equal or higher than minor response and without serious adverse events after 8 cycles
Period Title: Stage 1
STARTED	12
Cycle 1	12
Cycle 8	7
COMPLETED	7
NOT COMPLETED	5
Period Title: Stage 1
STARTED	1
Cycle 1	1
Cycle 8	0
COMPLETED	0
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (Pembrolizumab)
Arm/Group Description	Pembrolizumab 200 mg, 30 minute IV infusion every 21 days up to 24 cycles if equal or higher than minor response and without serious adverse events after 8 cycles
Overall Participants	13
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 38.5%
>=65 years	8 61.5%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	68
Sex: Female, Male (Count of Participants)
Female	5 38.5%
Male	8 61.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	13 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 7.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	12 92.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	13 100%
Myeloma related labs (gm/dL) [Median (Inter-Quartile Range) ]
Hemoglobin	12.4
Serum paraprotein	1.9
Myeloma related labs (mg/dL) [Median (Inter-Quartile Range) ]
Calcium	9.3
Creatinine	.88
Myeloma related labs (mg/L) [Median (Inter-Quartile Range) ]
B2 microglobulin	1.9
Kappa free light chain	127.04
Lambda free light chain	8.08
Myeloma related lab Lactate dehydrogenase (u/L) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [u/L]	439
Myeloma related lab Bone marrow biopsy plasma cells (percentage of plasma cells) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of plasma cells]	30
Myeloma related lab Bence Jones urine protein (mg/day) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/day]	6
Myeloma related labs (ratio) [Median (Inter-Quartile Range) ]
Free Light Chains (FLCs) ratio	12.27
Involved:Uninvolved ratio	17.95

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Overall response rate is defined as patients who have achieved partial response or higher as described per IMWG criteria for multiple myeloma after 8 cycles of therapy with pembrolizumab. Will be measured according to International Myeloma Working Group Criteria (IMWG) criteria. Response rate will be estimated accordingly. Each cycle has a duration of 21 days.
Time Frame	From cycle 1 to cycle 8, up to 168 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Pembrolizumab)
Arm/Group Description	Pembrolizumab 200 mg, 30 minute IV infusion every 21 days up to 24 cycles if equal or higher than minor response and without serious adverse events after 8 cycles
Measure Participants	13
Count of Participants [Participants]	1 7.7%

2. Secondary Outcome

Title	Number of Participants That Had Progression to Multiple Myeloma
Description	Progressive disease assessed by IMWG criteria for multiple myeloma after 8 cycles of therapy with pembrolizumab.
Time Frame	At 30 months from study entry

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Pembrolizumab)
Arm/Group Description	Pembrolizumab 200 mg, 30 minute IV infusion every 21 days up to 24 cycles if equal or higher than minor response and without serious adverse events after 8 cycles
Measure Participants	13
Count of Participants [Participants]	3 23.1%

3. Secondary Outcome

Title	Clinical Benefit Rate
Description	Minor response or better assessed by IMWG criteria for multiple myeloma after 8 cycles of therapy with pembrolizumab
Time Frame	From cycle 1 to cycle 8, up to 168 days

Outcome Measure Data

Analysis Population Description

Clinical benefit rate is described as minor response or better assessed by IMWG criteria for multiple myeloma after 8 cycles of therapy with pembrolizumab. 1 participant of 13 achieved sCR

Arm/Group Title	Treatment (Pembrolizumab)
Arm/Group Description	Pembrolizumab 200 mg, 30 minute IV infusion every 21 days up to 24 cycles if equal or higher than minor response and without serious adverse events after 8 cycles
Measure Participants	13
Count of Participants [Participants]	1 7.7%

4. Secondary Outcome

Title	Overall Survival
Description	Participants in a study or treatment group who are still alive for a certain period of time after they were diagnosed with or started treatment for a disease
Time Frame	Time of start of treatment to death from any cause up to 2 years and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Pembrolizumab)
Arm/Group Description	Pembrolizumab 200 mg, 30 minute IV infusion every 21 days up to 24 cycles if equal or higher than minor response and without serious adverse events after 8 cycles
Measure Participants	13
Count of Participants [Participants]	12 92.3%

Adverse Events

Time Frame	From time the consent form is signed through 90 days following cessation of treatment and at each examination on the Adverse Event case report/forms/worksheet, up to 2 years and 6 months
Adverse Event Reporting Description	All adverse events were recorded on the adverse event case report/worksheet by the principal investigator and/or research team, as well as evaluated by a qualified physician
Arm/Group Title	Single Arm, Intermediate-high Risk SMM Participants
Arm/Group Description	Pembrolizumab 200 mg, 30 minute IV infusion every 21 days up to 24 cycles if equal or higher than minor response and without serious adverse events after 8 cycles
All Cause Mortality
	Single Arm, Intermediate-high Risk SMM Participants
	Affected / at Risk (%)	# Events
Total	1/13 (7.7%)
Serious Adverse Events
	Single Arm, Intermediate-high Risk SMM Participants
	Affected / at Risk (%)	# Events
Total	3/13 (23.1%)
Hepatobiliary disorders
Transaminitis	1/13 (7.7%)
Musculoskeletal and connective tissue disorders
Myalgia	1/13 (7.7%)
Renal and urinary disorders
Acute kidney injury	1/13 (7.7%)
Other (Not Including Serious) Adverse Events
	Single Arm, Intermediate-high Risk SMM Participants
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Blood and lymphatic system disorders
Alanine aminotranferase increased	3/13 (23.1%)
Anemia	5/13 (38.5%)
Aspartate aminotransferase increased	2/13 (15.4%)
Creatinine increased	1/13 (7.7%)
Hypercalcemia	1/13 (7.7%)
Hyperglycemia	6/13 (46.2%)
Hyperuricemia	1/13 (7.7%)
Hypocalcemia	2/13 (15.4%)
Hypomagnesemia	4/13 (30.8%)
Hyponatremia	1/13 (7.7%)
Hypophosphatemia	2/13 (15.4%)
Lipase increased	3/13 (23.1%)
Neutrophil count decreased	1/13 (7.7%)
Platelet count decreased	1/13 (7.7%)
Cardiac disorders
Atrial fibrillation	1/13 (7.7%)
Palpitations	1/13 (7.7%)
Ear and labyrinth disorders
Dizziness	3/13 (23.1%)
Tinnutis	1/13 (7.7%)
Endocrine disorders
Endocrine disorders - Other, specify	3/13 (23.1%)
Eye disorders
Blurred vision	1/13 (7.7%)
Dry eye	3/13 (23.1%)
Eye disorders - Other, specify	1/13 (7.7%)
Eye pain	1/13 (7.7%)
Photophobia	1/13 (7.7%)
Gastrointestinal disorders
Anorexia	1/13 (7.7%)
Constipation	5/13 (38.5%)
Diarrhea	6/13 (46.2%)
Dyspepsia	1/13 (7.7%)
Gastrointestinal disorders - Other, specify	1/13 (7.7%)
Hemorrhoids	1/13 (7.7%)
Hepatobiliary disorders - Other, specify	1/13 (7.7%)
Nausea	2/13 (15.4%)
Vomiting	1/13 (7.7%)
General disorders
Chills	1/13 (7.7%)
Epistaxis	1/13 (7.7%)
Fatigue	10/13 (76.9%)
Fever	1/13 (7.7%)
General disorders and administration site conditions - Other, specify	1/13 (7.7%)
Headache	1/13 (7.7%)
Hot flashes	2/13 (15.4%)
Insomnia	2/13 (15.4%)
Memory impairment	1/13 (7.7%)
Mucositis oral	2/13 (15.4%)
Pain	4/13 (30.8%)
Hepatobiliary disorders
Transaminitis	1/13 (7.7%)
Immune system disorders
Autoimmune disorder	1/13 (7.7%)
Infections and infestations
Prostate infection	1/13 (7.7%)
Metabolism and nutrition disorders
Metabolism and nutrition - Other, specify	4/13 (30.8%)
Weight loss	2/13 (15.4%)
Musculoskeletal and connective tissue disorders
Back pain	2/13 (15.4%)
Generalized muscle weakness	1/13 (7.7%)
Muscoloeskeletal and connective tissue disorder - Other, specify	3/13 (23.1%)
Myalgia	4/13 (30.8%)
Neck edema	1/13 (7.7%)
Neck pain	2/13 (15.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm benign, malignant and unspecified (incl cyst and polyps) - Other, specify	1/13 (7.7%)
Nervous system disorders
Peripheral sensory neuropathy	2/13 (15.4%)
Tremor	1/13 (7.7%)
Psychiatric disorders
Psychiatric disorders - Other, specify	1/13 (7.7%)
Renal and urinary disorders
Acute kidney injury	2/13 (15.4%)
Hematuria	1/13 (7.7%)
Renal and urinary disorders - Other, specify	3/13 (23.1%)
Urinary frequency	2/13 (15.4%)
Urinary tract infection	1/13 (7.7%)
Urinary tract pain	1/13 (7.7%)
Urinary urgency	1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/13 (7.7%)
Bronchial infection	1/13 (7.7%)
Cough	2/13 (15.4%)
Nasal congestion	2/13 (15.4%)
Respiratory, thoracic and mediastinal disorders - Other, specify	1/13 (7.7%)
Serum amylase increased	3/13 (23.1%)
Upper respiratory infection	3/13 (23.1%)
Wheezing	1/13 (7.7%)
Skin and subcutaneous tissue disorders
Alopecia	1/13 (7.7%)
Edema limbs	4/13 (30.8%)
Pruritus	4/13 (30.8%)
Rash maculo-papular	5/13 (38.5%)
Skin and subcutaneous tissue disorders - Other, specify	3/13 (23.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.