Multiple Myeloma
Conditions
Brief summary
This is an open-label, Phase II, single center trial of pembrolizumab (MK-3475), lenalidomide and dexamethasone in subjects with high risk Multiple Myeloma (hrMM) post high-dose chemotherapy with autologous stem cell transplantation (ASCT). Patients with high-risk MM defined as those with one of the following abnormalities who have undergone induction therapy followed by single or tandem melphalan -based ASCT will be considered eligible.
Detailed description
The primary objectives of this trial are to establish the progression free survival (PFS) of ASCT followed by consolidative therapy with pembrolizumab plus lenalidomide and dexamethasone and to evaluate the safety of pembrolizumab plus lenalidomide and dexamethasone following ASCT. The immunological analysis of cells and cytokines pre and post-therapy will be determined from patient bone marrow aspirate and peripheral blood samples as exploratory objectives. The overall composition of the gut microbiome will also be determined in patient stool samples. Patients will be followed by response, EFS/PFS/OS and safety endpoints on an every 3 week basis. Bone marrow aspirate specimens will be obtained at screening and at completing of the study and peripheral blood specimens will be obtained on a monthly basis to evaluate in correlative studies.
Interventions
DRUGLenalidomide
Lenalidomide 25 mg po daily x 14 days once weekly for a 21-day cycle x 2 cycles. This is followed by lenalidomide 25 mg po daily x 14 days for a 21-day cycle x 2 cycles for 2 additional cycles.
DRUGPembrolizumab
Pembrolizumab 200 mg IV every 3 weeks x 2 cycles. This is followed by followed by pembrolizumab 200 mg IV every 3 weeks for 2 additional cycles.
DRUGDexamethasone
Dexamethasone 40 mg po once weekly for a 21-day cycle x 2 cycles only.
Sponsors
Hackensack Meridian Health
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Be willing and able to provide written informed consent/assent for the trial. * Be 18 years of age on day of signing informed consent. * Has a confirmed diagnosis of MM based on standard criteria. (See Appendix 2 for MM Diagnostic Criteria.) * Is between 60 and 180 days from peripheral blood autologous stem cell transplant. * At diagnosis, had MM with measurable disease, defined as: * A monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 g/dL and/or * Urine monoclonal levels of at least 200 mg/24 hours * For subjects without measurable serum and urine M-protein levels, an abnormal free light chain (FLC) ratio (normal value 0.26 - 1.65) with involved FLC ≥10 mg/dL * Radiographic evidence of disease for those without measurable M-spike or free light chains. * Has high-risk MM, which must be present at the time of diagnosis, and defined by: * International Staging System (ISS) stage 3 (See Appendix 3 for ISS Staging), and/or * Deletion 13q by cytogenetics, and/or * 1q amplification, 1p deletion, p53 deletions (17p deletions), t(4;14), t(14;16), t(14;20), hypodiploidy, and/or * High-risk gene expression profile (GEP) scores * Be able to provide a newly obtained bone marrow aspirate/biopsy material for biomarker analysis and disease assessment. * Have a performance status of ≤2 on the ECOG Performance Scale (See Appendix 4). * Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 28 days of treatment initiation. * All subjects must agree to follow the regional requirements for lenalidomide counseling, pregnancy testing, and birth control; and be willing and able to comply with the regional requirements (for example, periodic pregnancy tests, safety labs, etc.). * Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 10-14 days prior to and again within 24 hours prior to receiving the first dose of pembrolizumab (MK-3475), lenalidomide and dexamethasone or pembrolizumab (MK-3475) and lenalidomide. 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 agree to ongoing pregnancy testing. * Female subjects of childbearing potential must 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 (Reference Section 4.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 2 years. * Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential even if they have had a successful vasectomy starting with the first dose of study therapy through 120 days after the last dose of study therapy. * Subject is able to swallow capsules and is able to take or tolerate oral medications on a continuous basis. * 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
* Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. * 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. The use of physiologic doses of corticosteroids may be used at the investigator's discretion. * Has received an allogeneic stem cell transplant. * Has received any myeloma-directed therapy after ASCT. * Has a known history of active TB (Bacillus Tuberculosis) * Hypersensitivity to pembrolizumab or any of its excipients. * Progressive disease from autologous transplantation at the time of screening * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. * 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 known history of, or any evidence of active, non-infectious pneumonitis. * Has an active infection requiring intravenous 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-PD-L2 agent. * Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). * Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). * Has received a live vaccine within 30 days of planned start of study therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Up to 3 years | PFS will be assessed from the date of ASCT, with day 0 defined as date of stem cell infusion (if tandem transplant the 2nd of 2 transplants will be used) until the date of progression, defined as the date at which the patient starts the next line of therapy or the date of death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Serious Adverse Events | Up to 3 years | Safety will be assessed by quantifying the toxicities and grades experienced by subjects who have received pembrolizumab (MK-3475), lenalidomide and dexamethasone, including serious adverse events (SAEs). Result reflects count of participants who experienced an SAE. |
| Evaluation of Stringent Complete Response, Complete Response, and Very Good Partial Response Rate (sCR + CR + VGPR Rate). | Every 3 weeks (day 1 of every 21-day treatment cycle +/- 7 days) through 12 weeks. | Assessed by the investigator per International Myeloma Working Group criteria(IMWG) uniform response criteria. Result reflects number of participants whose best overall response qualified as sCR, CR, or VGPR in 2 year follow up period. |
| Number of Participants Who Progressed at 12 Months | Time from Day 0 (transplant) and date of enrollment to study completion (through 12 weeks) by investigator assessment. | Assessed at 12 months; Subjects without documented PD or death will be censored at the last disease assessment date. Those who died without documented PD will be censored at the time of death. Result reflects count of participants who had progressed at 12 months. |
| Duration of Response (DOR) | Interval between date of first response and date of study completion (through 12 weeks) | Assessed by the investigator per International Myeloma Working Group criteria(IMWG) uniform response criteria. Result reflects count of participants who did not have progressive disease at 2 years. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Comparison in Bone Marrow Aspirates of the Extent of Pre-pembrolizumab (MK-3475), Lenalidomide and Dexamethasone PD-L1 Expression and Change From Baseline PD-L1 Expression in Responders Versus Non-responders | Bone marrow aspirate specimens will be obtained at screening and at week 15 (completion of cycle 4). | Comparison of change from baseline in bone marrow aspirate/biopsy PD-L1 expression between responders with longer duration of response and non-responders or responders with a short duration of response will be performed using mixed regression analysis. Longitudinal analysis of bone marrow aspirate/biopsy PD-L1 expression over time will be examined using mixed model repeated measure design with levels observed serially over time and response type (long responders vs short responders/non-response) as a fixed variable. |
| Assessment of Immune Phenotype in Bone Marrow Aspirates and Peripheral Blood Samples and Plasma Cytokines. | Obtained monthly through week 12 (cycle 4 day 1). | Assays for these studies include flow cytometry, TCR Immunoseq for Vbeta CDR3 highest frequency specificities, real-time PCR analysis and multiplex cytokine ELISA. These data will be aggregated before and after treatment in responders versus non-responders. |
| Assessment of T Cell Repertoire in Bone Marrow Aspirates and Peripheral Blood Samples. | Obtained monthly through week 12 (cycle 4 day 1). | Assays for these studies include flow cytometry, TCR Immunoseq for Vbeta CDR3 highest frequency specificities, and real-time PCR analysis. T cells (CD8+) data will be aggregated before and after treatment in responders versus non-responders. |
| Assessment of Plasma Cytokines | Obtained monthly through week 12 (cycle 4 day 1). | Multiplex cytokine ELISA studies will assess inflammatory cytokine (TNF-alpha, IL-2, IL-4, IL-6, IL-10) data and will be aggregated before and after treatment in responders versus non-responders. |
| Identification and Assessment of Specific Intestinal Microbial Strains (Via Stool Specimens) Associated With Improved Outcome in Autologous Stem Cell Transplantation Patients Treated With PEM+LEN+DEX Compared to PEM+LEN. | Stool specimens at screening or cycle 1, day 1, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1, at completion of cycle 4, and at 90 days post treatment or start of new anti cancer therapy. Stool samples will also be collected at confirmation of response. | A 16S ribosomal RNA (rRNA) miSeq Illumina platform will be used for overall microbial composition and quantitative real-time PCR analysis will validate the specific microbial strains identified by miSeq. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + Lenalidomide This is an open label study.
* Pembrolizumab 200 mg IV every 3 weeks and lenalidomide 25 mg po daily x 14 days and dexamethasone 40 mg po once weekly for a 21-day cycle x 2 cycles.
* This is followed by pembrolizumab 200 mg every 3 weeks and lenalidomide 25 mg po daily x 14 days for a 21-day cycle x 2 cycles for a total of 4 cycles.
Pembrolizumab: Pembrolizumab 200 mg IV every 3 weeks x 2 cycles. This is followed by followed by pembrolizumab 200 mg IV every 3 weeks for 2 additional cycles.
Lenalidomide: Lenalidomide 25 mg po daily x 14 days once weekly for a 21-day cycle x 2 cycles. This is followed by lenalidomide 25 mg po daily x 14 days for a 21-day cycle x 2 cycles for 2 additional cycles.
Dexamethasone: Dexamethasone 40 mg po once weekly for a 21-day cycle x 2 cycles only. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Pembrolizumab + Lenalidomide |
|---|---|
| Age, Customized Age | 67.2 years |
| Race/Ethnicity, Customized Non-White | 2 Participants |
| Race/Ethnicity, Customized White | 10 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 1 / 12 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS will be assessed from the date of ASCT, with day 0 defined as date of stem cell infusion (if tandem transplant the 2nd of 2 transplants will be used) until the date of progression, defined as the date at which the patient starts the next line of therapy or the date of death.
Time frame: Up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Lenalidomide | Progression Free Survival (PFS) | 27.6 months |
Secondary
Duration of Response (DOR)
Assessed by the investigator per International Myeloma Working Group criteria(IMWG) uniform response criteria. Result reflects count of participants who did not have progressive disease at 2 years.
Time frame: Interval between date of first response and date of study completion (through 12 weeks)
Population: The FDA required enrollment to stop and patients to be removed from treatment due to updated risks of the investigational product. Following removal of the study data was not collected and patients were not analyzed due to this early termination of study intervention.
Secondary
Evaluation of Stringent Complete Response, Complete Response, and Very Good Partial Response Rate (sCR + CR + VGPR Rate).
Assessed by the investigator per International Myeloma Working Group criteria(IMWG) uniform response criteria. Result reflects number of participants whose best overall response qualified as sCR, CR, or VGPR in 2 year follow up period.
Time frame: Every 3 weeks (day 1 of every 21-day treatment cycle +/- 7 days) through 12 weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Lenalidomide | Evaluation of Stringent Complete Response, Complete Response, and Very Good Partial Response Rate (sCR + CR + VGPR Rate). | 11 Participants |
Secondary
Number of Participants Serious Adverse Events
Safety will be assessed by quantifying the toxicities and grades experienced by subjects who have received pembrolizumab (MK-3475), lenalidomide and dexamethasone, including serious adverse events (SAEs). Result reflects count of participants who experienced an SAE.
Time frame: Up to 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Lenalidomide | Number of Participants Serious Adverse Events | 1 Participants |
Secondary
Number of Participants Who Progressed at 12 Months
Assessed at 12 months; Subjects without documented PD or death will be censored at the last disease assessment date. Those who died without documented PD will be censored at the time of death. Result reflects count of participants who had progressed at 12 months.
Time frame: Time from Day 0 (transplant) and date of enrollment to study completion (through 12 weeks) by investigator assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Lenalidomide | Number of Participants Who Progressed at 12 Months | 10 Participants |
Other Pre-specified
Assessment of Immune Phenotype in Bone Marrow Aspirates and Peripheral Blood Samples and Plasma Cytokines.
Assays for these studies include flow cytometry, TCR Immunoseq for Vbeta CDR3 highest frequency specificities, real-time PCR analysis and multiplex cytokine ELISA. These data will be aggregated before and after treatment in responders versus non-responders.
Time frame: Obtained monthly through week 12 (cycle 4 day 1).
Other Pre-specified
Assessment of Plasma Cytokines
Multiplex cytokine ELISA studies will assess inflammatory cytokine (TNF-alpha, IL-2, IL-4, IL-6, IL-10) data and will be aggregated before and after treatment in responders versus non-responders.
Time frame: Obtained monthly through week 12 (cycle 4 day 1).
Other Pre-specified
Assessment of T Cell Repertoire in Bone Marrow Aspirates and Peripheral Blood Samples.
Assays for these studies include flow cytometry, TCR Immunoseq for Vbeta CDR3 highest frequency specificities, and real-time PCR analysis. T cells (CD8+) data will be aggregated before and after treatment in responders versus non-responders.
Time frame: Obtained monthly through week 12 (cycle 4 day 1).
Other Pre-specified
Comparison in Bone Marrow Aspirates of the Extent of Pre-pembrolizumab (MK-3475), Lenalidomide and Dexamethasone PD-L1 Expression and Change From Baseline PD-L1 Expression in Responders Versus Non-responders
Comparison of change from baseline in bone marrow aspirate/biopsy PD-L1 expression between responders with longer duration of response and non-responders or responders with a short duration of response will be performed using mixed regression analysis. Longitudinal analysis of bone marrow aspirate/biopsy PD-L1 expression over time will be examined using mixed model repeated measure design with levels observed serially over time and response type (long responders vs short responders/non-response) as a fixed variable.
Time frame: Bone marrow aspirate specimens will be obtained at screening and at week 15 (completion of cycle 4).
Other Pre-specified
Identification and Assessment of Specific Intestinal Microbial Strains (Via Stool Specimens) Associated With Improved Outcome in Autologous Stem Cell Transplantation Patients Treated With PEM+LEN+DEX Compared to PEM+LEN.
A 16S ribosomal RNA (rRNA) miSeq Illumina platform will be used for overall microbial composition and quantitative real-time PCR analysis will validate the specific microbial strains identified by miSeq.
Time frame: Stool specimens at screening or cycle 1, day 1, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1, at completion of cycle 4, and at 90 days post treatment or start of new anti cancer therapy. Stool samples will also be collected at confirmation of response.