This is a phase II, single-arm, open-label study in subjects with relapsed and/or refractory
multiple myeloma (RRMM) comparing Pembrolizumab (Pembro) in combination with Daratumumab
(Dara) to the historical control of Daratumumab.
Heavily pre-treated multiple myeloma patients who are treated with single agent daratumumab
have been reported to have median PFS of 4 months. A median PFS of 4 months corresponds to an
8-month progression-free survival rate of 25% (based on the exponential survival
distribution). For this population of patients treated with Daratumumab and Pembrolizumab,
the aim is to improve the 8-month PFS rate to 50%. Thirty-three RRMM patients who have
received ≥ 3 lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory
drug (IMiD) will be eligible for enrollment. Sixteen (16) subjects will be enrolled in the
first stage, and if at least 5 of the 16 patients are alive and progression free at 8 months,
an additional 17 subjects will be enrolled.
Inclusion Criteria Subjects must meet all of the following inclusion and exclusion criteria
to participate in the trial.
1. Written informed consent and HIPAA authorization for release of personal health
information.
2. Age ≥ 18 years at the time of consent.
3. ECOG Performance Status of ≤ 1.
4. Documented symptomatic/active multiple myeloma with measurable disease that has
previously responded to therapy (partial response or better by IMWG criteria) and
since relapsed or is refractory to the last line of therapy. Refractory disease is
defined as evidence of progressive disease per IMWG criteria within 60 days (measured
from the end of the last cycle) after completing treatment with the last anti-myeloma
drug regimen.
Note: measurable disease is defined as
- Serum monoclonal protein level ≥ 0.5 g/dL for IgG, IgA, or IgM disease
- Monoclonal protein or total serum IgD ≥ 0.5 g/dL for IgD disease
- Urinary M-protein excretion of ≥ 200 mg over a 24-hour period
- Involved free light chain level ≥ 10 mg/dL, along with an abnormal free light
chain ratio
5. Subjects must have a documented history of relapsed and/or refractory multiple myeloma
with 3 or more prior lines of therapy.
6. Subjects must have had prior exposure to daratumumab in one of the prior lines of
therapy.
7. Prior cancer treatment, including chemotherapy and radiation therapy, must be
completed at least 14 days prior to enrollment and the subject must have recovered
from all reversible acute toxic effects of the regimen to their previous baseline or
≤ Grade 1. Exceptions include alopecia (all grades) and neuropathy (grade 1 with
controlled pain, grade 2 without pain).
8. Demonstrate adequate organ function as defined below; all screening labs to be
obtained within 3 days prior to initiating study treatment:
- Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
- Platelets ≥ 75 x 109/L
- Hemoglobin ≥ 8 g/dL or 4.96 mmol/L
- Calculated creatinine clearance ≥ 30 mL/min/1.73m2
- Corrected serum calcium ≤ 14.0 mg/dL
- Serum total bilirubin ≤ 1.5 X ULN OR
- Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
- AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN
- Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is
receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range
of intended use of anticoagulants ≤1.5 X ULN unless subject is receiving
anticoagulant therapy, as long as PT or PTT is within therapeutic range of
intended use of anticoagulants
9. Female subject of childbearing potential should have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study treatment.
If a urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
10. As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study.
Exclusion Criteria
1. Subjects with active infection requiring systemic therapy such as known active
Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is
detected) or HIV. (NOTE: at discretion of investigator, subjects with uncomplicated
urinary tract infections may be eligible.)
2. Pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of trial participation, starting with consent through 120 days
after the last dose of pembrolizumab and 3 months of last dose of daratumumab (NOTE:
breast milk cannot be stored for future use while the mother is being treated on
study).
3. Autologous stem cell transplantation within 12 weeks of cycle 1, day 1
4. History of previous or concurrent malignancy other than MM within the past 2 years.
Exceptions include basal cell or squamous cell carcinoma of the skin that has
undergone potentially curative therapy, or in situ cervical cancer.
5. 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 (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
6. Known history of interstitial lung disease, known history of non-infectious
pneumonitis that required steroids, current pneumonitis, known chronic obstructive
pulmonary disease (COPD) with FEV1 ≤ 30% of predicted normal, known moderate or severe
persistent asthma within the past 2 years, SpO2 ≤ 90%.
7. Has known active CNS metastases and/or carcinomatous meningitis. Subjects with
previously treated brain metastases may participate provided they are stable without
evidence of progression for at least 4 weeks by repeat imaging (note that the repeat
imaging should be performed during study screening), with any neurologic symptoms
resolved or stabilized without requirement of steroid treatment for at least 14 days
prior to cycle 1, day 1.
8. Clinically significant cardiac disease including myocardial infarction within 6 months
before cycle 1 day 1, or unstable or uncontrolled disease/condition related to or
affecting cardiac function (e.g. unstable angina, congestive heart failure NYHA class
III-IV), clinically significant cardiac arrhythmia (NCI CTCAE grade ≥ 2).
9. Grade 2 peripheral neuropathy with associated pain or grade ≥3 peripheral neuropathy
regardless of the presence of pain.
10. Plasma cell leukemia, Waldenstrom macroglobulinemia, POEMS syndrome, or amyloidosis.
11. Major surgery within 2 weeks before Cycle 1, Day 1. Subjects with prior surgery must
be expected to have fully recovered from surgery during the time the subject is
expected to receive treatment on study.
12. Prior exposure to an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 agent.
13. Severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.
14. History of solid organ transplantation.
15. History of allogeneic stem cell transplantation.
16. 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 cycle 1, day 1.
17. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to Cycle 1, Day 1.
18. Has a known history of active TB (Bacillus Tuberculosis).
19. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Cycle 1,
Day 1.
20. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
21. 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.
