This study is intended for men and women at least 18 years of age who have relapsed and/or
refractory multiple myeloma. This 2-arm randomized pilot study will test the safety,
tolerability and efficacy of NY-ESO-1ᶜ²⁵⁹T alone (Arm 1) or in combination with pembrolizumab
(Arm 2) in subjects who have the appropriate HLA-A2 marker, and whose bone marrow expresses
the NY-ESO-1 and/or LAGE-1a protein.
This study will take a subject's T cells and give them a T cell receptor protein that
recognizes and attacks the tumors.
This is a randomized pilot study of the efficacy and safety of NY-ESO-1ᶜ²⁵⁹T alone or in
combination with pembrolizumab in patients with relapsed or refractory multiple myeloma, who
are HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 positive, and whose plasma cells from a bone
marrow (BM) aspirate test positive for NY-ESO-1 and/or LAGE-1a antigen.
Subjects meeting all eligibility criteria will be randomly assigned to a treatment Arm:
NY-ESO-1ᶜ²⁵⁹T alone (Arm 1) or NY-ESO-1ᶜ²⁵⁹T in combination with pembrolizumab (Arm 2).
Leukapheresis is performed to obtain cells for the manufacture of autologous NY-ESO-1ᶜ²⁵⁹T
cells. When the manufactured NY-ESO-1ᶜ²⁵⁹T cells are available, subjects will undergo
lymphodepleting chemotherapy with cyclophosphamide and fludarabine, followed by a single
infusion of NY-ESO-1ᶜ²⁵⁹T (transduced cell range: 1 to 8 billion cells) that will be
administered on Day 1.
In Arm 2, three (3) weeks after the infusion of NY-ESO-1ᶜ²⁵⁹T, an initial dose of
pembrolizumab will be administered on Day 22. If toxicities preclude Week 3 treatment, the
first dose of pembrolizumab may be given at Week 6 (Day 43). The second dose of pembrolizumab
will be administered 3 weeks later, at Week 6 (or Week 9), and subsequent doses of
pembrolizumab will be administered every 3 weeks thereafter up to Week 108 post T-cell
Treatment Limiting Toxicities (TLTs) will be evaluated for subjects in the combination arm
A complete safety review of the first 3 subjects dosed with T-cells and pembrolizumab on Arm
2 will be conducted before enrolling any further subject. The study may be paused to evaluate
safety at any time or if at an interim assessment the predictive probability that the TLT
rate at the end of the trial exceeds 33%, is greater than 50%.
Efficacy will be assessed using International Myeloma Working Group (IMWG) Uniform Response
Upon confirmation of their disease progression, subjects will be considered completing for
the primary analysis. Subjects will complete the study once they have met the criteria to be
transferred into a Long-Term Follow-Up protocol, where they will continue to be followed for
up to 15 years from the date of their T-cell infusion.
1. Subject has voluntarily agreed to participate by giving written informed consent in
accordance with International Council on Harmonisation (ICH) Good Clinical Practice
(GCP) Guidelines and applicable local regulations.
2. Subject has voluntarily agreed to abide by all protocol required procedures including
study related assessments, and management by the treating institution for the duration
of the study and long-term follow-up.
3. Subjects must be 18 years of age or older at the date of consent.
4. Histologically confirmed diagnosis of secretory multiple myeloma (must have measurable
M protein in serum or urine) with at least one of the following: a. Serum M- protein
≥0.5 g/dL (≥5 g/L) for IgG, IgM, IgA, or ≥0.05 g/dL for IgD; or b. Urine M-protein
≥200 mg/24 hours ; or c. Serum free light chain (FLC) assay: involved FLC level ≥10
mg/dL (100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65).
5. Subject must have documented diagnosis of either: a. primary refractory myeloma
(PRMM): subjects who have never achieved the minimal response or better to prior
therapy OR b. relapsed and refractory multiple myeloma (RRMM): subjects who have
received at least 2 prior regimen, were responsive to at least 1 prior regimen (as
defined by IMWG criteria) and then are refractory to their most recent therapy (≤ 25%
response or progression during therapy or within 60 days after completion of therapy).
Prior therapies for subjects with PRMM or RRMM must include an immunomodulatory drug
(IMiD) and a proteasome inhibitor as separate lines or a combined line of therapy. If
prior therapy includes autologous stem cell transplantation (ASCT), then the
succession of induction/ASCT/maintenance therapies will be considered as one line of
therapy altogether. Subjects who have relapsed after ASCT or are unable to receive
ASCT are eligible. The interval from ASCT to entry in the study must be ≥12 weeks.
6. Subject is HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 positive as determined by a
central laboratory. (This determination will be made under a pre enrollment screening
informed consent form [ICF]. There are no restrictions on the timing of HLA typing for
screening and data can be taken from subjects' records).
7. Subject has confirmed sufficient expression of NY-ESO-1 and/or LAGE-1a by reverse
transcription polymerase chain reaction (RT-PCR) as determined by a central laboratory
contracted by the Sponsor (this determination will also be made under a pre-enrollment
8. Left ventricular ejection fraction (LVEF) ≥50%. A lower LVEF (≥40%) is permissible if
a formal cardiologic evaluation reveals no evidence for clinically significant
functional impairment, otherwise the subject may not enter the study.
9. Subject is fit for leukapheresis and has adequate venous access for the cell
10. Subject has adequate vital organ function, as per protocol-defined laboratory values
for Absolute Neutrophil count (ANC), platelets, hemoglobin, Prothrombin Time (PT) or
International Normalized Ratio (INR), Partial Thromboplastin Time (PTT), measured or
calculated creatinine clearance, serum total bilirubin, Aspartate aminotransferase
(AST)/ Serum Glutamic Oxaloacetic Transaminase (SGOT), and Alanine aminotransferase
(ALT)/ Serum Glutamic Pyruvic Transaminase (SGPT).
11. For subjects who have received prior checkpoint inhibitors: a. Subjects with endocrine
AE of any grade are permitted to enroll if they are stably maintained on appropriate
replacement therapy and are asymptomatic. b. Must not have experienced any ≥ Grade 3
AE nor any neurologic or ocular AE of any grade while receiving prior checkpoint
inhibitors. c. Must not have required the use of additional immunosuppression other
than corticosteroids for the management of an AE related to checkpoint inhibitors, not
have experienced recurrence of an AE related to checkpoint inhibitors if re
challenged, and not currently require maintenance doses of corticosteroids.
12. Subject has Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
13. Male or Female subjects can participate. Contraceptive use by men or women should be
consistent with local regulations regarding the methods of contraception for those
participating in clinical studies. Male subjects are eligible to participate if they
agree to the following during the period starting at the first dose of chemotherapy
for at least 12 months after receiving the T-cell infusion, or 4 months after there is
no evidence of persistence/ gene modified cells in the subject's blood, whichever is
longer. If randomized to Arm 2 must use effective contraception for at least 4 months
after the last dose of pembrolizumab if this time frame is longer than the duration of
contraception required in the context of chemotherapy and gene modified cells. Males
should Refrain from donating sperm or either be abstinent from heterosexual or
homosexual intercourse as their preferred and usual lifestyle (abstinent on a long
term and persistent basis) and agree to remain abstinent OR must agree to use
contraception/barrier as follows: Agree to use a male condom and should also be
advised of the benefit for a female partner to use a highly effective method of
contraception as a condom may break or leak when having sexual intercourse with a
woman of childbearing (WOCBP) potential who is not currently pregnant, or agree to use
male condom when engaging in any activity that allows for passage of ejaculate to
another person. Female participant is eligible to participate if she is not pregnant
or breastfeeding, and at least one of the following conditions applies: she is not a
WOCBP OR she is a WOCBP who will agree to use a barrier method (male condom) and use a
contraceptive method that is highly effective (with a failure rate of <1% per year),
during the period starting at the first dose of chemotherapy, for at least 12 months
after receiving the T-cell infusion, or 4 months after there is no evidence of
persistence/ gene modified cells in the subject's blood, whichever is longer. If
randomized to Arm 2 must use a barrier method (male condom) and a highly effective
contraception (with a failure rate of <1% per year) for at least 4 months after the
last dose of pembrolizumab if this time frame is longer than the duration of
contraception required in the context of chemotherapy and gene modified cells. WOCBP
should also agree not to donate eggs (ova, oocytes) for the purpose of reproduction
during this period. The investigator should evaluate the effectiveness of the
contraceptive method in relationship to the first dose of study intervention. A WOCBP
must have a negative highly sensitive pregnancy test (urine or serum as required by
local regulations) within 24 hours before the first dose of study intervention. If a
urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum
pregnancy test is required. In such cases, the subject must be excluded from
participation if the serum pregnancy result is positive. The investigator is
responsible for review of medical history, menstrual history, and recent sexual
activity to decrease the risk for inclusion of a woman with an early undetected
1. Subjects with only plasmacytomas, plasma cell leukemia, monoclonal gammopathy of
undetermined significance (MGUS), smoldering multiple myeloma (SMM), nonsecretory
myeloma or primarily amyloidosis.
2. Subject has already received one of the following therapy/treatment: anti-PD-1,
anti-PD-L1, or anti-PD-L2 inhibitor.
3. Subject has received or plans to receive the following excluded therapy/treatment
within specified time frames prior to leukapheresis or lymphodepleting chemotherapy.
Required Wash-out periods: a. Cytotoxic chemotherapy -2 weeks b. Immune therapy
(including monoclonal antibody therapy) -6 weeks c. Immunomodulator therapy (IMiD e.g.
lenalidomide or thalidomide) -1 week d. Proteasome inhibitor therapy (e.g. bortezomib
or carfilzomib) -2 weeks e. Anticancer Vaccine -2 months NOTE: The subject should be
excluded if the Investigator considers their disease is responding to an experimental
vaccine given within 6 months f. Live-virus vaccination -4 weeks NOTE: Seasonal flu
vaccines that do not contain live virus are not an exclusion. g. Gene therapy using an
integrating vector Allogeneic hematopoietic stem cell transplant at any time not
permitted h. Corticosteroids or any other immunosuppressive therapy -2 weeks NOTE: Use
of inhaled or topical steroids is not an exclusion i. Investigational treatment - 4
weeks j. Radiotherapy - 2 weeks NOTE: Duration of any other anticancer therapies must
be discussed with the Sponsor Study Physician
4. Subjects who have previously participated in Merck pivotal trial NCT02576977: Study of
Pomalidomide and Low Dose Dexamethasone With or Without Pembrolizumab (MK-3475) in
Refractory or Relapsed and Refractory Multiple Myeloma (RRMM)
5. Subject has toxicity from previous anticancer therapy that has not recovered to ≤
Grade 1 or to their baseline level of organ function prior to enrollment (except for
non-clinically significant toxicities, e.g., alopecia, vitiligo). Subjects with Grade
2 toxicities that are deemed stable or irreversible (e.g. peripheral neuropathy) can
be enrolled on a case-by-case basis with prior consultation and agreement with the
Sponsor Study Physician.
6. Subject had major surgery within 4 weeks prior to randomization (kyphoplasty is not
considered major surgery); subjects should have been fully recovered from any surgical
7. Subject has history of allergic reactions attributed to compounds of similar chemical
or biologic composition to fludarabine, cyclophosphamide or other agents used in the
8. Known history of myelodysplasia.
9. Current active liver or biliary disease (with the exception of Gilbert's syndrome or
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease
per investigator assessment). NOTE: Stable chronic liver disease should generally be
defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia,
oesophageal or gastric varices, persistent jaundice or cirrhosis.
10. Known history of chronic active hepatitis or liver cirrhosis (if suspected by
laboratory studies, should be confirmed by liver biopsy).
11. Subject has an active infection with human immunodeficiency virus (HIV), hepatitis B
virus (HBV), hepatitis C virus (HCV), or human T-lymphotropic virus (HTLV) as defined
below: a. Positive serology for HIV. b. Presence of hepatitis B surface antigen
(HBsAg), positive hepatitis C antibody test result at screening or within 3 months
prior to first dose of chemotherapy. c. Active hepatitis C subjects as demonstrated by
test for hepatitis C ribonucleic acid (RNA). Subjects who are HCV antibody positive
will be screened for HCV RNA by any RT-PCR or by DNA assay. If HCV antibody is
positive, eligibility will be determined based on a negative screening RNA value. d.
Positive serology for HTLV 1 or 2. Re-screening for infection disease markers is not
required at baseline (prior to lymphodepleting chemotherapy).
12. History of severe immune disease, including non-infectious pneumonitis, requiring
steroids or other immunosuppressive treatments.
13. Active immune-mediated diseases including: connective tissue diseases, uveitis,
sarcoidosis, inflammatory bowel disease, multiple sclerosis, (non-infectious)
14. Evidence or history of significant cardiac disease (such as, but not limited to,
unstable angina pectoris, myocardial infarction within the prior 6 months, heart
failure within 6 months, symptomatic congestive heart failure, symptomatic or
uncontrolled arrhythmias, severe aortic stenosis, symptomatic mitral stenosis).
15. QTc > 450 msec or QTc > 480 msec for subjects with bundle branch block. Note: The QTc
is the QT interval corrected for heart rate according to Bazett's formula (QTcB),
Fridericia's formula (QTcF), and/or another method, machine-read or manually
over-read. The specific formula that will be used to determine eligibility and
discontinuation for an individual subject should be determined prior to initiation of
the study. In other words, several different formulae cannot be used to calculate the
QTc for an individual subject and then the lowest QTc value used to include or
discontinue the subject from the trial. For purposes of data analysis, QTcB, QTcF,
another QT correction formula, or a composite of available values of QTc will be used.
16. Evidence or history of other significant, hepatic, renal, ophthalmologic, psychiatric,
or gastrointestinal disease which would likely increase the risks of participating in
17. Subjects with concomitant second malignancies (except adequately treated
nonmelanomatous skin cancers, carcinoma in situ of the breast, treated superficial
bladder cancer or prostate cancer, or in situ cervical cancers) are excluded unless a
complete remission was achieved at least 2 years prior to study entry and no
additional therapy is required or anticipated to be required during the study period.
Long-term adjuvant therapy (example: breast cancer) is acceptable.
18. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided they are
radiologically stable, i.e., without evidence of progression for at least 4 weeks by
repeat imaging (note that the repeat imaging should be performed during study
screening), clinically stable, and without requirement of steroid treatment for at
least 14 days prior to first dose of study treatment.
19. Active bacterial or systemic viral or fungal infections.
20. Pregnant or breastfeeding.