Pembrolizumab and Radiation Therapy in Patients With Relapsed or Refractory Multiple Myeloma

PRIMARY OBJECTIVE:

I. To evaluate the safety of concurrent single/low dose radiation therapy (radiotherapy) (8
Gy/1fx) in combination with pembrolizumab in relapsed or refractory myeloma patients.

SECONDARY OBJECTIVES:

I. To characterize late toxicity (Common Terminology Criteria for Adverse Events [CTCAE] >
grade 2 toxicity at 6 and 12 months) and the effect of radiation in combination with
pembrolizumab on systemic response rates using international myeloma working group (IMWG)
uniform response criteria for multiple myeloma at 6 months and 12 months.

II. To assess changes in positron emission tomography/computed tomography (PET/CT) as a
result of combining pembrolizumab and radiotherapy at 6 months and 12 months.

OUTLINE:

Patients undergo radiation therapy on day 1. Patients also receive pembrolizumab
intravenously (IV) over 30 minutes on day 2 or 3. Courses with pembrolizumab repeat every 3
weeks for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12
weeks thereafter.

Inclusion Criteria:

- International Staging System (ISS) stage I-III multiple myeloma that has progressive,
relapsed, or refractory disease

- Able to give informed consent

- Eastern Cooperative Oncology Group (ECOG) 0-1

- Relapsed and/or refractory myeloma; there is no minimum or maximum number of previous
therapies that a patient may have received previously before being put on the current
trial

- ≥ 1 osseous and/or extra-osseous lesion that can be radiated

- Candidate for pembrolizumab (as determined by physician, and adequate organ function)

- Candidate for radiotherapy (as determined by treatment physician); these patients can
have symptomatic disease and/or asymptomatic disease; a minimum of one site of
radiation is required to any osseous and/or any extra-osseous disease; radiation to
any bony parts of the head and neck, skull, spine, ribs, and/or extremities are
allowed; radiation to any bony part for documented lytic disease is allowed; radiation
to any soft tissue plasmacytoma (including osseous and extra-osseous plasmacytoma) is
allowed; the only exclusion criteria for radiation, is central nervous system (CNS)
metastases

- Measurable myeloma disease (urine protein > 200 mg in 24 hours [hr] urine collection,
serum free light chain ratio > 100 with an abnormal k/l ratio, serum M protein > 0.5
g/dl); 6 of the 24 patients do not have to have measurable disease

- Negative urine pregnancy test within 2 weeks for female subjects; female subjects 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

- Abstinence is acceptable, if this is the usual life style and preferred
contraception for the patient

Exclusion Criteria:

- Previous anti-programmed cell death protein 1 (PD1) or anti-PD-L1

- Solitary plasmacytoma

- Smoldering (asymptomatic) multiple myeloma

- 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

- Known history of active TB (Bacillus tuberculosis)

- Hypersensitivity to pembrolizumab or any of its recipients

- 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)

- 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)

- Known history of, or any evidence of active, non-infectious pneumonitis

- Active infection requiring systemic therapy

- 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 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

- Patients requiring radiation for CNS diseases are excluded (CNS defined as brain soft
tissue/intra parenchymal metastases within the gray and white matter of the brain
and/or for cerebrospinal fluid [CSF] disseminated disease, including leptomeningeal
carcinomatous disease)

- Has a history of allogeneic stem cell transplantation