Avelumab in Combination With Hypofractionated Radiotherapy in Patients With Relapsed Refractory Multiple Myeloma

* INCLUSION CRITERIA:
* Patients must have a documented diagnosis of multiple myeloma defined by the International Myeloma Working Group Criteria (IMWG)(3). Patients at initial diagnosis must have had a serum M-protein greater than or equal to 3 g/dL and/or bone marrow plasma cells greater than or equal to 10%, and at least one of the following:

  * Anemia: Hemoglobin less than or equal to10 g/dL, or
  * Renal failure: serum creatinine greater than or equal to 2.0 mg/dL, or
  * Hypercalcemia: Calcium (Ca) greater than or equal to10.5 mg/dL, or
  * Lytic bone lesions on X-ray, computed tomography (CT), or positron emission tomography (PET)/CT, or
  * greater than or equal to 2 focal lesions on spinal magnetic resonance imaging (MRI), or
  * greater than or equal to 60% bone marrow plasma cells, or
  * Involved/un-involved serum free light chain ratio greater than or equal to 100
* Have at least one extramedullary plasmacytoma or lytic lesion which at the discretion of the investigators is amenable to and clinically indicated for localized radiation therapy
* Must have Relapsed or Relapsed and Refractory Multiple Myeloma. Patients must have documented evidence of progressive disease (PD) as defined by the IMWG criteria on or after their last regimen and must have achieved a minimal response (MR) or better to at least one prior regimen. Definitions by the IMWG:

  * Relapsed and refractory: disease that is nonresponsive while on salvage therapy or progresses within 60 days of last therapy in patients who have achieved minor response (MR) or better
  * Relapsed: disease that progresses and requires the initiation of salvage therapy but does not meet criteria for either primary refractory or relapsed and refractory MM categories
* Patients must have been previously treated for MM and be refractory to, not a candidate for (ineligible), or intolerant of available therapeutic regimens known to provide clinical benefit including immunomodulatory (IMiD), proteasome inhibitor, and anti-cluster of differentiation (CD)38 monoclonal antibody-based treatments.
* Documented measurable disease within the 4 weeks prior to registration defined by any one of the following:

  * Monoclonal Bone marrow plasma cells greater than or equal to 5%
  * Serum monoclonal protein greater than or equal to 0.2 g/dl
  * Urine monoclonal protein \>200 mg/24 hour
  * Serum immunoglobulin free light chain \>10 mg/dL AND abnormal kappa/lambda ratio
  * A measurable lesion on PET/CT or MRI
* Be greater than or equal to 18 years of age on day of signing informed consent

Note: The estimated 2017 US incidence of MM of patients under the age of 20 is 0.0%; therefore, children are excluded from enrollment in this study.

* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
* Adequate organ function as evidenced by the following laboratory parameters:

  * Absolute neutrophil count (ANC) greater than or equal to 1000 /mcL
  * Platelets greater than or equal to 75,000 / mcL
  * Hemoglobin greater than or equal to 8 g/dL (transfusions permitted)
  * Serum creatinine less than or equal to 1.5 X upper limit of normal (ULN) (except if due to myeloma)

OR

* Measured creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) formula may be used to estimate CrCl/eGFR greater than or equal to 30 mL/min/1.73 m(2) for subject with creatinine levels \> 1.5 X ULN
* Serum total bilirubin less than or equal to 1.5 X ULN OR Direct bilirubin less than or equal to ULN for patients with total bilirubin levels \> 1.5 ULN (except if due to myeloma)
* Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) less than or equal to 2.5 X ULN (except if due to myeloma)

  * The effects of avelumab on the developing human fetus are unknown, however, given the known role of Programmed Cell Death Ligand 1 (PD-1)/Programmed death-ligand 1 (PD-L1) in maintaining the maternal/fetal tolerance, avelumab can be expected to have an adverse effect on pregnancy, including embryo-lethality. Women of child-bearing potential (WOCBP) and men must agree to use highly effective contraception (such as implants, injectables, combined oral contraceptives, intrauterine device (IUDs), sexual abstinence or vasectomised partner) prior to study entry and for the duration of study treatment, and for at least 30 days after the last dose of avelumab. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

NOTE: WOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.

* Negative serum or urine pregnancy test at screening for WOCBP.
* Ability of patient to understand and the willingness to sign a written informed consent document

EXCLUSION CRITERIA:

* Patients with clinically unstable lesions (e.g., impending cord compression) where a delay in receiving radiation therapy (XRT) would be detrimental are not eligible
* Current or prior anti-cancer treatment prior to the first dose of avelumab as defined below:

  * Chemotherapy, targeted small molecule therapy, or other anti-cancer treatment not otherwise specified below within 2 weeks
  * Radiation therapy within 2 weeks
  * Anti-cancer monoclonal antibody (mAb) treatment within 4 weeks
  * Use of an investigational agent (e.g., biologic, drug, or other) within 4 weeks
  * Allogeneic stem cell transplant
* No autoimmune disease, as follows:

  * Active (acute or chronic) autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with type I diabetes, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment may be eligible.
  * History of serious autoimmune-related disorders including immune colitis, inflammatory bowel disease, pneumonitis, or pulmonary fibrosis whether drug- mediated or not.
* Current use of immunosuppressive medication, EXCEPT for the following:

  * Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection)
  * Systemic corticosteroids at physiologic doses
  * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
* Uncontrolled intercurrent illness including, but not limited to the following that may limit interpretation of results or that could increase risk to the patient in the judgment of the investigator:

  * Patients with a positive hepatitis B core antibody \[HBcAb\] and negative surface antigen (HBsAg) may be included if hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is undetectable
  * Patients who are positive for hepatitis C virus (HCV) antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation
  * Known acquired immunodeficiency syndrome (AIDS). Controlled and stable human immunodeficiency virus (HIV) positivity is allowed
  * Prior organ transplantation including allogenic stem-cell transplantation
  * Clinically significant cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (greater than or equal to New York Heart Association Classification Class III), or serious cardiac arrhythmia requiring medication. Mild arrhythmias, e.g. stable atrial fibrillation, may be allowed at the discretion of the investigator
  * Active infection requiring systemic therapy (minor infections may be allowed at the discretion of the investigator)
  * Known mental or physical illness that would interfere with cooperation with the requirements of the trial or confound the results or interpretation of the results of the trial and, in the opinion of the treating investigator, would make the patient inappropriate for entry into the study.
* Persisting toxicity related to prior therapy (Grade \> 1); however, alopecia, sensory neuropathy Grade less than or equal to 2, or other Grade less than or equal to 2 not constituting a safety risk based on investigator s judgment are acceptable.
* Vaccination with live vaccines within 4 weeks of the first dose of avelumab and while on study is prohibited (inactivated vaccines may be administered).
* Pregnant or lactating females. Because there is an unknown but potential risk for adverse events in nursing infants, on-study breastfeeding is not allowed.
* History of allergic reactions or hypersensitivity to avelumab or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (Grade greater than or equal to 3) unless felt to be in the best interests of the patient at the discretion of the investigator.
* Known additional malignancy that is symptomatic or requires active systemic treatment (at the discretion of the principal investigator (PI), exceptions may be made if in the best interest of the patient).
* Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.