Radiotherapy With Immunotherapy for Systemic Effect in Myeloma (RISE-M)

Inclusion Criteria:

1. Subject is, in the investigator's opinion, willing and able to comply with the protocol requirements.
2. Subject has given voluntary written informed consent before performance of any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to their future medical care.
3. Must have received 2 consecutive cycles of systemic myeloma therapy.
4. Documented refractory or relapsed and refractory (R/R) multiple myeloma

   1. patients had less than minimal response, or had achieved at least a minimal response to previous treatment, but progressed within 6 months
   2. patients must have failed, be intolerant or are ineligible to treatment with an IMiD, proteasome inhibitor and anti-CD38 agent
5. Targetable plasmacytoma, either intra-or extramedullary that is visualized on imaging (PET/CT or MRI) and is causing symptoms (eg. pain, neurological compromise) or potential to cause symptom as per clinician's judgement; and measurable disease at screening, defined as one or more of the following:

   1. Serum IgG, IgA, or IgM M-protein ≥ 0.5 g/dL
   2. Urine M-Protein ≥ 200 mg excreted in a 24-hour collection sample
   3. Involved serum free light chain (sFLC) \> 100 mg/L provided the FLC ratio is abnormal
6. Males and Females at least 18 years or legal age of consent per local regulations.
7. Women of childbearing potential (WOCBP) must have two negative serum or urine pregnancy tests (minimum sensitivity 25 mIU/mL or equivalent units of HCG). One 10-14 days prior to start of the study drug and one within 24 hours prior to the start of study drug.
8. Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of \< 1% when used consistently and correctly.
9. No condition which would cause unacceptable risk.

Exclusion Criteria:

1. Subjects with solitary bone or extramedullary plasmacytoma as the only evidence of plasm cell dyscrasia.
2. Subjects with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), Waldenstrom's macroglobulinemia, or POEMS syndrome (plasma cell dyscrasia with poly neuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
3. Subjects with active plasma cell leukemia (defined as either 20% of peripheral blood white blood cell count comprised of plasma/CD138+ cells or an absolute plasma cell count of 2 x 109/L).
4. Subjects within 100 days of stem cell transplantation.
5. Subjects within 4 weeks of surgery, unless cleared by surgeon.
6. Women who are of childbearing potential not complying to the above described contraceptive measures or are breastfeeding, and sexually active fertile men whose partners are WOCBP if they are not complying to the above described contraceptive measures.
7. Any uncontrolled or severe cardiovascular or pulmonary disease determined by the investigator, including:

   1. NYHA functional classification III or IV, congestive heart failure, unstable or poorly controlled angina, uncontrolled hypertension, arrhythmia, or myocardial infarction in the past 12 months
   2. Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
8. Active infection or know HBV/HCV/HIV.
9. Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
10. Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of initiation of study drug. Inhaled or topical steroids, and adrenal replacement steroid doses \> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
11. Previous radiotherapy to the area of the target area.
12. Prior exposure to immunotherapy.