Radiotherapy With Immunotherapy for Systemic Effect in Myeloma (RISE-M)
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Nivolumab 240mg; Radiation therapy
Intervention description: Patients with multiple myeloma will receive Nivolumab intravenously at 240 mg every two weeks. Infusions will be given over 60 minutes (not bolus or IV push). Patients will continue to receive infusions every two weeks until disease progression or dose limiting toxicity is reached.; Patients will receive radiation for 5 consecutive days. A dose of 6 Gy x 5 days will be administered. Patients may receive radiotherapy to an additional site at 12 weeks if they have stable disease.
Intervention MeSH terms: Nivolumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Patients with multiple myeloma will receive Nivolumab intravenously at 240 mg every two weeks. Infusions will be given over 60 minutes (not bolus or IV push). Patients will continue to receive infusions every two weeks until disease progression or dose limiting toxicity is reached. Patients will receive radiation for 5 consecutive days. A dose of 6 Gy x 5 days will be administered. Patients may receive radiotherapy to an additional site at 12 weeks if they have stable disease.
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Maximum age: 90 Years
Healthy volunteers: No

Summary:

      Eligible patients have multiple myeloma with measurable disease in the blood and a targetable
      soft tissue or bony lesion with radiotherapy. All eligible patients will receive
      immunotherapy (Nivolumab) plus radiotherapy, 6 Gy x 5 fractions, to a targetable lesion.
      Immunotherapy treatment starts with the first radiotherapy fraction. Nivolumab will be given
      every 2 weeks. Patients will have specified laboratory values measured bi-monthly and
      evaluated for response at 12 weeks as defined by International Myeloma Working Group
      Criteria. Patients will continue to receive their respective immunotherapy until disease
      progression or dose limiting toxicity is reached.
    

Eligibility criteria:

        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.