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

• ClinicalTrials.gov Identifier: NCT03634800
• Recruitment Status: Terminated
• First Posted: August 16, 2018
• Results First Posted: August 5, 2021
• Last Update Posted: August 5, 2021
• Sponsor: Weill Medical College of Cornell University
• Information provided by (Responsible Party): Weill Medical College of Cornell University

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma	Drug: Nivolumab 240mg; Radiation: Radiation therapy	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6 participants
• Allocation: N/A
• 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)
• Primary Purpose: Treatment
• Official Title: Radiotherapy With Immunotherapy for Systemic Effect in Myeloma (RISE-M)
• Actual Study Start Date: October 23, 2018
• Actual Primary Completion Date: January 9, 2020
• Actual Study Completion Date: January 16, 2020

Arms and Interventions

Arm

Intervention/treatment

Experimental: nivolumab/radiotherapy; All eligible patients will receive immunotherapy (Nivolumab) plus radiotherapy (6 Gy x 5 fractions) to a targetable lesion.; Nivolumab 240 mg IV starts with the first radiotherapy fraction 240 mg IV every 2 weeks from first radiotherapy fraction until disease prograssion or dose limiting toxicity is reached; Radiotherapy Dose of 6 Gy x 5 days will be given (patients will receive 1 fraction over 5 days for a total of 5 fractions) during the first week of starting Nivolumab

Drug: Nivolumab 240mg; 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.; Other Name: Immunotherapy; Radiation: Radiation therapy; 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.

Outcome Measures

Primary Outcome Measures :

1. To Determine Overall Response at 12 Weeks Using International Myeloma Working Group (IMWG) Criteria in Patients Will be Measured [ Time Frame: 12 weeks ]
   The primary aim is to estimate the overall response at 12 weeks using IMWG criteria. Per IMWG response criteria, Complete Response (CR) is defined as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow; Very Good Partial Response (VGPR) is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or > 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h; Partial Response (PR) is defined as > 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >90% or to < 200 mg/24 h, No change/Stable disease is defined as not meeting criteria for CR, VGPR, PR, or progressive disease; Progressive disease (PD) is defined as an increase of > 25% from lowest response value; Relapse is define as development of new soft tissue plasmacytomas or Definite increase in the size of existing plasmacytomas or bone lesions.

Secondary Outcome Measures :

1. To Determine the Median Progression Free Survival (PFS) Will be Assessed in Patients Treated With Immunotherapy and Radiotherapy. [ Time Frame: through study completion ]
   Median progression free survival for patients treated with immunotherapy and radiotherapy will be assessed. Progression free survival (PFS) will be defined as the time from first treatment day until objective or symptomatic progression. PFS will be defined as the time from first treatment day until objective or symptomatic progression and PFS will be assessed by Kaplan-Meier survival analysis and 95% confidence interval.
2. To Determine the Median Overall Survival for Patients Treated With Immunotherapy and Radiotherapy Will be Assessed. [ Time Frame: through study completion ]
   Median overall survival for patients treated with immunotherapy and radiotherapy will be assessed. overall survival will be defined as the time from first treatment day until death. Overall survival will be assessed by Kaplan-Meier survival analysis and 95% confidence interval.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, New York

Weill Cornell Medicine

New York, New York, United States, 10065

Sponsors and Collaborators

Weill Medical College of Cornell University

Investigators

• Principal Investigator: Adriana Rossi, M.D.; Weill Cornell Medicine - New York Presbyterian Hospital
• Principal Investigator: Himanshu Nagar, M.D.; Weill Cornell Medicine - New York Presbyterian Hospital

  Study Documents (Full-Text)

Documents provided by Weill Medical College of Cornell University:

Study Protocol and Statistical Analysis Plan  [PDF] July 10, 2019

More Information

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT03634800
• Other Study ID Numbers: 1612017831
• First Posted: August 16, 2018
• Results First Posted: August 5, 2021
• Last Update Posted: August 5, 2021
• Last Verified: July 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action