Phase 2 Multi-center Study of Anti-PD-1 During Lymphopenic State After HDT/ASCT for Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
Multiple myeloma (MM) is a common incurable blood cancer causing debilitating symptoms-bone pain, kidney failure, low blood counts and infection. Chemotherapy outcomes are disappointing due to short-term response and long-term toxicities. Studies showed these patients have weak immune against MM due to the immune checkpoint mediated by the PD1/PD-L1 interaction between immune cells and MM. Anti-PD-1 antibody (anti-PD1) disrupts this interaction, thus unleashing immune cell function and leading to killing of MM cells. Studies further showed enhancement of this unleash after autologous transplant and better MM control by anti-PD1 when used after transplant. Anti-PD1 has been extensively studied in patients with other cancers. It is very safe and effective and has been FDA-approved. Complications are of mild degree and easy to manage successfully in out-patient setting. Severe complications are rare. Thus, investigators proposed an efficacy study of anti-PD1 treatment after transplant to improve MM treatment outcomes. This was a collaborative study with Medical College of Wisconsin (headquarter of Center for International blood and Marrow Transplant Research). Investigators hypothesized that anti-PD1 treatment would increase the MM response and the MM control duration when added to the standard MM treatment after transplant. Anti-PD1 was given at the dose and interval, which had been studied previously (200 mg intravenous injection every 3 weeks) between 2 weeks until 6 months after transplant. Subjects were monitored closely during and after anti-PD1 therapy until at least 1 year post transplant. Late complications were followed for 3 years.

Official Title
-----------------
Phase 2 Multi-center Study of Anti-Programmed-Death-1 [Anti-PD-1] During Lymphopenic State After High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplant [HDT/ASCT] for Multiple Myeloma

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Procedure: Autologous Stem Cell Transplant
* Drug: Melphalan
* Drug: Lenalidomide
* Drug: MK-3475


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with MM (Multiple Myeloma) of any stage Has no Progressive Disease (PD) AND has suboptimal response with primary therapy Has measurable disease Has no prior hematopoietic stem cell transplant of any type Has performance status of 0 or 1 (Eastern Cooperative Oncology, ECOG, Performance Scale) Has had a successful peripheral blood stem cell collection with G-CSF (Filgrastim) +/- Plerixafor (Mozobil) only Be willing and able to provide written informed consent Female subjects of child bearing age should have negative urine or serum pregnancy test Female subjects of child bearing age must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity Male subjects must agree to use an adequate method of contraception Subject must be able to swallow capsules Must demonstrate adequate organ function Exclusion Criteria: Has history of repeat infections, amyloidosis, hyperviscosity, plasma cell leukemia, POEMS syndrome, Waldenstrom's macroglobulinemia, non-secretory multiple myeloma, or IgM myeloma Has known CNS (Central Nervous System) involvement or history of resolved CNS involvement Has an active autoimmune disease or history of autoimmune disease that requires systemic treatment with steroids of immunosuppressive agents. Has active, non-infectious pneumonitis Has diagnosis of immunosuppressive disorder or on immunosuppressive therapy within 7 days of transplant admission Is currently participating in or has previously participated in the study of an investigational drug/device within 4 weeks of transplant admission Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or CTLA-4 Has had prior monoclonal antibody, chemotherapy, small molecule therapy, or radiation within 2 weeks of transplant admission Has not recovered from adverse events due to previously administered agent Must be free of additional malignancy for at least 5 years Has an active infection requiring systemic therapy Has known psychiatric or substance abuse disorders that would interfere with requirements of the study Is pregnant or breastfeeding or expecting to conceive Has known HIV, Hepatitis B, or Hepatitis C infection Has clinically significant coagulopathy Has known symptomatic heart failure, unstable angina pectoris, or cardiac arrhythmia Has received any type of hematopoietic cell transplant Has received a live vaccine within 30 days of transplant admission Is or has an immediate family member whos is investigational site or sponsor staff directly involved with this study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-PD-1 (MK-3475)<br>Standard Treatment: High-dose Melphalan and autologous stem cell transplantation with post-transplant maintenance of Lenalidomide. Study Treatment: 200 mg/day of MK-3475 administered every 3 weeks, starting day +14 post-transplant for a total of 9 doses. | Procedure: Autologous Stem Cell Transplant<br> <br> Drug: Melphalan<br>* 140-200 mg/m^2<br>Drug: Lenalidomide<br>* 5-15 mg/day starting 45-90 days post-transplant<br>Drug: MK-3475<br>* 200 mg/day every 3 weeks starting day +14 post-transplant for a total of 9 doses.<br>* Other names: Pembrolizumab;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Patients That Achieve Complete Response | The primary efficacy endpoint is complete response rate. The complete response rate was estimated by the observed proportion of complete responders at day 180. Complete response (CR) was defined as negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow and negative bone marrow flow cytometry. | 180 days post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Estimated Percentage of Patients Alive Without Relapse or Progression at 2 Years | Progression is defined as an increase of ≥ 25% from the lowest response value in any one or more of the following: Serum M-component with an absolute increase ≥ 0.5 g/dL; and/or Urine M-component with an absolute increase ≥ 200 mg/24 hours; and/or Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be >100mg/l) Bone marrow plasma cell percentage (absolute % must be ≥10% Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcemia (corrected serum calcium >11.5mg/100ml) that can be attributed solely to the plasma cell proliferative disorder | 2 Years | 
| The Estimated Percentage of Patients Alive at 2 Years |  | 2 Years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Multiple Myeloma, Anti-PD-1, Pembrolizumab, Post-transplant, Maintenance