Tadalafil and Lenalidomide Maintenance With or Without Activated Marrow Infiltrating Lymphocytes (MILs) in High Risk Myeloma
Study Details
Study Description
Brief Summary
This research is being done to find out if altering the immune system by giving activated marrow infiltrating lymphocytes (MILs) can improve outcomes for multiple myeloma patients who receive a standard autologous stem cell transplant.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: aMIL Arm Patients receive activated Marrow Infiltrating Lymphocytes (aMIL) |
Biological: aMIL
On day 0, patients will receive auto transplant followed by Tadalafil and aMIL. At day 60, patients will receive Lenalidomide.
Drug: No aMIL
On day 0, patients will receive auto transplant followed by Tadalafil. At day 60, patients will receive Lenalidomide.
|
| Active Comparator: No aMIL Patients do not receive activated Marrow Infiltrating Lymphocytes (aMIL) |
Drug: No aMIL
On day 0, patients will receive auto transplant followed by Tadalafil. At day 60, patients will receive Lenalidomide.
|
Outcome Measures
Primary Outcome Measures
- Feasibility of MILs as Assessed by the Ability to Harvest, Expand, and Infuse the MILs Product [120 days]
Feasibility is defined as the ability to harvest, expand, and infuse the MILs product within 120 days. After treating 60 patients with MILs, we will declare MILs not feasible if we can only harvest, expand, and deliver MILs to 40 or fewer patients.
Secondary Outcome Measures
- Toxicity as Determined by Total Number of Grade 3 or Higher Adverse Events [60 days from aMILs harvest until day 60 after transplant]
Total number of adverse events grade 3 or higher that occur from MILs harvest through 60 days after transplant.
- Overall Survival (OS) [3 years]
OS assessed by number of participants alive at the end of follow up period.
- Progression-free Survival (PFS) [5 years]
Median PFS time equals the time of randomization (in months) until disease progression, death from any cause, or protocol deviation due to lenalidomide dosing (above 10mg), whichever occurs first.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age 18 - 80 years old;
-
Patients with active myeloma requiring systemic treatment;
-
Newly diagnosed patients. Relapsed myeloma patients that have not previously had a transplant;
-
Meeting criteria for high-risk disease;
-
Measurable serum and/or urine M-protein from prior to induction therapy documented and available. A positive serum free lite assay is acceptable;
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 (see Appendix C).
-
Meet all institutional requirements for autologous stem cell transplantation;
-
The patient must be able to comprehend and have signed the informed consent;
-
Patients must have had > than PR after last therapy.
Exclusion Criteria:
-
Diagnosis of any of the following cancers:
-
POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein] and skin changes);
-
Non-secretory myeloma (no measurable protein on Serum Free Lite Assay);
-
Plasma cell leukemia;
-
Diagnosis of amyloidosis;
-
Failed to achieve at least a partial response (PR) to latest therapy;
-
Previous hematopoietic stem cell transplantation;Patients can have had prior relapsed disease as long as they have never been previously transplanted;
-
Known history of HIV infection;
-
Use of corticosteroids (glucocorticoids) within 21 days of bone marrow collection;
-
Use of any myeloma-specific therapy within 21 days of bone marrow collection;
-
Infection requiring treatment with antibiotics, antifungal, or antiviral agents within seven days of registration;
-
Participation in any clinical trial within 28 days of registration on this trial, which involved an investigational drug or device;
-
History of malignancy other than multiple myeloma within five years of registration, except adequately treated basal or squamous cell skin cancer;
-
Active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosis) requiring active systemic treatment. Hypothyroidism without evidence of Grave's disease or Hashimoto's thyroiditis is permitted.
-
Human T-lymphotropic virus (HTLV) 1 or 2 positive;
-
Known hypersensitivity to Prevnar or any of its components;
-
Contraindication to phosphodiesterase-5 inhibitors (e.g. currently on nitrates).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore | Maryland | United States | 21231 |
Sponsors and Collaborators
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- The Leukemia and Lymphoma Society
Investigators
- Principal Investigator: Philip Imus, M.D., Johns Hopkins University
Study Documents (Full-Text)
More Information
Publications
None provided.- J1343
- NA_00084466
Study Results
Participant Flow
| Recruitment Details | Participants were enrolled at four sites: Johns Hopkins University, Moffitt Cancer Center, Mayo Clinic (Jacksonville) and the Blood and Marrow Transplant Group of Georgia (Northside). |
|---|---|
| Pre-assignment Detail | Of the 102 patients randomized, one was randomized to the control group who was lost to follow-up prior to start; did not have aMILs harvested, and was not transplanted. This patient is therefore not included in this report. |
| Arm/Group Title | aMIL Arm | No aMIL |
|---|---|---|
| Arm/Group Description | Patients receive activated Marrow Infiltrating Lymphocytes (aMIL) aMIL: On day 0, patients will receive auto transplant followed by Tadalafil and aMIL. At day 60, patients will receive Lenalidomide. | Patients do not receive activated Marrow Infiltrating Lymphocytes (aMIL) No aMIL: On day 0, patients will receive auto transplant followed by Tadalafil. At day 60, patients will receive Lenalidomide. |
| Period Title: Overall Study | ||
| STARTED | 70 | 31 |
| COMPLETED | 61 | 29 |
| NOT COMPLETED | 9 | 2 |
Baseline Characteristics
| Arm/Group Title | aMIL Arm | No aMIL | Total |
|---|---|---|---|
| Arm/Group Description | Patients receive activated Marrow Infiltrating Lymphocytes (aMIL) aMIL: On day 0, patients will receive auto transplant followed by Tadalafil and aMIL. At day 60, patients will receive Lenalidomide. | Patients do not receive activated Marrow Infiltrating Lymphocytes (aMIL) No aMIL: On day 0, patients will receive auto transplant followed by Tadalafil. At day 60, patients will receive Lenalidomide. | Total of all reporting groups |
| Overall Participants | 70 | 31 | 101 |
| Age (years) [Median (Inter-Quartile Range) ] | |||
| Median (Inter-Quartile Range) [years] |
62.5
|
59.0
|
61.7
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
36
51.4%
|
15
48.4%
|
51
50.5%
|
| Male |
34
48.6%
|
16
51.6%
|
50
49.5%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| Asian |
1
1.4%
|
1
3.2%
|
2
2%
|
| Black |
14
20%
|
8
25.8%
|
22
21.8%
|
| Other |
2
2.9%
|
1
3.2%
|
3
3%
|
| White |
53
75.7%
|
21
67.7%
|
74
73.3%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
70
100%
|
31
100%
|
101
100%
|
| Disease Status (Count of Participants) | |||
| Newly Diagnosed |
60
85.7%
|
26
83.9%
|
86
85.1%
|
| Relapsed |
10
14.3%
|
5
16.1%
|
15
14.9%
|
| Myeloma Prognostic Risk Signature (MYPRS) Risk Category (Count of Participants) | |||
| High Risk |
12
17.1%
|
4
12.9%
|
16
15.8%
|
| Low Risk |
25
35.7%
|
15
48.4%
|
40
39.6%
|
| N/A |
8
11.4%
|
2
6.5%
|
10
9.9%
|
| Indeterminate |
25
35.7%
|
10
32.3%
|
35
34.7%
|
| 70-gene expression Prognostic Risk Score (GEP-70) (Count of Participants) | |||
| Not High Risk |
58
82.9%
|
27
87.1%
|
85
84.2%
|
| High Risk |
12
17.1%
|
4
12.9%
|
16
15.8%
|
| Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants) | |||
| 0 |
27
38.6%
|
7
22.6%
|
34
33.7%
|
| 1 or 2 |
34
48.6%
|
21
67.7%
|
55
54.5%
|
| Missing |
9
12.9%
|
3
9.7%
|
12
11.9%
|
| International Staging System (ISS) Multiple Myeloma Classification (Count of Participants) | |||
| Stage I |
20
28.6%
|
10
32.3%
|
30
29.7%
|
| Stage II |
19
27.1%
|
7
22.6%
|
26
25.7%
|
| Stage III |
17
24.3%
|
8
25.8%
|
25
24.8%
|
| missing |
14
20%
|
6
19.4%
|
20
19.8%
|
| Salmon Stage multiple myeloma classification (Count of Participants) | |||
| IA-IB |
9
12.9%
|
0
0%
|
9
8.9%
|
| IIA-IIB |
14
20%
|
7
22.6%
|
21
20.8%
|
| IIIA-IIIB |
35
50%
|
21
67.7%
|
56
55.4%
|
| missing |
12
17.1%
|
3
9.7%
|
15
14.9%
|
| Number of Prior Multiple Myeloma Treatments (prior treatments) [Median (Inter-Quartile Range) ] | |||
| Median (Inter-Quartile Range) [prior treatments] |
1
|
2
|
1
|
| Time to Diagnosis (years) [Median (Inter-Quartile Range) ] | |||
| Median (Inter-Quartile Range) [years] |
0.53
|
0.76
|
0.55
|
| Time to stem cell transplant (SCT) (Days) [Median (Inter-Quartile Range) ] | |||
| Median (Inter-Quartile Range) [Days] |
63.0
|
56.0
|
60.0
|
Outcome Measures
| Title | Feasibility of MILs as Assessed by the Ability to Harvest, Expand, and Infuse the MILs Product |
|---|---|
| Description | Feasibility is defined as the ability to harvest, expand, and infuse the MILs product within 120 days. After treating 60 patients with MILs, we will declare MILs not feasible if we can only harvest, expand, and deliver MILs to 40 or fewer patients. |
| Time Frame | 120 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| 71 patients were evaluable in the feasibility set: 70 randomized to the aMILs Arm, plus one patient who was not randomized due to harvest failure. |
| Arm/Group Title | aMIL Arm |
|---|---|
| Arm/Group Description | Patients receive activated Marrow Infiltrating Lymphocytes (aMIL) aMIL: On day 0, patients will receive auto transplant followed by Tadalafil and aMIL. At day 60, patients will receive Lenalidomide. |
| Measure Participants | 71 |
| Total number who received aMILS |
71
101.4%
|
| Feasible |
46
65.7%
|
| Reason not feasible- failed harvest |
1
1.4%
|
| Reason not feasible- disease progression |
4
5.7%
|
| Reason not feasible- death |
1
1.4%
|
| Reason not feasible- lost to follow-up |
1
1.4%
|
| Reason not feasible- failed expansion |
2
2.9%
|
| Reason not feasible- cell product contamination |
2
2.9%
|
| Reason not feasible- greater than 120 days |
14
20%
|
| Title | Toxicity as Determined by Total Number of Grade 3 or Higher Adverse Events |
|---|---|
| Description | Total number of adverse events grade 3 or higher that occur from MILs harvest through 60 days after transplant. |
| Time Frame | 60 days from aMILs harvest until day 60 after transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | aMIL Arm | No aMIL |
|---|---|---|
| Arm/Group Description | Patients receive activated Marrow Infiltrating Lymphocytes (aMIL) aMIL: On day 0, patients will receive auto transplant followed by Tadalafil and aMIL. At day 60, patients will receive Lenalidomide. | Patients do not receive activated Marrow Infiltrating Lymphocytes (aMIL) No aMIL: On day 0, patients will receive auto transplant followed by Tadalafil. At day 60, patients will receive Lenalidomide. |
| Measure Participants | 70 | 31 |
| Number [adverse events] |
129
|
65
|
| Title | Overall Survival (OS) |
|---|---|
| Description | OS assessed by number of participants alive at the end of follow up period. |
| Time Frame | 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| This is an analysis by intention-to-treat and only considers transplanted patients randomized to the aMILs arm. |
| Arm/Group Title | aMIL Arm |
|---|---|
| Arm/Group Description | Patients receive activated Marrow Infiltrating Lymphocytes (aMIL) aMIL: On day 0, patients will receive auto transplant followed by Tadalafil and aMIL. At day 60, patients will receive Lenalidomide. |
| Measure Participants | 70 |
| Count of Participants [Participants] |
55
78.6%
|
| Title | Progression-free Survival (PFS) |
|---|---|
| Description | Median PFS time equals the time of randomization (in months) until disease progression, death from any cause, or protocol deviation due to lenalidomide dosing (above 10mg), whichever occurs first. |
| Time Frame | 5 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| This is an analysis by intention-to-treat and only considers transplanted patients randomized to the aMILs arm. |
| Arm/Group Title | aMIL Arm |
|---|---|
| Arm/Group Description | Patients receive activated Marrow Infiltrating Lymphocytes (aMIL) aMIL: On day 0, patients will receive auto transplant followed by Tadalafil and aMIL. At day 60, patients will receive Lenalidomide. |
| Measure Participants | 70 |
| Median (Inter-Quartile Range) [months] |
21.82
|
Adverse Events
| Time Frame | 60 Days from aMILs harvest until Day 60 after transplant | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | aMIL Arm | No aMIL | ||
| Arm/Group Description | Patients receive activated Marrow Infiltrating Lymphocytes (aMIL) aMIL: On day 0, patients will receive auto transplant followed by Tadalafil and aMIL. At day 60, patients will receive Lenalidomide. | Patients do not receive activated Marrow Infiltrating Lymphocytes (aMIL) No aMIL: On day 0, patients will receive auto transplant followed by Tadalafil. At day 60, patients will receive Lenalidomide. | ||
All Cause Mortality |
||||
| aMIL Arm | No aMIL | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/70 (1.4%) | 1/31 (3.2%) | ||
Serious Adverse Events |
||||
| aMIL Arm | No aMIL | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 64/70 (91.4%) | 29/31 (93.5%) | ||
| Blood and lymphatic system disorders | ||||
| Febrile neutropenia | 36/70 (51.4%) | 45 | 18/31 (58.1%) | 22 |
| Anemia | 3/70 (4.3%) | 3 | 0/31 (0%) | 0 |
| Pancytopenia | 2/70 (2.9%) | 2 | 0/31 (0%) | 0 |
| lymphocyte count decreased | 1/70 (1.4%) | 1 | 1/31 (3.2%) | 2 |
| neutrophil count decreased | 7/70 (10%) | 10 | 3/31 (9.7%) | 4 |
| platelet count decreased | 3/70 (4.3%) | 7 | 4/31 (12.9%) | 4 |
| white blood cell decreased | 2/70 (2.9%) | 4 | 1/31 (3.2%) | 1 |
| Cardiac disorders | ||||
| Atrial Fibrillation | 1/70 (1.4%) | 1 | 1/31 (3.2%) | 2 |
| ventricular arrhythmia | 1/70 (1.4%) | 1 | 0/31 (0%) | 0 |
| Gastrointestinal disorders | ||||
| Colitis | 1/70 (1.4%) | 1 | 0/31 (0%) | 0 |
| Diarrhea | 8/70 (11.4%) | 8 | 1/31 (3.2%) | 1 |
| Esophagitis | 1/70 (1.4%) | 1 | 0/31 (0%) | 0 |
| Gastric ulcer | 0/70 (0%) | 0 | 1/31 (3.2%) | 1 |
| nausea | 1/70 (1.4%) | 2 | 2/31 (6.5%) | 3 |
| vomiting | 0/70 (0%) | 0 | 2/31 (6.5%) | 2 |
| General disorders | ||||
| Fatigue | 2/70 (2.9%) | 2 | 0/31 (0%) | 0 |
| fever | 4/70 (5.7%) | 4 | 1/31 (3.2%) | 1 |
| Infections and infestations | ||||
| Enterocolitis infection | 0/70 (0%) | 0 | 1/31 (3.2%) | 1 |
| bacteremia | 3/70 (4.3%) | 3 | 2/31 (6.5%) | 2 |
| lung infection | 2/70 (2.9%) | 2 | 2/31 (6.5%) | 2 |
| mucosal infection | 11/70 (15.7%) | 11 | 5/31 (16.1%) | 5 |
| Scrotal Infection | 1/70 (1.4%) | 1 | 0/31 (0%) | 0 |
| Sepsis | 2/70 (2.9%) | 2 | 0/31 (0%) | 0 |
| upper respiratory infection | 1/70 (1.4%) | 1 | 1/31 (3.2%) | 1 |
| Injury, poisoning and procedural complications | ||||
| Device related infection | 0/70 (0%) | 0 | 1/31 (3.2%) | 1 |
| Metabolism and nutrition disorders | ||||
| dehydration | 1/70 (1.4%) | 1 | 0/31 (0%) | 0 |
| hypocalcemia | 1/70 (1.4%) | 1 | 0/31 (0%) | 0 |
| hypophosphatemia | 4/70 (5.7%) | 5 | 0/31 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Back Pain | 1/70 (1.4%) | 1 | 1/31 (3.2%) | 2 |
| Bone Pain | 3/70 (4.3%) | 3 | 0/31 (0%) | 0 |
| Nervous system disorders | ||||
| headache | 1/70 (1.4%) | 1 | 0/31 (0%) | 0 |
| Stroke | 0/70 (0%) | 0 | 1/31 (3.2%) | 1 |
| syncope | 2/70 (2.9%) | 2 | 2/31 (6.5%) | 2 |
| Renal and urinary disorders | ||||
| Acute Kidney Injury | 0/70 (0%) | 0 | 1/31 (3.2%) | 1 |
| Kidney infection | 0/70 (0%) | 0 | 1/31 (3.2%) | 1 |
| renal calculi | 0/70 (0%) | 0 | 1/31 (3.2%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| hypoxia | 1/70 (1.4%) | 1 | 0/31 (0%) | 0 |
| Vascular disorders | ||||
| hypotension | 1/70 (1.4%) | 1 | 1/31 (3.2%) | 1 |
| thromboembolic event | 1/70 (1.4%) | 1 | 1/31 (3.2%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| aMIL Arm | No aMIL | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 11/70 (15.7%) | 0/31 (0%) | ||
| General disorders | ||||
| infusion related reaction | 8/63 (12.7%) | 8 | 0/31 (0%) | 0 |
| Product Issues | ||||
| manufacture failure | 2/70 (2.9%) | 2 | 0/31 (0%) | 0 |
| product contamination | 1/70 (1.4%) | 1 | 0/31 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Philip Imus, MD |
|---|---|
| Organization | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins |
| Phone | 410-955-8873 |
| pimus1@jhmi.edu |
- J1343
- NA_00084466