Tadalafil and Lenalidomide Maintenance With or Without Activated Marrow Infiltrating Lymphocytes (MILs) in High Risk Myeloma

• ClinicalTrials.gov Identifier: NCT01858558
• Recruitment Status: Completed
• First Posted: May 21, 2013
• Results First Posted: June 29, 2020
• Last Update Posted: June 29, 2020
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborator: The Leukemia and Lymphoma Society
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma
• Interventions: Biological: aMIL; Drug: No aMIL
• Enrollment: 102

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 Details	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
Reason Not Completed
Death	1	1
Lost to Follow-up	1	0
Disease progression	3	1
Product contamination	2	0
Failed expansion of cell product	2	0

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 Number of Baseline Participants		70	31	101
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Inter-Quartile Range); Unit of measure: Years
	Number Analyzed	70 participants	31 participants	101 participants
		62.5; (35.0 to 74.8)	59.0; (37.1 to 75.9)	61.7; (35.0 to 75.9)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	70 participants	31 participants	101 participants
	Female	36 51.4%	15 48.4%	51 50.5%
	Male	34 48.6%	16 51.6%	50 49.5%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	70 participants	31 participants	101 participants
Asian		1 1.4%	1 3.2%	2 2.0%
Black		14 20.0%	8 25.8%	22 21.8%
Other		2 2.9%	1 3.2%	3 3.0%
White		53 75.7%	21 67.7%	74 73.3%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	70 participants	31 participants	101 participants
		70	31	101
Disease Status; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	70 participants	31 participants	101 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 [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	70 participants	31 participants	101 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%
		[1] Measure Description: The Myeloma Prognostic Risk Signature (MyPRS®) (Signal Genetics™) is used to estimate the underlying activity of disease progression in patients diagnosed with active multiple myeloma.
70-gene expression Prognostic Risk Score (GEP-70) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	70 participants	31 participants	101 participants
	Not High Risk	58 82.9%	27 87.1%	85 84.2%
	High Risk	12 17.1%	4 12.9%	16 15.8%
		[1] Measure Description: The 70-gene Prognostic Risk Score (GEP-70) quantifies the expression of 70 genes commonly altered in multiple myeloma. Primarily prognostic, GEP-70 assesses risk of disease relapse and survival outcomes and is the randomization stratification of the MYPRS multiple myeloma specific gene expression profile risk categories.
Eastern Cooperative Oncology Group (ECOG) Performance Status [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	70 participants	31 participants	101 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%
		[1] Measure Description: ECOG Scoring System 0= Fully active, able to carry on all pre-disease performance without restriction; Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours; Capable of only limited self care, confined to bed or chair more than 50% of waking hours; Completely disabled. Cannot carry on any self care. Totally confined to bed or chair; Dead
International Staging System (ISS) Multiple Myeloma Classification [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	70 participants	31 participants	101 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 20.0%	6 19.4%	20 19.8%
		[1] Measure Description: Prognosticates the severity of multiple myeloma and patient survival based on routinely obtained lab values. Stage I= Serum β2 microglobulin < 3.5 mg/l; serum albumin ≥ 3.5 g/dl; standard-risk chromosomal abnormalities (CA) and normal lactate dehydrogenase (LDH) Stage II= not stage I or Stage III Stage III= Serum β2 microglobulin ≥ 5.5 mg/L and either high-risk CA by florescent in situ hybridization (FISH) or high LDH
Salmon Stage multiple myeloma classification [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	70 participants	31 participants	101 participants
	IA-IB	9 12.9%	0 0.0%	9 8.9%
	IIA-IIB	14 20.0%	7 22.6%	21 20.8%
	IIIA-IIIB	35 50.0%	21 67.7%	56 55.4%
	missing	12 17.1%	3 9.7%	15 14.9%
		[1] Measure Description: demonstrates the correlation between the amount of myeloma and the damage it has caused based on number of bone lesions, anemia, serum calcium levels, and serum and urine light chain levels, and can be measured as myeloma cell mass (myeloma cells in billions/m2)* . Stage I= low cell mass (600 billion) Stage II= intermediate cell mass (600-1200 billion) Stage III= high cell mass (>1200 billion) Subcategory: A = normal renal function. B= abnormal renal function
Number of Prior Multiple Myeloma Treatments; Median (Inter-Quartile Range); Unit of measure: Prior treatments
	Number Analyzed	70 participants	31 participants	101 participants
		1; (1 to 6)	2; (1 to 5)	1; (1 to 6)
Time to Diagnosis; Median (Inter-Quartile Range); Unit of measure: Years
	Number Analyzed	70 participants	31 participants	101 participants
		0.53; (0.07 to 8.15)	0.76; (0.38 to 4.80)	0.55; (0.07 to 8.15)
Time to stem cell transplant (SCT); Median (Inter-Quartile Range); Unit of measure: Days
	Number Analyzed	70 participants	31 participants	101 participants
		63.0; (35.0 to 403.0)	56.0; (33.0 to 246.0)	60.0; (33.0 to 403.0)

Outcome Measures

1. Primary Outcome

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.
Overall Number of Participants Analyzed	71
Measure Type: Count of Participants; Unit of Measure: Participants
Total number who received aMILS	71 100.0%
Feasible	46 64.8%
Reason not feasible- failed harvest	1 1.4%
Reason not feasible- disease progression	4 5.6%
Reason not feasible- death	1 1.4%
Reason not feasible- lost to follow-up	1 1.4%
Reason not feasible- failed expansion	2 2.8%
Reason not feasible- cell product contamination	2 2.8%
Reason not feasible- greater than 120 days	14 19.7%

2. Secondary Outcome

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.
Overall Number of Participants Analyzed	70	31
Measure Type: Number; Unit of Measure: adverse events
	129	65

3. Secondary Outcome

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.
Overall Number of Participants Analyzed	70
Measure Type: Count of Participants; Unit of Measure: Participants
	55 78.6%

4. Secondary Outcome

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.
Overall Number of Participants Analyzed	70
Median (Inter-Quartile Range); Unit of Measure: months
	21.82; (18.53 to 41.82)

Adverse Events

Time Frame	60 Days from aMILs harvest until Day 60 after transplant
Adverse Event Reporting 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.
All-Cause Mortality
	aMIL Arm		No aMIL
	Affected / at Risk (%)		Affected / at Risk (%)
Total	1/70 (1.43%)		1/31 (3.23%)
Serious Adverse Events
	aMIL Arm		No aMIL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	64/70 (91.43%)		29/31 (93.55%)
Blood and lymphatic system disorders
Febrile neutropenia * 1 [1]	36/70 (51.43%)	45	18/31 (58.06%)	22
Anemia * 1 [2]	3/70 (4.29%)	3	0/31 (0.00%)	0
Pancytopenia * 1 [2]	2/70 (2.86%)	2	0/31 (0.00%)	0
lymphocyte count decreased * 1 [2]	1/70 (1.43%)	1	1/31 (3.23%)	2
neutrophil count decreased * 1 [2]	7/70 (10.00%)	10	3/31 (9.68%)	4
platelet count decreased * 1 [2]	3/70 (4.29%)	7	4/31 (12.90%)	4
white blood cell decreased * 1	2/70 (2.86%)	4	1/31 (3.23%)	1
Cardiac disorders
Atrial Fibrillation * 1 [2]	1/70 (1.43%)	1	1/31 (3.23%)	2
ventricular arrhythmia * 1 [2]	1/70 (1.43%)	1	0/31 (0.00%)	0
Gastrointestinal disorders
Colitis * 1 [2]	1/70 (1.43%)	1	0/31 (0.00%)	0
Diarrhea * 1 [2]	8/70 (11.43%)	8	1/31 (3.23%)	1
Esophagitis * 1 [2]	1/70 (1.43%)	1	0/31 (0.00%)	0
Gastric ulcer * 1 [2]	0/70 (0.00%)	0	1/31 (3.23%)	1
nausea * 1 [2]	1/70 (1.43%)	2	2/31 (6.45%)	3
vomiting * 1 [2]	0/70 (0.00%)	0	2/31 (6.45%)	2
General disorders
Fatigue * 1 [2]	2/70 (2.86%)	2	0/31 (0.00%)	0
fever * 1 [2]	4/70 (5.71%)	4	1/31 (3.23%)	1
Infections and infestations
Enterocolitis infection * 1 [2]	0/70 (0.00%)	0	1/31 (3.23%)	1
bacteremia * 1 [2]	3/70 (4.29%)	3	2/31 (6.45%)	2
lung infection * 1 [2]	2/70 (2.86%)	2	2/31 (6.45%)	2
mucosal infection * 1 [2]	11/70 (15.71%)	11	5/31 (16.13%)	5
Scrotal Infection * 1 [2]	1/70 (1.43%)	1	0/31 (0.00%)	0
Sepsis * 1 [2]	2/70 (2.86%)	2	0/31 (0.00%)	0
upper respiratory infection * 1 [2]	1/70 (1.43%)	1	1/31 (3.23%)	1
Injury, poisoning and procedural complications
Device related infection * 1 [2]	0/70 (0.00%)	0	1/31 (3.23%)	1
Metabolism and nutrition disorders
dehydration * 1 [2]	1/70 (1.43%)	1	0/31 (0.00%)	0
hypocalcemia * 1 [2]	1/70 (1.43%)	1	0/31 (0.00%)	0
hypophosphatemia * 1 [2]	4/70 (5.71%)	5	0/31 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back Pain * 1 [2]	1/70 (1.43%)	1	1/31 (3.23%)	2
Bone Pain * 1 [2]	3/70 (4.29%)	3	0/31 (0.00%)	0
Nervous system disorders
headache * 1 [2]	1/70 (1.43%)	1	0/31 (0.00%)	0
Stroke * 1 [2]	0/70 (0.00%)	0	1/31 (3.23%)	1
syncope * 1 [2]	2/70 (2.86%)	2	2/31 (6.45%)	2
Renal and urinary disorders
Acute Kidney Injury * 1 [2]	0/70 (0.00%)	0	1/31 (3.23%)	1
Kidney infection * 1 [2]	0/70 (0.00%)	0	1/31 (3.23%)	1
renal calculi * 1 [2]	0/70 (0.00%)	0	1/31 (3.23%)	1
Respiratory, thoracic and mediastinal disorders
hypoxia * 1 [2]	1/70 (1.43%)	1	0/31 (0.00%)	0
Vascular disorders
hypotension * 1 [2]	1/70 (1.43%)	1	1/31 (3.23%)	1
thromboembolic event * 1 [2]	1/70 (1.43%)	1	1/31 (3.23%)	1
1 Term from vocabulary, CTCAE (4.0); * Indicates events were collected by non-systematic assessment; [1] Grade 3 or higher Adverse Events (AEs) from aMILs harvest to 60 days following autologous stem cell transplant (ASCT); [2] Grade 3 or higher AEs from aMILs harvest to 60 days following ASCT
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	aMIL Arm		No aMIL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/70 (15.71%)		0/31 (0.00%)
General disorders
infusion related reaction * 1 [1]	8/63 (12.70%)	8	0/31 (0.00%)	0
Product Issues
manufacture failure * 1	2/70 (2.86%)	2	0/31 (0.00%)	0
product contamination * 1	1/70 (1.43%)	1	0/31 (0.00%)	0
1 Term from vocabulary, CTCAE (4.0); * Indicates events were collected by non-systematic assessment; [1] 63 participants in the aMILs Arm had infusions, of those, 8 had record of infusion reaction.

Limitations and Caveats

[Not Specified]

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
• EMail: pimus1@jhmi.edu

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT01858558
• Other Study ID Numbers: J1343; NA_00084466 ( Other Identifier: JHMIRB )
• First Submitted: May 14, 2013
• First Posted: May 21, 2013
• Results First Submitted: June 11, 2020
• Results First Posted: June 29, 2020
• Last Update Posted: June 29, 2020