Melphalan, Prednisone, and Lenalidomide in Treating Patients With Newly Diagnosed Multiple Myeloma

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00477750
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 33
• Locations: 3
• Arm: 1
• Duration (Months): 98.1
• Patients Per Site: 11
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as melphalan, prednisone, and lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of melphalan and lenalidomide when given together with prednisone and to see how well they work in treating patients with newly diagnosed multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Drug: lenalidomide; Drug: melphalan; Drug: prednisone	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of melphalan and lenalidomide in combination with prednisone in patients with newly diagnosed multiple myeloma.

• Determine the response rate in patients treated with this regimen. Secondary

• Determine the toxicity of this regimen in these patients. OUTLINE: This is a dose-escalation study of melphalan and lenalidomide followed by a phase II study.

• Phase I: Patients receive oral melphalan and oral prednisone daily on days 1-4. Patients also receive oral lenalidomide daily on days 1-21. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of melphalan and lenalidomide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients receive oral melphalan and oral lenalidomide as in phase I at the MTD. Patients also receive oral prednisone as in phase I. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Trial of Melphalan, Prednisone Plus Lenalidomide in Patients With Newly Diagnosed Multiple Myeloma Who Are Not Candidates for Stem Cell Transplant
• Study Start Date: Jun 1, 2005
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Aug 5, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (Lenalidomide, Melphalan, Prednisone) Intervention: Drug: lenalidomide Dose determined by Phase I treatment schedule. Taken orally days 1-21 every 28 days until progression Intervention: Drug: melphalan Dose determined by Phase I treatment schedule. Taken orally days 1-4 every 28 days until progression Intervention: Drug: prednisone 60mg/m^2, orally days 1-4 every 28 days until progression

Drug: lenalidomide; Phase I - dose escalating: 5mg level -1, 10mg level 0, 10mg level 1, 15mg level 2, 20mg level 3, 25mg level 4, orally days 1-21 every 28 days until progression Phase II - 10 mg orally days 1-21 every 28 days until progression; Drug: melphalan; Phase I - dose escalating: 5mg/m^2 dose level -1, 5 mg/m^2 dose level 0, 8 mg/m^2 dose level 1 - 4, daily x 4 orally days every 28 days until progression Phase II - 5mg/m^2 orally days 1-4 every 28 days until progression; Drug: prednisone; 60mg/m^2, orally days 1-4 every 28 days until progression

Outcome Measures

Primary Outcome Measures

1. Patients With Overall Confirmed Response [Every cycle during treatment]

   Response that was confirmed on 2 consecutive evaluations.> Complete Response (CR): Complete disappearance of M-protein from serum and urine on immunofixations, normalization of Free Light Chain (FLC) ratio and <=5% plasma cells in bone marrow> Very Good Partial Response (VGPR): >=90% reduction in serum M-spike, Urine M-spike <100mg per 24 hours> Partial Response (PR): >=50% reduction in serum M-spike, Urine M-spike >=90% reduction or < 200mg per 24 hours, or >=50% decrease in difference between involved and uninvolved FLC levels or 50% decrease in bone marrow plasma cells

Secondary Outcome Measures

1. Progression-free Survival [registration to progressive disease (up to 3 years)]

   Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression was defined as any one or more of the following: An increase of 25% from lowest confirmed response in: Serum M-component (absolute increase >= 0.5g/dl) Urine M-component (absolute increase >= 200mg/24hour Difference between involved and uninvolved Free Light Chain levels (absolute increase >= 10mg/dl Bone marrow plasma cell percentage (absolute increase of >=10%)

2. Overall Survival (OS) at 3 Years [registration to death (up to 3 years)]

   OS was defined as the time from registration to death due to any cause. Patients who were alive were censored at date of last follow-up. The overall survival at 3 years (a percentage) is reported below.

3. Duration of Response (DOR) [from first response to progression or death (up to 3 years)]

   Duration of response was calculated from documentation of first response to date of progression in the subset of patients who responded. Patients without progression were censored at the date of last tumor evaluation.

4. Percentage of Participants With Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3) [Every cycle during treatment up to 3 years]

   The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of multiple myeloma

• Newly diagnosed disease

• Requires treatment, in the judgment of the treating physician

• Not a candidate for (or patient declines) autologous stem cell transplantation

• Meets 1 of the following criteria:

• Measurable disease, defined by any of the following:

• Serum monoclonal protein ≥ 1 g/dL

• Urine protein monoclonal light chain ≥ 200 mg/24 hours by electrophoresis

• Measurable serum free light chains ≥ 10 mg/dL, kappa or lambda, AND κ/λ ratio is abnormal (if serum and urine are not measurable as defined above)

• Evaluable disease, defined as monoclonal bone marrow plasmacytosis ≥ 30%

PATIENT CHARACTERISTICS:

• ECOG performance status 0-3

• Life expectancy > 3 months

• ANC ≥ 1,500/mm³

• Bilirubin ≤ 2.0 mg/dL

• Alkaline phosphatase ≤ 3 times upper limit of normal (ULN)

• AST ≤ 3 times ULN

• Creatinine ≤ 3.0 mg/dL

• Platelet count ≥ 100,000/mm³

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use 2 effective methods of contraception, including ≥ 1 highly effective method, ≥ 4 weeks before and during study treatment

• No uncontrolled infection

• No peripheral neuropathy ≥ grade 2

• No serious medical condition, laboratory abnormality, or psychiatric illness that would preclude study compliance

• No other active malignancy except for nonmelanoma skin cancer or carcinoma in situ

• Prior malignancy allowed if treated with curative intent and is free of disease for a period appropriate for that cancer

• No known hypersensitivity to thalidomide

• No known HIV positivity

• No infectious hepatitis A, B or C

• No history of deep vein thrombosis or other medical condition requiring the use of warfarin

• Able to take daily prophylactic acetylsalicylic acid (81 or 325 mg)

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• More than 4 weeks since prior radiotherapy for treatment of multiple myeloma

• No prior lenalidomide

• No other concurrent anticancer agents or treatments

• No concurrent steroids except prednisone ≤ 20 mg/day (or the equivalent) for concurrent illness or adrenal replacement therapy

• No other concurrent investigational therapy or agent for treatment of multiple myeloma

• No concurrent warfarin

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259-5499
2	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224
3	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Vivek Roy, MD, FACP, Mayo Clinic
• Principal Investigator: Philip R. Greipp, MD, Mayo Clinic
• Principal Investigator: Craig B. Reeder, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00477750
• Other Study ID Numbers: CDR0000546642; P30CA015083; MC038A; 2387-04; RV-MM-PI-025
• First Posted: May 24, 2007
• Last Update Posted: Oct 11, 2019
• Last Verified: Oct 1, 2015

• Keywords provided by Mayo Clinic: stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Prednisone; Lenalidomide; Melphalan

Study Results

Participant Flow

Pre-assignment Detail	This was as Phase I/II trial. There were 7 patients recruited to the Phase I portion; no patients qualified for the Phase II portion. Twenty-six (26) patients were recruited for the Phase II portion. Results presented here are on the 26 Phase II patients.

Arm/Group Title	Treatment (Lenalidomide, Melphalan, Prednisone)
Arm/Group Description	Intervention: Drug: lenalidomide 10 mg orally days 1-21 every 28 days until progression Intervention: Drug: melphalan 5mg/m^2 orally days 1-4 every 28 days until progression Intervention: Drug: prednisone 60mg/m^2, orally days 1-4 every 28 days until progression
Period Title: Overall Study
STARTED	26
COMPLETED	15
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	Treatment (Lenalidomide, Melphalan, Prednisone)
Arm/Group Description	Intervention: Drug: lenalidomide 10 mg orally days 1-21 every 28 days until progression Intervention: Drug: melphalan 5mg/m^2 orally days 1-4 every 28 days until progression Intervention: Drug: prednisone 60mg/m^2, orally days 1-4 every 28 days until progression
Overall Participants	26
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	73.5
Sex: Female, Male (Count of Participants)
Female	9 34.6%
Male	17 65.4%
Region of Enrollment (participants) [Number]
United States	26 100%
Durie-Salmon Stage at Diagnosis (participants) [Number]
I - Low Cell Mass	1 3.8%
II - Intermediate Cell Mass	11 42.3%
III - High Cell Mass	11 42.3%
unknown	3 11.5%
Parameter of Hematologic Response - Serum M-spike >= 1g/dL (participants) [Number]
Yes	20 76.9%
No	6 23.1%
Parameter of Hematologic Response - Serum Immunoglobulin Free Light Chain >= 10mg/dL (participants) [Number]
Yes	12 46.2%
No	14 53.8%
Parameter of Hematologic Response - Urine M-spike >= 200 mg/24 hours (participants) [Number]
Yes	6 23.1%
No	20 76.9%
Parameter of Hematologic Response - None (non-secretory myeloma, bone marrow only) (participants) [Number]
Yes	0 0%
No	26 100%

Outcome Measures

1. Primary Outcome

Title	Patients With Overall Confirmed Response
Description	Response that was confirmed on 2 consecutive evaluations.> Complete Response (CR): Complete disappearance of M-protein from serum and urine on immunofixations, normalization of Free Light Chain (FLC) ratio and <=5% plasma cells in bone marrow> Very Good Partial Response (VGPR): >=90% reduction in serum M-spike, Urine M-spike <100mg per 24 hours> Partial Response (PR): >=50% reduction in serum M-spike, Urine M-spike >=90% reduction or < 200mg per 24 hours, or >=50% decrease in difference between involved and uninvolved FLC levels or 50% decrease in bone marrow plasma cells
Time Frame	Every cycle during treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Lenalidomide, Melphalan, Prednisone)
Arm/Group Description	Intervention: Drug: lenalidomide 10 mg orally days 1-21 every 28 days until progression> > Intervention: Drug: melphalan 5mg/m^2 orally days 1-4 every 28 days until progression> > Intervention: Drug: prednisone 60mg/m^2, orally days 1-4 every 28 days until progression
Measure Participants	26
CR	3 11.5%
VGPR	5 19.2%
PR	10 38.5%

2. Secondary Outcome

Title	Progression-free Survival
Description	Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression was defined as any one or more of the following: An increase of 25% from lowest confirmed response in: Serum M-component (absolute increase >= 0.5g/dl) Urine M-component (absolute increase >= 200mg/24hour Difference between involved and uninvolved Free Light Chain levels (absolute increase >= 10mg/dl Bone marrow plasma cell percentage (absolute increase of >=10%)
Time Frame	registration to progressive disease (up to 3 years)

Outcome Measure Data

Analysis Population Description

Phase 2 patients

Arm/Group Title	Treatment (Lenalidomide, Melphalan, Prednisone)
Arm/Group Description	Intervention: Drug: lenalidomide 10 mg orally days 1-21 every 28 days until progression Intervention: Drug: melphalan 5mg/m^2 orally days 1-4 every 28 days until progression Intervention: Drug: prednisone 60mg/m^2, orally days 1-4 every 28 days until progression
Measure Participants	26
Median (95% Confidence Interval) [months]	21.4

3. Secondary Outcome

Title	Overall Survival (OS) at 3 Years
Description	OS was defined as the time from registration to death due to any cause. Patients who were alive were censored at date of last follow-up. The overall survival at 3 years (a percentage) is reported below.
Time Frame	registration to death (up to 3 years)

Outcome Measure Data

Analysis Population Description

Phase 2 patients.

Arm/Group Title	Treatment (Lenalidomide, Melphalan, Prednisone)
Arm/Group Description	Intervention: Drug: lenalidomide 10 mg orally days 1-21 every 28 days until progression Intervention: Drug: melphalan 5mg/m^2 orally days 1-4 every 28 days until progression Intervention: Drug: prednisone 60mg/m^2, orally days 1-4 every 28 days until progression
Measure Participants	26
Number (95% Confidence Interval) [percentage of patients]	58

4. Secondary Outcome

Title	Duration of Response (DOR)
Description	Duration of response was calculated from documentation of first response to date of progression in the subset of patients who responded. Patients without progression were censored at the date of last tumor evaluation.
Time Frame	from first response to progression or death (up to 3 years)

Outcome Measure Data

Analysis Population Description

Phase 2 Patients who had a response of PR or better are included in this analysis.

Arm/Group Title	Treatment (Lenalidomide, Melphalan, Prednisone)
Arm/Group Description	Intervention: Drug: lenalidomide 10 mg orally days 1-21 every 28 days until progression Intervention: Drug: melphalan 5mg/m^2 orally days 1-4 every 28 days until progression Intervention: Drug: prednisone 60mg/m^2, orally days 1-4 every 28 days until progression
Measure Participants	18
Median (95% Confidence Interval) [months]	16.3

5. Secondary Outcome

Title	Percentage of Participants With Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3)
Description	The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
Time Frame	Every cycle during treatment up to 3 years

Outcome Measure Data

Analysis Population Description

Patients who experienced an adverse event that is at least possibly related are included in this analysis.

Arm/Group Title	Treatment (Lenalidomide, Melphalan, Prednisone)
Arm/Group Description	Intervention: Drug: lenalidomide 10 mg orally days 1-21 every 28 days until progression Intervention: Drug: melphalan 5mg/m^2 orally days 1-4 every 28 days until progression Intervention: Drug: prednisone 60mg/m^2, orally days 1-4 every 28 days until progression
Measure Participants	3
Grade 3	33
Grade 4	67
Grade 5	0

Adverse Events

Arm/Group Title	Treatment (Lenalidomide, Melphalan, Prednisone)
Arm/Group Description	Intervention: Drug: lenalidomide 10 mg orally days 1-21 every 28 days until progression Intervention: Drug: melphalan 5mg/m^2 orally days 1-4 every 28 days until progression Intervention: Drug: prednisone 60mg/m^2, orally days 1-4 every 28 days until progression
All Cause Mortality
	Treatment (Lenalidomide, Melphalan, Prednisone)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Lenalidomide, Melphalan, Prednisone)
	Affected / at Risk (%)	# Events
Total	7/26 (26.9%)
Gastrointestinal disorders
Diarrhea	1/26 (3.8%)	1
Infections and infestations
Sepsis	1/26 (3.8%)	1
Skin infection	1/26 (3.8%)	1
Investigations
Creatinine increased	1/26 (3.8%)	1
Leukocyte count decreased	1/26 (3.8%)	1
Neutrophil count decreased	2/26 (7.7%)	2
Platelet count decreased	2/26 (7.7%)	2
Metabolism and nutrition disorders
Dehydration	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders
Rash desquamating	1/26 (3.8%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Lenalidomide, Melphalan, Prednisone)
	Affected / at Risk (%)	# Events
Total	26/26 (100%)
Blood and lymphatic system disorders
Hemoglobin decreased	24/26 (92.3%)	103
Lymphatic disorder	1/26 (3.8%)	1
Cardiac disorders
Myocardial ischemia	1/26 (3.8%)	1
Gastrointestinal disorders
Abdominal pain	1/26 (3.8%)	1
Constipation	1/26 (3.8%)	1
Dyspepsia	4/26 (15.4%)	5
Ear, nose and throat examination abnormal	2/26 (7.7%)	2
Nausea	8/26 (30.8%)	12
General disorders
Edema limbs	11/26 (42.3%)	27
Fatigue	21/26 (80.8%)	63
Fever	1/26 (3.8%)	1
Pain	2/26 (7.7%)	5
Immune system disorders
Hypersensitivity	1/26 (3.8%)	1
Infections and infestations
Colitis, infectious (e.g., Clostridium difficile)	1/26 (3.8%)	1
Pneumonia	1/26 (3.8%)	1
Skin infection	2/26 (7.7%)	5
Upper respiratory infection	1/26 (3.8%)	1
Urinary tract infection	1/26 (3.8%)	1
Investigations
Alkaline phosphatase increased	1/26 (3.8%)	1
Aspartate aminotransferase increased	1/26 (3.8%)	1
Blood bilirubin increased	1/26 (3.8%)	1
Leukocyte count decreased	6/26 (23.1%)	13
Lymphocyte count decreased	1/26 (3.8%)	1
Neutrophil count decreased	18/26 (69.2%)	58
Platelet count decreased	18/26 (69.2%)	70
Metabolism and nutrition disorders
Blood glucose increased	15/26 (57.7%)	32
Serum albumin decreased	1/26 (3.8%)	1
Serum calcium decreased	1/26 (3.8%)	1
Serum glucose decreased	1/26 (3.8%)	1
Serum potassium decreased	1/26 (3.8%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness	9/26 (34.6%)	17
Pain in extremity	1/26 (3.8%)	1
Nervous system disorders
Headache	1/26 (3.8%)	1
Peripheral sensory neuropathy	5/26 (19.2%)	8
Syncope	2/26 (7.7%)	2
Psychiatric disorders
Confusion	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders
Rash desquamating	6/26 (23.1%)	14
Vascular disorders
Hypotension	1/26 (3.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.