Anakinra With or Without Dexamethasone in Treating Patients With Smoldering or Indolent Multiple Myeloma

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00635154
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 55
• Location: 1
• Arm: 1
• Duration (Months): 95
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

RATIONALE: Some cancers need growth factors which are made by the body's white blood cells to keep growing.Anakinra may interfere with the growth factor and stop multiple myeloma from growing. Dexamethasone may stop cancer cells from growing. Giving anakinra together with dexamethasone may be an effective treatment for multiple myeloma.

PURPOSE: This phase II trial is studying how well anakinra works when given with or without dexamethasone in treating patients with smoldering myeloma or indolent multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Biological: Anakinra (IL-1Ra); Drug: Dexamethasone acetate	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the response rate in patients with smoldering or indolent multiple myeloma treated with anakinra.

Secondary

• Determine the toxicity of anakinra alone or in combination with dexamethasone in these patients.

• Evaluate the response rate in patients treated with anakinra in combination with dexamethasone.

• Evaluate the proportion of patients who are progression-free at 6 months.

• Determine the tolerability of anakinra in combination with dexamethasone in these patients.

• Determine the time to progression to active multiple myeloma in patients treated with anakinra alone or in combination with dexamethasone.

• Assess the duration of response in these patients.

OUTLINE:

• Induction therapy: Patients receive anakinra subcutaneously (SC) once daily for 6 months (months 1-6). Based on response, patients continue on treatment in one of three ways.

• Complete response [CR], very good partial response [VGPR], partial response [PR], or minimal response [MR]: Patients continue to receive anakinra SC once daily for 6 additional months (months 7-12). Patients who develop disease progression at anytime proceed to treatment with high dose dexamethasone.

• Stable disease: Patients receive low-dose oral dexamethasone once weekly for 6 months (months 7-12) with anakinra SC once daily. Patients who maintain stable disease or responded will continue low-dose oral dexamethasone and anakinra SC once daily for 6 additional months (months 13-18). Patients who develop disease progression at any time proceed to treatment with high dose dexamethasone.

• Progressive disease: Patients receive high-dose oral dexamethasone on days 1-4, 9-12, and 17-20 in months 7, 9, and 11 and on days 1-4 in months 8, 10, and 12 with anakinra SC once daily for 6 additional months (months 7-12).

NOTE: Patients may continue on treatment beyond 12 months at treating physician discretion.

After completion of study treatment, patients are followed every 6 months for up to 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Anakinra (IL-1 Receptor Antagonist) in Patients With Smoldering/Indolent Multiple Myeloma
• Study Start Date: Dec 1, 2002
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Anakinra with/without Dexamethasone Anakinra was given alone for 6 months at which time response was assessed. If participants achieved a minor response or better they continued on Anakinra alone until disease progression. If participants achieved stable disease, they added low dose Dexamethasone to Anakinra until progression. If at any time a participant progresses, they were administered high dose Dexamethasone with Anakinra.

Biological: Anakinra (IL-1Ra); 100mg daily subcutaneously administered; Drug: Dexamethasone acetate; Low dose - 20 mg/week High dose - 40mg days 1-4, 9-12, 17-20 every 28 days ODD cycles OR 40 mg days 1-4 every 28 days EVEN cycles. (Starting dose was determined by treating physician)

Outcome Measures

Primary Outcome Measures

1. Patients With Confirmed Response (Complete Response, Very Good Partial Response, Partial Response, or Minimal Response) on 2 Consecutive Months During the First 6 Months of Treatment With Anakinra Alone [6 months]

   Response Definitions: Complete Response(CR):disappearance of M-Protein from serum & urine and immunofixation, <5% bone marrow(BM) plasma cells & disappearance of soft tissue plasmacytomas(STP); Very Good Partial Response(VGPR):>=90% decrease in serum M-Protein, Urine M-protein <100 mg/24 hours, <=5% BM plasma cells, disappearance of STP; Partial response(PR):>=50% reduction in serum M-protein, >=90% decrease in Urine M-protein or <200 mg/24 hours & >=50% decrease in STP; Minor response(MR):25-49% decrease in serum M-protein, 50-89% decrease in urine M-protein & 25-49% decrease in STP

Secondary Outcome Measures

1. Number of Patients With Response to Treatment With Dexamethasone and Anakinra [During Active treatment (up to 5 years)]

   Response on 2 consecutive months during active treatment with anakinra alone or in combination with dexamethasone. Response criteria is the same as in Primary Outcome Measure.

2. Number of Patients Who Are Progression-free and Alive at 6 Months [at 6 months]

   Disease stability was assessed by evaluating the proportion of participants who are progression free (and alive) at 6 months. Progression was defined as any one or more of the following: An increase of 25% from lowest confirmed response: Serum M-component (absolute increase >=1.0 g/dL) Urine M-component (absolute increase >=200 mg/24 hours) An increase of 50% above the lowest remission value in bone marrow plasmacytosis (absolute increase 25% bone marrow plasma cells) Development of new bone lesions or soft tissue plasmacytomas.

3. Number of Patients With Severe Non-hematological Adverse Events in Patients Receiving Anakinra Alone or in Combination With Dexamethasone. [Duration of treatment (up to 5 years)]

   Severe non-hematologic adverse events were defined as adverse events grade 4 (life threatening or disabling) or grade 5 (death), regardless of attribution to study drug. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (CTC) version 2.

4. Progression Free Survival (PFS) in Patients Treated With Anakinra Alone or in Combination With Dexamethasone [Time from registration to progression or death (up to 5 years)]

   PFS was defined as the time from registration to progression or death due to any cause. Progression is defined the same as outcome measure #3.

5. Number of Patients With Severe Non-hematological Adverse Events in Participants Receiving Anakinra in Combination With Dexamethasone [every cycle during treatment (up to 5 years)]

   Severe non-hematologic adverse events were defined as adverse events grade 4 (life threatening or disabling) or grade 5 (death), regardless of attribution to study drug. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (CTC) version 2.

6. Duration of Response [From first documentation of response to progression or last follow-up (up to 5 years)]

   Duration of response is defined for all evaluable participants (receiving Anakinra alone or in combination with Dexamethasone) who have achieved an objective response as the date at which the participants status was first noted to be MR or better to the date progression is documented or the date of last follow-up.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• New or preexisting diagnosis of multiple myeloma

• Smoldering or indolent multiple myeloma meeting one of the following criteria:

• Bone marrow plasma cells ≥ 10%

• Serum monoclonal IgG or IgA protein ≥ 3.0 g/dL OR urine monoclonal light chain ≥ 1g by 24-hour urine protein electrophoresis

• Measurable disease

• Does not require immediate chemotherapy, in the opinion of the treating physician

• No active myeloma or primary amyloidosis requiring chemotherapy or any agents that may interact with anakinra (e.g., etanercept, infliximab, or thalidomide)

PATIENT CHARACTERISTICS:

• Eastern Cooperative Oncology Group (ECOG) performance status 0

• Total WBC ≥ 3,500/mm^3

• ANC ≥ 1,700/mm^3

• Creatinine ≤ 1.5 times upper limit of normal

• Able to self-inject medication or have a caregiver who can administer the drug

• Not pregnant or nursing

• Negative pregnancy test

• No acute or chronic infections, open wounds, or any active infection requiring intravenous antibiotic therapy within the past 12 weeks

• No active malignancy within the past 5 years except basal cell carcinoma of the skin or carcinoma in situ of cervix

• Patients with a previously resected malignancy that does not require further treatment are eligible

• No New York Heart Association (NYHA) class III or IV congestive heart failure

• No rheumatoid arthritis or other diseases requiring immunosuppressive therapy

• No asthma, inflammatory bowel disease, or any debilitating physical or psychiatric illness that, in the judgment of the investigator, would interfere with the conduct of the study

PRIOR CONCURRENT THERAPY:

• More than 30 days since prior treatment with dehydroepiandrosterone (DHEA), clarithromycin, pamidronate, steroids, or any other agent that may affect M-protein

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: John A. Lust, MD, PhD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00635154
• Other Study ID Numbers: CDR0000583300; P30CA015083; MC0282; 1316-02
• First Posted: Mar 13, 2008
• Last Update Posted: Jun 7, 2018
• Last Verified: Dec 1, 2010

• 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; Dexamethasone; Dexamethasone acetate; Interleukin 1 Receptor Antagonist Protein; BB 1101

Study Results

Participant Flow

Recruitment Details	55 patients were recruited from November 2002 through December 2007 at Mayo Clinic. One patient had progressive disease prior to starting treatment. This patient was excluded from all analysis.
Pre-assignment Detail	Patients received induction therapy of Anakinra alone for 6 months. Based on response, dexamethasone could be added or increased in subsequent cycles. See the Outline section for more detail. Unless otherwise stated, results are reported for all patients (regardless of dexamethasone administration).

Arm/Group Title	Anakinra With/Without Dexamethasone
Arm/Group Description
Period Title: Overall Study
STARTED	54
COMPLETED	21
NOT COMPLETED	33

Baseline Characteristics

Arm/Group Title	Anakinra With/Without Dexamethasone
Arm/Group Description
Overall Participants	54
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60.0
Sex: Female, Male (Count of Participants)
Female	25 46.3%
Male	29 53.7%
Region of Enrollment (participants) [Number]
United States	54 100%
Diagnosis (participants) [Number]
Smoldering Multiple Myeloma (SMM)	44 81.5%
Indolent Multiple Myeloma (IMM)	10 18.5%
Prior treatment for M-protein (participants) [Number]
Yes	10 18.5%
No	44 81.5%

Outcome Measures

1. Primary Outcome

Title	Patients With Confirmed Response (Complete Response, Very Good Partial Response, Partial Response, or Minimal Response) on 2 Consecutive Months During the First 6 Months of Treatment With Anakinra Alone
Description	Response Definitions: Complete Response(CR):disappearance of M-Protein from serum & urine and immunofixation, <5% bone marrow(BM) plasma cells & disappearance of soft tissue plasmacytomas(STP); Very Good Partial Response(VGPR):>=90% decrease in serum M-Protein, Urine M-protein <100 mg/24 hours, <=5% BM plasma cells, disappearance of STP; Partial response(PR):>=50% reduction in serum M-protein, >=90% decrease in Urine M-protein or <200 mg/24 hours & >=50% decrease in STP; Minor response(MR):25-49% decrease in serum M-protein, 50-89% decrease in urine M-protein & 25-49% decrease in STP
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Participants who met the eligibility criteria, signed the consent form and have began treatment were considered evaluable.

Arm/Group Title	Anakinra Without Dexamethasone
Arm/Group Description	Patients in this outcome received only Anakinra (100mg daily subcutaneously administered).
Measure Participants	54
Number [participants]	1 1.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anakinra Without Dexamethasone
	Comments	Proportion of confirmed responses to Anakinra alone was estimated by the number of patients who achieved a confirmed response divided by the total number of assessable patients.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion of confirmed responses (%)
	Estimated Value	1.8
	Confidence Interval	() 95%; 0.5 to 10
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% Confidence intervals were calculated for the true confirmed response rate using properties of the binomial distribution.

2. Secondary Outcome

Title	Number of Patients With Response to Treatment With Dexamethasone and Anakinra
Description	Response on 2 consecutive months during active treatment with anakinra alone or in combination with dexamethasone. Response criteria is the same as in Primary Outcome Measure.
Time Frame	During Active treatment (up to 5 years)

Outcome Measure Data

Analysis Population Description

Only participants who received Anakinra with dexamethasone were analyzed.

Arm/Group Title	Anakinra With Dexamethasone
Arm/Group Description	Patients in this outcome received both Anakinra (100mg daily subcutaneously administered) and dexamethasone (either 20mg/week OR 40mg days 1-4, 9-12, 17-20 every 28 days during odd cycles OR 40 mg days 1-4 every 28 days during even cycles)
Measure Participants	29
Number [participants]	14 25.9%

3. Secondary Outcome

Title	Number of Patients Who Are Progression-free and Alive at 6 Months
Description	Disease stability was assessed by evaluating the proportion of participants who are progression free (and alive) at 6 months. Progression was defined as any one or more of the following: An increase of 25% from lowest confirmed response: Serum M-component (absolute increase >=1.0 g/dL) Urine M-component (absolute increase >=200 mg/24 hours) An increase of 50% above the lowest remission value in bone marrow plasmacytosis (absolute increase 25% bone marrow plasma cells) Development of new bone lesions or soft tissue plasmacytomas.
Time Frame	at 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anakinra With/Without Dexamethasone
Arm/Group Description
Measure Participants	54
Number [participants]	49 90.7%

4. Secondary Outcome

Title	Number of Patients With Severe Non-hematological Adverse Events in Patients Receiving Anakinra Alone or in Combination With Dexamethasone.
Description	Severe non-hematologic adverse events were defined as adverse events grade 4 (life threatening or disabling) or grade 5 (death), regardless of attribution to study drug. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (CTC) version 2.
Time Frame	Duration of treatment (up to 5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anakinra With/Without Dexamethasone
Arm/Group Description
Measure Participants	54
Number [participants]	7 13%

5. Secondary Outcome

Title	Progression Free Survival (PFS) in Patients Treated With Anakinra Alone or in Combination With Dexamethasone
Description	PFS was defined as the time from registration to progression or death due to any cause. Progression is defined the same as outcome measure #3.
Time Frame	Time from registration to progression or death (up to 5 years)

Outcome Measure Data

Analysis Population Description

PFS results were published in Mayo Clin Proc, Feb 2009. 47 patients were analyzed for this publication.

Arm/Group Title	Anakinra With/Without Dexamethasone
Arm/Group Description
Measure Participants	47
Median (95% Confidence Interval) [months]	37.5

6. Secondary Outcome

Title	Number of Patients With Severe Non-hematological Adverse Events in Participants Receiving Anakinra in Combination With Dexamethasone
Description	Severe non-hematologic adverse events were defined as adverse events grade 4 (life threatening or disabling) or grade 5 (death), regardless of attribution to study drug. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (CTC) version 2.
Time Frame	every cycle during treatment (up to 5 years)

Outcome Measure Data

Analysis Population Description

Only participants who received Anakinra with low or high dose dexamethasone were analyzed.

Arm/Group Title	Anakinra With Dexamethasone
Arm/Group Description	Patients in this outcome received both Anakinra (100mg daily subcutaneously administered) and dexamethasone (either 20mg/week OR 40mg days 1-4, 9-12, 17-20 every 28 days during odd cycles OR 40 mg days 1-4 every 28 days during even cycles)
Measure Participants	29
Number [participants]	4 7.4%

7. Secondary Outcome

Title	Duration of Response
Description	Duration of response is defined for all evaluable participants (receiving Anakinra alone or in combination with Dexamethasone) who have achieved an objective response as the date at which the participants status was first noted to be MR or better to the date progression is documented or the date of last follow-up.
Time Frame	From first documentation of response to progression or last follow-up (up to 5 years)

Outcome Measure Data

Analysis Population Description

Participants (receiving Anakinra alone or in combination with Dexamethasone) who achieved a MR or better were analyzed.

Arm/Group Title	Anakinra With/Without Dexamethasone
Arm/Group Description
Measure Participants	15
Median (95% Confidence Interval) [months]	41.9

Adverse Events

Arm/Group Title	Anakinra With/Without Dexamethasone
Arm/Group Description
All Cause Mortality
	Anakinra With/Without Dexamethasone
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Anakinra With/Without Dexamethasone
	Affected / at Risk (%)	# Events
Total	8/54 (14.8%)
Blood and lymphatic system disorders
Anemia	1/54 (1.9%)	1
Cardiac disorders
Supraventricular arrhythmias (SVT/atrial fibrillation/flutter)	1/54 (1.9%)	1
Infections and infestations
Infection without neutropenia	2/54 (3.7%)	2
Investigations
Neutropenia	1/54 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	2/54 (3.7%)	2
Vascular disorders
Hemorrhage	2/54 (3.7%)	2
Thrombosis	3/54 (5.6%)	4
Other (Not Including Serious) Adverse Events
	Anakinra With/Without Dexamethasone
	Affected / at Risk (%)	# Events
Total	53/54 (98.1%)
Blood and lymphatic system disorders
Anemia	3/54 (5.6%)	5
Anemia-Leukemia	1/54 (1.9%)	1
Cardiac disorders
Cardiovascular	1/54 (1.9%)	1
Edema	10/54 (18.5%)	19
Ischemia/Infarction	1/54 (1.9%)	1
Left ventricular failure	1/54 (1.9%)	1
Supraventricular arrhythmias (SVT/atrial fibrillation/flutter)	2/54 (3.7%)	2
Ear and labyrinth disorders
Middle Ear	1/54 (1.9%)	1
Eye disorders
Cataract	2/54 (3.7%)	2
Vision-Blurred	5/54 (9.3%)	6
Gastrointestinal disorders
Colitis	1/54 (1.9%)	1
Dyspepsia	16/54 (29.6%)	27
Gastrointestinal disorder	1/54 (1.9%)	1
Nausea	1/54 (1.9%)	1
Oral cavity Mucositis/stomatitis (functional/symptomatic)	2/54 (3.7%)	2
Pain-Abdominal	1/54 (1.9%)	1
General disorders
Fatigue	4/54 (7.4%)	4
Injection site reaction	46/54 (85.2%)	92
Pain-Chest	1/54 (1.9%)	1
Immune system disorders
Hypersensitivity	3/54 (5.6%)	3
Infections and infestations
Infection without neutropenia	32/54 (59.3%)	89
Investigations
Alanine aminotransferase increased	1/54 (1.9%)	1
Aspartate aminotransferase increased	1/54 (1.9%)	1
Creatinine	13/54 (24.1%)	53
GGT (Gamma-Glutamyl transpeptidase)	1/54 (1.9%)	1
Leukopenia	24/54 (44.4%)	140
Neutropenia	36/54 (66.7%)	236
Metabolism and nutrition disorders
Hypercalcemia	2/54 (3.7%)	2
Hyperglycemia	22/54 (40.7%)	94
Musculoskeletal and connective tissue disorders
Bone pain	1/54 (1.9%)	1
Muscle Weakness	3/54 (5.6%)	7
Musculoskeletal	1/54 (1.9%)	1
Psychiatric disorders
Anxiety	12/54 (22.2%)	27
Confusion	1/54 (1.9%)	1
Depression	1/54 (1.9%)	1
Insomnia	10/54 (18.5%)	23
Renal and urinary disorders
Dyruria	1/54 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome (ARDS)	1/54 (1.9%)	1
Cough	1/54 (1.9%)	1
Dyspnea	1/54 (1.9%)	1
Pneumonitis	1/54 (1.9%)	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.