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

A Phase II Study of Anakinra (IL-1 Receptor Antagonist) in Patients With Smoldering/Indolent Multiple Myeloma

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.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma and Plasma Cell Neoplasm
• Intervention / Treatment: Biological: Anakinra (IL-1Ra); Drug: Dexamethasone acetate

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 Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Response to Treatment With Dexamethasone and Anakinra	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.	During Active treatment (up to 5 years)
Number of Patients Who Are Progression-free and Alive 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.	at 6 months
Number of Patients With Severe Non-hematological Adverse Events in Patients Receiving Anakinra Alone or in Combination With Dexamethasone.	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.	Duration of treatment (up to 5 years)
Progression Free Survival (PFS) in Patients Treated With Anakinra Alone or in Combination With Dexamethasone	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 from registration to progression or death (up to 5 years)
Number of Patients With Severe Non-hematological Adverse Events in Participants Receiving Anakinra in Combination With Dexamethasone	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.	every cycle during treatment (up to 5 years)
Duration of Response	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.	From first documentation of response to progression or last follow-up (up to 5 years)

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: John A. Lust, MD, PhD, Mayo Clinic

Publications and helpful links

General Publications

• Lust JA, Lacy MQ, Zeldenrust SR, Witzig TE, Moon-Tasson LL, Dinarello CA, Donovan KA. Reduction in C-reactive protein indicates successful targeting of the IL-1/IL-6 axis resulting in improved survival in early stage multiple myeloma. Am J Hematol. 2016 Jun;91(6):571-4. doi: 10.1002/ajh.24352. Epub 2016 Apr 13.
• Lust JA, Lacy MQ, Zeldenrust SR, Dispenzieri A, Gertz MA, Witzig TE, Kumar S, Hayman SR, Russell SJ, Buadi FK, Geyer SM, Campbell ME, Kyle RA, Rajkumar SV, Greipp PR, Kline MP, Xiong Y, Moon-Tasson LL, Donovan KA. Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1beta-induced interleukin 6 production and the myeloma proliferative component. Mayo Clin Proc. 2009 Feb;84(2):114-22. doi: 10.4065/84.2.114.

Study record dates

Study Major Dates

• Study Start: December 1, 2002
• Primary Completion (ACTUAL): December 1, 2009
• Study Completion (ACTUAL): November 1, 2010

Study Registration Dates

• First Submitted: March 12, 2008
• First Submitted That Met QC Criteria: March 12, 2008
• First Posted (ESTIMATE): March 13, 2008

Study Record Updates

• Last Update Posted (ACTUAL): June 7, 2018
• Last Update Submitted That Met QC Criteria: May 8, 2018
• Last Verified: December 1, 2010

More Information

Terms related to this study

• Keywords: stage II multiple myeloma; stage III multiple myeloma; stage I multiple myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Dexamethasone; Dexamethasone acetate; BB 1101; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: CDR0000583300; P30CA015083 (U.S. NIH Grant/Contract); MC0282 (OTHER: Mayo Clinic Cancer Center); 1316-02 (OTHER: Mayo Clinic IRB)