Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the myeloma proliferative component

Abstract

Objective: To conduct in vitro studies as well as a phase 2 clinical trial in patients with smoldering or indolent multiple myeloma to determine if interleukin 1 (IL-1) inhibitors can delay or prevent active myeloma.

Patients and methods: Stromal cells were cocultured with IL-1beta-expressing myeloma cells in the presence of dexamethasone, IL-1 receptor antagonist (IL-1Ra), or both. Levels of interleukin 6 (IL-6) and of apoptosis were also quantified. Between November 19, 2002, and May 24, 2007, 47 patients were enrolled in the study and subsequently treated with IL-1Ra. In 25 (53%) of the 47 study patients, low-dose dexamethasone (20 mg/wk) was added. The primary end point was progression-free survival (PFS).

Results: In vitro, IL-1Ra was superior to dexamethasone at inhibiting IL-6 production; maximal IL-6 inhibition and apoptosis induction were achieved by addition of both IL-1Ra and dexamethasone. In the clinical trial, 3 patients achieved a minor response to IL-1Ra alone; 5 patients achieved a partial response and 4 patients a minor response after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling index that paralleled a decrease in high-sensitivity C-reactive protein (hs-CRP) levels. The median overall PFS was 37.5 months. The median PFS for patients without (n=12) or with (n=35) a greater than 15% decrease in 6-month vs baseline hs-CRP levels was 6 months and more than 3 years, respectively (P=.002). Disease stability was maintained in 8 patients who received therapy for more than 4 years.

Conclusion: In patients with smoldering or indolent multiple myeloma who were at risk of progression to active myeloma, treatment with IL-1 inhibitors decreased the myeloma proliferative rate and hs-CRP levels in those who responded, leading to a chronic disease state and an improved PFS.

Trial registration: clinicaltrials.gov identifier: NCT00635154.

FIGURE 1.

Effects of an interleukin 1 receptor antagonist (IL-1Ra) and dexamethasone on myeloma cell apoptosis and interleukin 6 (IL-6) production in myeloma cell-stromal cell cocultures. Normal stromal cells (1 × 10⁵ cells/mL) were cocultured directly with either an empty vector control or IL-1β-expressing myeloma cells (1 × 10⁶ cells/mL) in the absence or presence of dexamethasone, IL-1Ra, or both for 48 h at 37°C. Supernatants were assayed for IL-6, and apoptosis was determined using Annexin V/propidium iodide staining and flow cytometry. “None” refers to control cultures without drug, and data are expressed as the percent increase in apoptotic cells above levels in control cultures. Numbers in pg/mL refer to the amount of IL-6 detected by enzyme-linked immunosorbent assay in cocultures of myeloma and stromal cells.

FIGURE 2.

Clinical effects of the combination of interleukin 1 (IL-1) receptor antagonist (IL-1Ra) and low-dose dexamethasone. Left, This patient received IL-1Ra alone at month 0 and the combination of IL-1Ra and low-dose dexamethasone at month 6. Right, This patient received IL-1Ra alone at month 0 and the combination of IL-1Ra and low-dose dexamethasone at month 4.5. Arrows indicate the initiation of dexamethasone. Levels of IL-1 are determined using interleukin 6 (IL-6) fold increase (see Patients and Methods). BMPC = bone marrow plasma cell; hs-CRP = high-sensitivity C-reactive protein; PCLI = plasma cell labeling index. SI conversion factors: To convert hs-CRP values to to nmol/L, multiply by 9.524.

FIGURE 3.

Progression-free survival (PFS). Left, The median PFS for patients without (n=12) and with (n=35) a decrease at 6 mo of greater than 15% from the baseline hs-CRP level was 6 mo and more than 3 y, respectively (P=.002). Right, The median PFS for patients with (n=19) and without (n=28) an increase at 6 mo of 5% or greater in the M-protein level was 6 mo and more than 3 y, respectively (P<.001).

FIGURE 4.

Schematic of the role of an interleukin 1 receptor antagonist (IL-1Ra) and dexamethasone in the myeloma microenvironment. Bone marrow plasma cells (BMPCs) from patients with progressive smoldering multiple myeloma (SMM) or indolent multiple myeloma (IMM) produce IL-1β that stimulates stromal cells to make interleukin 6 (IL-6), which can be monitored by the high-sensitivity C-reactive protein (hs-CRP) levels (upper panel). The IL-6 can then stimulate the growth of the proliferative myeloma component, resulting in an elevated plasma cell labeling index (PCLI). Interleukin 1Ra selectively targets the proliferative myeloma component, resulting in a decrease in the hs-CRP levels and the PCLI. The proliferative component is crossed out (lower left) because it is unknown whether these cells are induced into a nonproliferative state or eliminated. Dexamethasone complements IL-1Ra biologic activity by inducing myeloma cell apoptosis and decreasing the percentage of BMPCs, M-protein levels, and myeloma cell-produced IL-1 levels (lower right).