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.
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.


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.


CONCLUSIONS
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.


BACKGROUND
clinicaltrials.gov identifier: NCT00635154.
Lust
John A
JA
Division of Hematology, Mayo Clinic, Rochester, MN 55905. lust.john@mayo.edu
Lacy
Martha Q
MQ
Zeldenrust
Steven R
SR
Dispenzieri
Angela
A
Gertz
Morie A
MA
Witzig
Thomas E
TE
Kumar
Shaji
S
Hayman
Suzanne R
SR
Russell
Stephen J
SJ
Buadi
Francis K
FK
Geyer
Susan M
SM
Campbell
Megan E
ME
Kyle
Robert A
RA
Rajkumar
S Vincent
SV
Greipp
Philip R
PR
Kline
Michael P
MP
Xiong
Yuning
Y
Moon-Tasson
Laurie L
LL
Donovan
Kathleen A
KA
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000473:pathology; D002097:C-Reactive Protein / Q000032:analysis; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality; D010950:Plasma Cells / Q000473:pathology
D000970:Antineoplastic Agents; D005938:Glucocorticoids; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D003907:Dexamethasone; D002097:C-Reactive Protein