Witzig, Thomas E.

Abstract Background: Lenalidomide (Revlimid®) has demonstrated activity with manageable side effects in relapsed/refractory aggressive non-Hodgkin’s lymphoma (NHL). In the initial pilot study, response to lenalidomide was associated with low tumor burden, long duration from prior rituximab and high absolute lymphocyte count. Aims: To confirm the activity and safety of lenalidomide monotherapy in patients with relapsed/refractory aggressive NHL in an international setting and Determine whether predictors of response identified in the previous study were valid. Methods: Patients with relapsed/refractory aggressive NHL with measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test were conducted to investigate and characterize associations of prognostic variables with response. Results: Eighteen patients who received lenalidomide were eligible for response assessment as of May 15, 2007. The median age was 66 (43–81) and 17 were male. Histology was diffuse large B-cell lymphoma [DLBCL] (n=11), mantle cell lymphoma [MCL] (n=5) and transformed (n=2). Median time from diagnosis was 2 (0.4–12) years and median number of prior treatment regimens was 3 (1–13). Four patients (22%) exhibited an objective partial response including 2/11(18%) DLBCL and 2/5 (40%) MCL. Five patients had stable disease. Lenalidomide response was associated with low disease burden (29% for < 50 cm2v 0% for ≥ 50 cm2), time from last rituximab to lenalidomide treatment (36% for ≥ 230 days v 0% for < 230 days) and absolute lymphocyte count [ALC] (33% for ≥ 0.6×109/L v 0% < 0.6×109/L). Patients with favorable values for these three prognostic factors (N = 7) had a 57% response rate (compared with a 0% response rate for patients with unfavorable values (N = 11; P = 0.01). Grade 4 adverse events were neutropenia (22%) and thrombocytopenia (11%). Most common Grade 3 adverse events were fatigue (17%), thrombocytopenia (11%) and leukopenia (11%). Conclusion: Lenalidomide has activity in relapsed/refractory aggressive NHL with a favorable safety profile. Initial results from this ongoing study are confirming that patients with low tumor burden, long duration from prior rituximab, and high ALC are more likely to respond.

Abstract The objective of this study was to investigate the underlying molecular alteration in multiple myeloma at the protein level in order to identify regulators of pathogenesis, discover novel targets of therapy, and compare genetic and proteomic alterations. We employed antibody protein microarrays (BD Clonetech, CA) to measure changes in the patterns of protein expression between MM and normal plasma cells. The antibody array is a new technique enabling protein differences to be assayed directly by hybridizing fluorescently labeled protein mixtures from cell extracts onto glass slides spotted with 512 different monoclonal antibodies. CD138+purified plasma cells were obtained from cryopreserved bone marrow samples of 12 newly diagnosed patients with MM. The labeling index was high (1% cutoff) in 7 samples and low in the other 5. Control plasma cells were obtained from 9 pooled CD138+ purified normal donor bone marrow plasma cells. Interphase FISH analysis for 17p deletion, 13q deletion, and t(11:14) were performed. To assess differential expression, the mean of the ratios of Cy5/Cy3 for each sample were analyzed using the Clontech software to calculate an internally normalized ratio. The normalized data were analyzed by the Genespring software. Unsupervised clustering identified 4 groups of MM. Changes of protein expression ≥2 fold in 70% of the samples as compared to control were identified. There were 6 proteins differentially expressed between all MM samples and control cells including proteins in the ras signaling pathway (KSR-1), the ubiquitin pathway (Ubc-H6), cyclin-dependent kinases (CDK4), cytokines (IL-6), DNA toposisomerase II, and the rho-interacting serine-threonine kinase CRIK. Proteins differentially expressed in MM groups 1 and 2 compared to normal control included cell cycle regulators (cul-2, MCM6, PCNA, TGFb1), kinases (p70S6K, PKC), and chromatin regulators (Ran, AKAP450, Rad50). Protiens differentially expressed in MM group 3 included cell cycle regulators (CDK2, CLK1, MENA), apoptosis regulators (XIAP, caspase 4, perforin) kinases (IKKa and RAC1 in the Wnt signaling pathway) and P53 regulators, while proteins identified in MM group 4 included NFkB/ubiquitin proteins (IKKa and Ubch6), cell cycle regulators (c-myc, CDK4), p53 pathway proteins (53bp2), ras-signaling proteins (KSR1), and the kinase CRIK. There were no differences in protein expression between the high and low labeling index groups. 13q was identified in 5 (42%), 17 p in 1(8%) and t(11:14) in 1(8%) patients. 80% of the 13 q deletion cases clustered in MM group 1 and 2 patients. Cyclin D-1 was upregulated in 5 (42%) patients including the patient with (11:14) translocation. This is the first proteomic study of patients with MM. The results are consistent with previously identified genetic alterations in MM indicating that this novel technique could be used in identifying molecular changes in MM. It identifies novel proteins dysregulated in MM that differ between the 4 MM groups. These results may be used in the future to individualize therapy based on the proteins dysregulated in each group. For example, IKK inhibitors may be useful in group 3 MM patients, while mTOR inhibitors (upstream of p70S6K) could be used in groups 1 and 2 patients. Future correlations with gene expression arrays and prognosis in a larger cohort of patients is warranted.

Abstract Background: mTOR inhibition has produced responses in mantle cell lymphoma as well as other non-Hodgkin lymphomas. This phase II study tested the oral mTOR inhibitor everolimus (RAD001, Novartis Pharmaceuticals) in simultaneous two-stage phase II lymphoma studies, including one arm involving Hodgkin lymphoma. The goals were to learn the toxicity profile and to assess the anti-tumor response. A total of 17 patients with Hodgkin lymphoma were enrolled in the uncommon arm at completion of enrollment. Methods: Patients (pts) received 10 mg PO daily for each 28 day cycle (up to 12, with a possible extension in responders) and restaged after 2, 6, and 12 cycles. The primary endpoint is the confirmed response rate, including CR, CRu or PR. Results: The median age of the 17 pts with Hodgkin lymphoma was 37 yrs (range: 27–68), with a median of 6 (range, 4–14) prior therapies. Fourteen pts (82.4%) had a prior stem cell transplant (SCT). Pts completed a median of 6 (range, 1–13) cycles of therapy. Fifteen of 17 patients were evaluable for response as of this analysis. The overall response rate was 47% (7/15), all partial responses. Ten patients are continuing on study while 6 have gone off due to disease progression and 1 due to other reasons. Common grade 3 adverse events (AEs) include thrombocytopenia (5 pts), anemia (5 pts) and alkaline phosphatase elevation (1 pts). 1 patient was reported to have grade 4 neutropenia. Conclusions: Oral everolimus has promising activity with acceptable toxicity in Hodgkin lymphoma. These results provide the rationale for additional studies with this novel class of agents and to integrate mTOR inhibitors into salvage treatment regimens for Hodgkin lymphoma.

Abstract Waldenström macroglobulinemia (WM) is a monoclonal B cell disorder characterized by a circulating monoclonal IgM protein that may lead to serum hyperviscosity in association with an infiltration of lymphoplasmacytic cells into the bone marrow. Although proinflammatory and chemotactic cytokines can profoundly affect tumor cells and the tumor microenvironment, and many cytokines have been shown to have potent therapeutic efficacy in preclinical cancer models, the role of cytokine networks in WM is not fully understood. In this study, we used a high-throughput xMAP multiplex immunobead assay technology (Luminex Corp., Austin, TX) to simultaneously test 30 cytokines, chemokines, angiogenic factors as well as growth factors and soluble receptors in the sera of WM patients and compared them with other B cell malignancies including IgM monoclonal gammopathy of undetermined significance (MGUS), follicular lymphoma, chronic lymphocytic leukemia (CLL) as well as healthy controls. Using a Mann-Whitney U test to analyze the differences between the groups, 15 of the 30 cytokines tested had significantly different levels in WM compared to healthy controls. Of those 15 cytokines, 11 were elevated in WM patients and 4 were decreased. Cytokines were grouped into 3 groups; those with < 2-fold difference, 2–8 fold difference and those having > 8-fold difference in their cytokine levels compared to healthy donors. There was a greater than 8-fold increase in the serum levels of Rantes, G-CSF and IL-2R (p<0.0001) in WM patients. Furthermore, 3 cytokines had between 2–8-fold increase in WM patients including IL-4 (p<0.0001), IL-6 (p<0.0019) and IP-10 (p<0.0006). Five cytokines had statistically elevated levels in WM patients compared to healthy controls, however the fold increase was < 2 including HGF (p<0.0185), IL-10 (p<0.0002), MIP-1α (P<0.0484), IL-2 (P<0.0130) and IL-12 (P<0.0155). Of the cytokines that had significantly lower levels in the sera of WM patients, IL-8 (p<0.0001) and EGF (p<0.0001) were > 8-fold decreased, MCP-1 (p<0.0001) was 2–8 fold lower and Eotaxin (p<0.0004) was < 2-fold lower in WM patients. All of the cytokines that had the greatest fold difference (> 8-fold) in WM patients compared to healthy donors also differed significantly from the MGUS patients. Rantes, G-CSF, IL-2R and EGF had significantly different levels compared to other B cell malignancies. We tested for a correlation between the cytokines that had > 2-fold difference between the WM group and control group with clinical features of the disease and found the cytokines IL-6 and IL-2R had a significant correlation with β2-microglobulin levels (p<0.01). We analyzed cytokine levels in the bone marrow plasma of the same patients and found that high levels of IL-2R in the bone marrow microenvironment significantly correlated with anemia and elevated serum β2-microglobulin (p<0.01). In conclusion, we have simultaneously analyzed sera from WM patients for 30 cytokines and found the most significantly elevated cytokines are Rantes, G-CSF and IL-2R and the most significantly downregulated cytokines are IL-8 and EGF. Furthermore, we found that elevated serum levels of IL-6 and IL-2R correlated with β2-microglobulin levels, a measure of disease activity. Further analysis of the biological role of these cytokines in WM may offer insight into disease pathogenesis and provide a basis for novel targeted therapies.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell dyscrasia with limited therapeutic options. Based on the observed 25 to 50% partial response rates in myeloma patients, thalidomide has been tried in patients with AL. Two reports (Dispenzieri et al, Amyloid10:247; 2003; Seldin et al, Clinical Lymphoma3:241; 2003) have demonstrated that standard dose, single agent thalidomide (≥ 200 mg per day) has a higher than expected rate of adverse events in AL patients without hematologic or organ response, potentially due to rapid patient attrition. We therefore performed a prospective clinical trial using low dose, single agent thalidomide in patients with AL. Methods: In August 2001, we began accrual to a phase II trial of low dose thalidomide for patients with AL. Eligibility included: age ≥ 18 years, creatinine <3mg/dL, total bilirubin < 3 mg/dL, ANC ≥ 1 x 10(9)/L, left ventricular ejection fraction of >45%, histochemical proof of amyloid and a monoclonal plasma cell dyscrasia, symptomatic organ involvement, and ability to supply informed consent. Patients were started with thalidomide 50 mg per day, with a dose escalation to a maximum dose of 400 mg per day over a 19 week period as tolerated. Patients were evaluated monthly by their physician. These office visits were staggered with telephone toxicity checks monthly by the primary investigator. The endpoint of the study was hematologic and organ response by 12 months. Results: Eighteen patients were treated. The median age was 66 years (range 43–83). Eight were male. Twenty-eight percent had an ECOG performance status of 2 or 3. Five patients (28%) had received no prior therapy. Five had received one prior regimen; 6, two prior; and 2, ≥ three. Three had received prior PBSCT. Sixteen patients had a monoclonal lambda plasma cell disorder; two, monoclonal kappa. Immunoglobulin heavy chains were IgG (n=9), IgM (n=5), IgA (n=1), and none (n=3). Twelve patients (67%) had cardiac involvement; twelve (67%) renal; two liver; two symptomatic gastrointestinal; one pulmonary; and two nerve involvement. Study participants had significant symptomatology at baseline with dyspnea (n=12), light-headedness (n=6), and edema (n=13). Median number of organs involved was 1, range (1 to 4). Median time on study drug was 5.6 months, range 0.7–24 months. Reasons for discontinuation included: progression, 7 (39%); 3 each (17%) for adverse events, death, and patient refusal; and other causes in 2. The median tolerated dose was 100 mg. There were no hematologic responses observed. The overall organ response rate was 11%. There was one renal response at 1 year and a gastrointestinal response at 3 months with 24 hour fecal fat changing from 21 to 8.7 grams. The most common adverse effects attributable to thalidomide were: constipation (78%), edema (44%), sinus bradycardia (17%), dyspnea (11%), and paresthesias (11%). Light-headedness, rising creatinine, thrombosis, infection, syncope, and rash was attributed to the thalidomide in 5.6% of patients. Conclusions: Low dose thalidomide is tolerable in this fragile group of patients, but as a single agent efficacy is limited. Further study of combination therapy of thalidomide and low dose dexamethasone may be warranted. A study using the next generation immune modulatory drug Revlimid is scheduled to open to accrual. Funded by NIH grant CA 91561 and Celgene.

Abstract Angiogenesis plays an important role in tumor growth. Endothelial cells express the chemokine receptor CXCR4, and interact with its ligand SDF-1/CXCL12. Previous studies have demonstrated that the ERK MAP kinase and the PI3Kinase pathways are activated in response to SDF-1 stimulation. In this study, we investigate the effect of the role of inhibitors of CXCR4, ERK MAP kinase and PI3Kinase on angiogenesis. The AngioKit (TCS Cellworks, U.K) is a 24 well plate in which human endothelial cells are co-cultured with other human myoblasts and fibroblasts in a specially designed medium. Control wells in the kit include media alone, VEGF (+control) and suramin (-control). Test samples were added on the day the kits arrive, then changed on days 4, 7, and 9, and stained on day 11 with CD31 (PECAM). The wells are then photographed and subjected to image analysis. The software measures angiogenesis as total tubule length per well in microns. Test samples can then be compared to the control wells to determine the drugs affect on angiogenesis in vitro. The following drugs were tested in this angiogenesis model system, a human CXCR4 neutralizing antibody (MAB 171, R&D systems, MN), SDF-1, the MAP kinase inhibitor PD098059, and the PI3Kinase inhibitor LY294002. Treatment with the CXCR4 inhibitory antibody, PD098059, and LY294002 caused marked decrease in angiogenesis (below the level of the negative control suramin). Inhibition of angiogenesis below the level of suramin was first detected at 1mg/ml CXCR4 antibody, and10mg/ml CXCR4 antibody resulted in complete inhibition of angiogenesis. The effect of PD098059 on angiogenesis was dependent on its concentration; 20mM PD098059 inhibited angiogenesis while lower concentrations did not. These results are consistent with the drug’s known concentration-dependent inhibition of MEK-1 and indicate that the MEK-1 inhibitor leads to angiostasis secondary to its specific inhibitory effect on MEK-1. The lowest level tested of 1μM LY294002 led to inhibition of angiogenesis, and 50μM of LY294002 led to complete abrogation of angiogenesis. SDF-1 has been reported to be angiogenic. In this model system, the effect of SDF-1 alone on angiogenesis was subtle. However, the endothelial cells used in this model system may be secreting endogenous SDF-1 leading to the saturation of the CXCR4 receptor and minimal effects of exogenous SDF-1 stimulation. This was demonstrated by the significant effect of the CXCR4 inhibitor on angiogenesis without the addition of exogenous SDF-1. These results indicate that CXCR4 inhibition and its downstream pathways PI3K and ERK MAP kinase lead to significant inhibition of angiogenesis, and suggest that selective inhibitors of CXCR4 may be useful agents to inhibit angiogenesis.

Abstract Sublethal doses of ionizing radiation induce a complex cellular survival response, one component of which is activation of the nuclear factor kappa B (NF-kB) pathway. PS-341 is a selective inhibitor of the 26S proteasome which prevents the proteasomal degradation of I-kB and thereby inhibits the activation of NF-kB. We therefore hypothesized that PS-341 should synergistically enhance the anti-myeloma effect of ionizing radiation (IR). The individual and combined effects of PS-341 and IR were analyzed using human MM cell lines (MM1, RPMI 8226, JJN-3 and ARH-77) and bone marrow samples from myeloma patients. Treatment of myeloma cell lines with 10nM PS-341 produced a modest anti-proliferative effect with G2/M-phase arrest and p21cip/waf-1 induction but minimal procaspase-3 cleavage and minimal apoptotic cell death: Similar sublethal damage was observed after single exposure to IR at a dose of 6 Gy. In contrast, sequential exposure to PS-341 (10 nM) and IR (6 Gy) resulted in potent (synergistic) induction of apoptosis, assayed by both fluorescein isothiocyanate conjugated annexin V-propidium iodide assay and cell cycle analysis. Overall cell viability was greatly reduced by the combination of PS3451 and IR, but not by either modality alone, as determined by 3-(4,5 dimethylthiazol-2yl) 2–5 diphenyltetrazolium bromide (MTT) assay and analysis of polyadenosine-5′-diphosphate-ribose polymerase (PARP) cleavage -product after 72 hours. As predicted, exposure to 6 Gy IR led to potent induction of nuclear NF-kB activity and this response was almost completely inhibited by simultaneous treatment with PS-341. The combination of PS341 and IR was next evaluated on CD138+ve and CD138-ve cell fractions from bone marrow aspirates of myeloma patients. Synergistic killing of primary myeloma (CD138+) cells was observed with relative sparing of normal marrow elements (CD138−). We conclude that PS-341 is a potent radiosensitizer for myeloma cell lines and primary myeloma cells. This provides a strong rationale to combine PS-341 with conventional external beam or with targeted radionuclide therapy for effective treatment of MM patients.

Abstract Multiple myeloma remains incurable and novel therapeutics are urgently needed. We have shown that live attenuated Edmonston strain measles virus (MV-Edm) is potently oncolytic in multiple myeloma xenograft models and can efficiently infect CD138 sorted primary myeloma cells inducing extensive intercellular fusion which leads to cell death (Blood, 2001, v98, p2002). In contrast, the virus causes minimal damage to normal PHA-stimulated peripheral blood lymphocytes, fibroblasts and smooth muscle cells. To facilitate non-invasive imaging of sites of viral gene expression, we introduced the human thyroidal sodium iodide symporter (NIS) gene into the viral genome (MV-NIS). MV-NIS infected myeloma cells efficiently concentrate radioiodine which provides a basis for noninvasive imaging and destruction of infected tumors using beta emitters such as 131I (Blood, 2004, v103, p1641). Clinical translation of MV-NIS in patients with refractory myeloma is planned. However, the mechanism underlying the tumor selectivity of MV-Edm has not previously been defined. MV-Edm uses either of two cellular receptors for cell entry and cell fusion; CD46, a regulator of complement activation, is expressed on all nucleated cells, wheras SLAM (signaling lymphocyte activation molecule) is expressed only on activated B lymphocytes, T lymphocytes, and monocytes, and is not present on myeloma plasma cells. Using a panel of CHO cell transfectants, we demonstrated that MV-Edm -mediated cell killing increases exponentially above a threshold CD46 receptor density (Can Res, 2004, v64, p4919). We subsequently obtained bone marrow aspirates from 18 myeloma patients and performed multi-parameter flow cytometry to determine the relative expression levels of CD46 on the myeloma plasma cells versus the rest of the hematopoietic cells in the bone marrow. The myeloma cells expressed significantly higher levels (5-fold) of CD46 receptors (MFI=294.9 + 204.4, means ± SD) on their cell surfaces compared to hematopoietic cells of the erythroid, myeloid and lymphoid lineages (MFI=58.6 ± 9.0). Analysis of the myeloma array data generated by the Shaughnessy lab indicated that, in comparison to plasma cells from healthy volunteers (2997 ± 1053, n=30, means ± SD), primary myeloma cells express 2-fold elevated levels of CD46 mRNA (6592 ± 4029, n=72, p=0.001, Wilcoxon signed rank test). Taken together, these findings provide strong support for the hypothesis that selective destruction of myeloma cells by oncolytic measles viruses is a direct consequence of their overexpression of the cellular receptor CD46.

Abstract Background: As the first radiolabled monoclonal antibody approved for the treatment for the treatment of cancer, yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) achieves both high response rates and durable remissions in patients with relapsed or refractory, low-grade, follicular, or transformed B-cell NHL. Because of the stability of 90Y ibritumomab tiuxetan and its favorable pharmacokinetic profile (ie, predictable urinary clearance and absence of dehalogenation), dosing is based on patient weight and platelet counts. Yttrium 90 ibritumomab tiuxetan is typically delivered at a dose of 0.4 mCi/kg (in patients with platelets >150,000/mm3) or 0.3 mCi/kg (in patients with platelets ≤150,000/mm3) to a maximum recommended dose (MRD) of 32 mCi. However, patients >80 kg with platelet counts exceeding 150,000/mm3 may receive a lower drug concentration (ie, <0.4 mCi/kg 90Y) as a result of dose capping. We evaluated whether the 32 mCi dose cap influences the safety or efficacy of ibritumomab tiuxetan therapy in patients >80 kg. Methods: Efficacy and safety data were collected for patients from 3 registrational trials that received either 0.4 mCi/kg 90Y (patients ≤80 kg) or 32 mCi 90Y (patients >80 kg). Results: Clinical responses in 170 patients were evaluated. Patients ≤80 kg (n = 103) had a median weight of 70 kg (range, 45–80 kg) versus a median weight of 95 kg (range, 81–159) for patients >80 kg (n = 67). Gender (41% M vs 73% M, respectively; P <.01) was the only significantly different baseline characteristic between the ≤80 kg and >80 kg groups. Similar efficacy and safety results were reported for both subsets of patients. Overall response rates of 79% and 70% were observed for patients ≤80 kg and >80 kg, respectively (P =.27); and no significant differences were seen in complete response rates (28% vs 34%, respectively; P =.40). Median TTP (8.9 months vs 9.5 months; P =.53) and median DR (8.5 months vs 11.5 months; P =.34) were equivalent between the 2 weight-based groups. In addition, there were no statistically significant differences in safety measures including grade 3/4 nonhematologic adverse events, neutropenia, thrombocytopenia, or anemia. Conclusions: As a consequence of dose capping at an MRD of 32 mCi, 39% of patients received a lower dose/kg of 90Y ibritumomab tiuxetan. However, despite the difference in dose administered on a unit of body weight basis, the efficacy and safety results were similar between patients ≤80 kg and >80 kg. We conclude that the 32 mCi dose cap does not influence the efficacy or safety profile of 90Y ibritumomab tiuxetan for patients >80 kg.

Abstract Background: It has been hypothesized that multiple myeloma (MM) remains incurable due to a stemcell/proliferative component that responds only partially to standard treatment regimens. We have shown that abnormal production of IL-1beta in the myeloma microenvironment stimulates the generation of paracrine IL-6, the central myeloma growth factor, and that IL-1Ra will inhibit paracrine IL-6 production in vitro. Based on these preclinical studies, we have developed a Phase II trial using IL-1Ra. Purpose: To determine the biologic and clinical activity of IL-1Ra (Anakinra) in a subgroup of smoldering MM (SMM) patients that present with an elevated plasma cell labeling index (PCLI; a measure of myeloma cell proliferation). Methods: Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. Patients received 100 mg of Anakinra (IL-1Ra) SQ qd for a total duration of 6 months. Results: Eleven of 29 patients enrolled on the protocol had an on-study PCLI > 0 and have completed six months of therapy with IL-1Ra. Seven of the 11 patients had a decrease in the PCLI of 75–100% (see Table), three had only modest changes (≤ 50%), and one had an increase. The decrease in the PCLI paralleled a decrease in the high sensitivity C-reactive protein (CRP) in all cases (43–90% decrease). The above results suggested that IL-1Ra inhibited IL-6 production in the myeloma microenvironment, as evidenced by a reduction in the CRP, resulting in suppression of myeloma cell growth. However, there was little effect on the M-protein. To investigate these clinical observations, we co-cultured IL-1beta transduced +/− myeloma cells with stromal cells +/− dexamethasone (DEX), IL-1Ra, or both for 48 hours and quantitated the percent apoptotic cells by flow cytometry and IL-6 production by ELISA. The results showed: 1) IL-1Ra was superior at inhibition of IL-6 but caused no increase in apoptosis; 2) the DEX apoptotic effect was eliminated by IL-6 3) DEX and IL-1Ra combined induced maximal IL-6 inhibition and apoptosis of myeloma cells. Based on these in vitro results, 5 of the 11 patients have been advanced to IL-1Ra + low dose DEX (20 mg/week) resulting in 4/5 minor responses (25–50% decrease M-spike) and 1/5 with stable disease. Conclusion: The use of IL-1Ra is a novel targeted therapeutic strategy that interferes with myeloma cell growth. By inhibiting IL-1beta induced IL-6 production, IL-1Ra specifically targets the proliferative myeloma fraction and also complements DEX induced apoptosis. Preliminary studies on the use of IL-1 inhibitors in SMM patients to delay/prevent progression to active MM and to minimize toxicity appear encouraging, however, more patients need to be studied. Patient # On Study 6 months % Change 1 PCLI 0.8% 0% −100% CRP (mg/L) 2.01 0.58 − 71% M-spike (g/dL) 2.5 2.4 − 4% 2 PCLI 0.2% 0% − 100% CRP 0.89 0.51 − 43% M-spike 2.8 2.7 − 3% 3 PCLI 0.2% 0% − 100% CRP 5.7 1.02 − 82% M-spike 2.9 2.9 0% 4 PCLI 4.1% 1% − 75% CRP 3.39 1.51 − 55% M-spike 3.8 3.6 − 5% 5 PCLI 0.4% 0% − 100% CRP 3.46 0.34 − 90% M-spike 2.7 3.1 15% 6 PCLI 0.3% 0% − 100% CRP 17 5.35 − 68% M-spike 4.4 3.9 − 11% 7 PCLI 1.2% 0% − 100% CRP 1.06 0.32 − 70% M-spike 3.1 2.9 − 6%