Greipp, Philip R.

Abstract Background: While the therapeutic armamentarium for plasma cell disorders have expanded recently with introduction of thalidomide, lenalidomide and bortezomib, these diseases are still incurable and more agents are needed. We have previously demonstrated expression of CD 52 on plasma cells in MM, MGUS and AL amyloidosis. Based on this data we conducted a Phase II Study of Campath (Alemtuzumab; Monoclonal Anti-CD52 Antibody) in Primary Systemic Amyloidosis and Relapsed or Refractory Multiple Myeloma. Methods: The study was an IRB approved, Phase II protocol, with a two stage design and interim analysis at 14 patients, to assess the efficacy and toxicity of Alemtuzumab. The regimen involved a dose escalation during week one (Day I 3 mg SQ; Day II 10 mg SQ; Day III 30 mg SQ; then 30 mg SQ three times a week for a planned total of 17 additional weeks). All patients received concurrent Co-Trimoxazole, Fluconazole and Valacyclovir prophylaxis. The planned accrual was 32 patients. Results: A total of 14 patients were accrued, 8 patients with MM and 6 patients with AL. There were 8 females and 6 males in the study. The median age was 62 years (range: 50–78) years. The patients were heavily pretreated with the median number of treatments being 4. There were 5 grade 3–4 toxicities (CMV viremia (2 pts), skin rash (2 pts), and febrile neutropenia (1 pt)). Seven patients had evidence of disease progression and were removed from study. One patient completed the treatments with a mixed response. One patient had a sudden death while on study. The median duration of therapy was 6 weeks (range 3 weeks to 17 weeks). The accrual was stopped after 14 patients when the interim analysis showed a lack of anti-tumor efficacy and significant toxicity. Conclusion: This phase II study in patients with relapsed / refractory myeloma or amyloidosis demonstrated no evidence of clinical activity with use of Campath. In addition it was also associated with significant toxicity in this population. We do not recommend use of campath as a primary treatment modality in these patients. The lack of efficacy despite demonstrated expression of CD52 on clonal plasma cells once again highlights the need for combining treatments with multiple mechanisms in order to improve the response and outcome in these patients. Whether it can synergize with other therapies at lower doses without significant toxicity remains unknown.

Abstract Background: The p53 tumor suppressor gene has a common sequence polymorphism that results in either proline or arginine at amino-acid position 72. The Pro72 and Arg72 variants have been reported to differ in its functional activity. The Arg72 variant induces apoptosis more efficiently than Pro72 variant by its greater ability to localize to the mitochondria and increase the release of cytochrome c into the cytoplasm. In addition, recent studies have demonstrated that Arg72 variant was a better suppressor of cellular transformation, an activity believed to rely on the pro-apoptotic function of p53. Moreover, the Pro72 variant has been associated with a higher incidence of tumors. Aim: To evaluate the effect of the polymorphic variants of codon 72 and clinical outcome in patients with plasma cell malignancies. Patients and Methods: We analyzed 79 patients with plasma cell malignancies seen at Mayo Clinic between 2000 and 2003. Genomic DNA was extracted from CD138+ sorted plasma cell from bone marrow aspirates. PCR amplification of codon 72 and posterior sequencing was used for the analysis. Results: A total of 79 patients were analyzed. Thirty-four patients (34%) were heterozygous for p53, 57 (59%) homozygous for Arginine and 6 (6%) homozygous for Proline. The distribution among disorders was as follow, 52 patients had MM, 14 patients with SMM and 13 with MGUS. Among patient with MM 25% were Pro/Arg heterozygous, 71 % were Arg/Arg homozygous and 3.8% Pro/Pro homozygous. Survival data among MM patients and genotype were analyzed to Kaplan- Meier method. No significant differences were found among patients who carried homozygous (72R) or heterozygous genotype and overall survival. We exclude the analysis in MGUS and SMM for a low number of patients available. Conclusions: These findings indicate that codon 72 arginine p53 may not be associated with a prolonged survival in patients with Multiple Myeloma, but further study is needed to assess whether this polymorphism is associated with progression of MGUS to MM, age of onset, clinical manifestations, response to treatment etc.

Abstract Background: We reported a high response rate with the combination of lenalidomide plus dexamethasone (Rev/Dex) as initial therapy for newly diagnosed multiple myeloma (Blood2005;106:4050–3). We now present new data on time to progression (TTP), progression free survival (PFS), and overall survival (OS) from this phase II trial, and also include updated response data. Patients and Methods: 34 patients (23 male and 11 female) were enrolled. Lenalidomide was given orally 25 mg daily on days 1–21 of a 28-day cycle. Dexamethasone was given orally at a dose of 40 mg daily on days 1–4, 9–12, 17–20 of each cycle. Patients were allowed to go off treatment after 4 cycles of therapy to pursue autologous stem cell transplantation (SCT), but treatment beyond four cycles was permitted at the physician’s discretion. For patients continuing therapy beyond 4 months, the dose of dexamethasone was reduced to 40 mg on days 1–4 of each cycle. Response was assessed by modified EBMT/International Myeloma Working Group Uniform Response criteria. All patients received aspirin (81 mg or 325 mg daily) as prophylaxis against DVT. Results: The median age was 64 years (range, 32–78). All patients were evaluable for response and toxicity. Median follow up is 21 months. Thirteen patients proceeded to SCT following initial therapy with Rev/Dex and were censored at that time point for purposes of calculation of response, TTP and PFS. Patients who discontinued therapy to proceed to SCT received a median of 4 cycles of therapy (range, 4–13), while those staying on Rev/Dex (n=21) received a median of 19 cycles of therapy (range, 2–30). Thirty-one of 34 patients (91%) achieved an objective response to therapy; including 6 patients (18%) achieving a complete response (CR) and 13 patients (38%) achieving very good partial response for a CR+VGPR rate of 56%. The CR+VGPR rate among the 21 patients staying on Rev/Dex as primary therapy without SCT was 67% (CR 24%, VGPR 43%). Median TTP, PFS, and OS have not been reached (Figure). By Kaplan-Meier method, the estimated 2 year progression rate was 18%. The 2-year PFS rate and OS rate were 74% and 91%, respectively. Fifty-five percent of patients experienced grade 3 or higher non-hematologic toxicity at any point during therapy, most commonly fatigue (21%), neutropenia (21%), anxiety (6%), pneumonitis (6%), muscle weakness (6%), and rash (6%). Two patients died on study: one attributed to infection unrelated to therapy, the patient had stopped all therapy for over a month before the fatal infection occurred; the other death was due to infection felt possibly related to therapy. One patient developed a pulmonary embolism (grade 4 toxicity), but recovered with therapy; no other patient developed deep vein thrombosis or pulmonary embolism. Conclusion: Rev/Dex is highly active and well tolerated in the treatment of newly diagnosed multiple myeloma with a high CR+VGPR rate of 56% for the trial, and 67% among the subset of patients receiving this regimen as primary therapy. Responses are durable with a low progression rate at 2 years.

Abstract Background: Plasma cell leukemia (PCL) is a rare plasma cell (PC) dyscrasia which may be designated as primary (PPCL) or de novo PCL when recognized at the time of diagnosis and secondary (SPCL) when there is leukemic transformation of a previously recognized multiple myeloma (MM). PCL has been reported to exhibit distinct clinical and immunophenotypic features that distinguish it from MM, but little is known about the specific genetics of this disease. To better understand the genetic features of the clonal PC from PPCL and SCPL we assessed in these patients the molecular and cytogenetic abnormalities most commonly found in MM. Patients and Methods: In our study we analyzed 3 groups of patients; 18 with PPCL, 23 with SPCL and a control group of 345 newly diagnosed MM previously published. Diagnostic criteria for PCL followed the presence of >2 x103/L PC in PB (Kyle et al. Arch Intern Med1974; 133–813–8). Cytogenetic abnormalities were assessed by the c-Ig FISH method; mutational analysis was performed using Conformational-sensitive gel electrophoresis (CSGE). Methylation was analyzed by methyl specific PCR (MSP) after bisulfite genomic DNA modification. Results: Translocation of immunoglobulin heavy chain with Cyclin D1 (t (11; 14)) was present in 76.9% (10 of 13) of PPCL, 71% (5 of 7) of SPCL, in contrast to 15.8% (53 of 336) of MM cases. Translocations’ involving the FGFR3-MMSET genes (4p16.3 locus) and c-MAF (16q32) genes were not observed among 10 patients studied with PPCL, but were present in 12.7 % each in SPCL. The t (4;14)(p16;q32) was present in 12.7% cases of MM and the t(14;16)(q32;q23) was present in 4.6 % of MM cases. Deletion of 17p13.1 (p53 locus) was found in 10% (37 of 345) of MM cases, 53.8% (7 of 13) for PPCL and 42.8% (3 of 7) for SPCL. Deletion of 13q was present in 54.2% (176 of 325) of MM, 76.9 % (10 of 13) of PPCL and 57.1% of SPCL. Ras mutations were found in 15% (2/13) of PPCL, located in codon 1 and 2 of the K-ras gene. In addition, 23% for SPCL presented mutations in the N-ras gene. Two mutations were located in codon 2 of N-ras and 1 patients in showed a mutation in codon 1 of K-ras gene. Ras mutations were present in 27% of MM cases. Mutations for p53 gene were present in 30.7% (4/13) of PPCL, 17% (3/17) for SPCL and 5% for MM. Methylation specific PCR for p16 gene was found in 23% (3/13) of PPCL, 29% of SPCL and 33.9% (149/439) of MM. Hypermethylation of p14 was not detected in PPCL but a 23 % was found in SPCL. Conclusions: In this study we demonstrate that PCs from PPCL more frequently carry the t (11; 14). Comparing SPCL and MM, PC’s from de novo PPCL do not show t (4; 14) or (16; 14). Deletion of 13q was more prevalent among patients with PPCL. Ras mutations appear to be as frequent in MM as in PPCL and SPCL. Mutations in p53 appeared to be more prevalent in PPCL than in SPCL and MM. Hypermethylation of p16 does not differ while hypermethylation of p14 is more frequent in SPCL than PPCL. These characteristics may lead to a different onset or disease evolution of PPCL compared to MM and secondary plasma cell leukemia and this may be important for diagnostic and treatment.

Abstract Although multiple myeloma is clinically defined as the accumulation of clonal, malignant plasma cells in the bone marrow, the disease shows significant heterogeneity with regard to progression and therapeutic response. It is likely that germline genetic polymorphisms contribute significantly to an individual’s disease course and response. Bank On A CureTM (BOAC) is a collaborative project initiated with the International Myeloma Foundation (IMF) to develop a DNA bank of myeloma patient samples, through international cooperation. As the bank continues to expand, it provides a resource for the development of cooperative partnerships to assess specific clinical trials as well as conglomerate data. In this study, we have combined data from 3 phase III trials: ECOG trial E9486 (VBMCP + cyclophosphamide or interferon); SWOG trial 9321 (VAD induction followed by randomization to PBSC-supported high dose therapy versus standard dose therapy of VBMCP); and the MRC7 trial (comparing conventional chemotherapy [ABCM] with intravenous chemotherapy and high dose melphalan [CVAMP + HDM +PBSCT]). Five single nucleotide polymorphisms were examined based on associations demonstrated in previous individual trials: GSTP1, IL-6, LT-a, TNF-a, and ERCC2 (DNA repair). Patient samples included 412 from E9486, 569 from S9321, and 232 from MRC7 (total=1213). As a combined data set, genotype associations with overall survival did not reach statistical significance, suggesting SNP associations with survival may be therapy specific. One single association that did reach significance in the conglomerate data was TNF-a genotype association with age of disease onset (the high producer variant AA genotype showing a 5 year later age of onset than the AG/GG genotypes, or the overall mean of the trial, age 61 vs 56; p=.03). This is interesting in light of reports suggesting high production of TNF-a is found in myeloma patients and may actually promote myeloma. Yet, high production may also delay disease onset due to its role in other immunologic processes. Additional parameters including genotype associations with bone disease, CR rates, toxicities, and stage are being evaluated and will be presented. Preliminary results show that when SNPs from S9321 were included in a linear regression model, genotype risk groups could be identified; showing 73% correct association with ISS stage 1, and 75% correct association with ISS stage 3. This model, however, was not validated in the E9486 trial, with less than 50% genotype predictive ISS stage association. A number of highly significant ethnic genotype associations were noted, and are presented in a separate abstract. Given the likely complex interactions of multiple genetic variations, collective genotype comparisons may be required from larger pooled data sets BOAC is assembling to increase significant associations.

Abstract Cancer/testis antigens (CTAs), comprising the MAGE, CTAG, SSX and GAGE families, are expressed in different tumor types and restricted in normal tissues to germ cells of the testis. Many CTAs contain epitopes recognized by cytotoxic T cells and are potential targets for active immunotherapy. In MM, different CTAs have been shown to be expressed in cell lines and patient cells, and are associated with more proliferative and advance stage tumors. However, correlation with survival has never been reported. We undertook a global survey of CTA expression using gene expression profiling of CD138-enriched plasma-cell (PC) RNA in 15 normal, 101 MM, 22 MGUS and 24 SMM samples using the Affymetrix U133A chip (Affymetrix, Santa Clara, CA). 22 CTA genes were differentially expressed across the samples and unsupervised clustering using these genes clearly identifies a group of patients with high CTA expression. Most CTAs have significantly higher expression in MM as compared to SMM and especially MGUS, which has similar expression as normal PCs. As these antigens are not expressed in normal PCs, an upper limit of normal expression (ULN) was derived based on mean+3SD of expression in normal PCs for each CTA. A strict cut-off of normalized expression value greater than 2xULN was used to assign positive expression for each CTA genes. Using this method, the most commonly expressed CTAs are MAGE-A3 (73% of MM), MAGE-C1 (45%), MAGE-A6 (35%), SSX-1 (21%), GAGE-5 (18%) and NY-ESO-1 (14%). We then assigned patients with expression of more than 2 of these genes as having a CTA signature and correlated with clinical parameters. 45 patents (41 MM and 4 SMM) have the CTA signature. These patients have a significantly higher PCLI (median 0.2 v 0.7, p=0.0003). In fact, there is a significant correlation between the number of positive CTAs and PCLI (r=0.59, p<0.0001). Interestingly, there is no association between patients with a CTA signature and any of the recurrent genetic abnormalities (IgH translocations, chromosome 13 deletion and TC classes), yet MM patients with this signature have a significantly shorter survival (median 459 days vs not reached, log-rank p=0.017). A prognostic hierarchy exists amongst these CTAs. Only MAGE-A6, MAGE-A12, SSX-1 and SSX-5 expression has significant prognostic implications with the SSX family conferring the worse prognosis. Using a restricted panel of 3 CTAs (SSX-1, -5 and MAGE-A12), about 28% of MM patients expressing one or more of these genes can be identified with poor survival (median less than 1 year) that is independent of genetic subtypes. The genes differentially expressed between patients with and without the CTA signature are mainly involved in cell cycle regulation. Since the expression of this large set of CTAs appears to be under epigenetic control, we speculate that the same epigenetic processes that lead to dysregulation of the cell cycle also cause ectopic expression of CTA genes. As CTA expression is rare in MGUS, epigenetic processes may therefore also mediate transformation from MGUS to MM. These poor prognosis patients represent good candidates for novel therapies targeting the epigenetic machinery.

Abstract Background: Patients with SMM/IMM are at high risk for progression to active MM and are appropriate candidates for chemoprevention trials. High IL-1beta levels are a useful surrogate marker for progression from SMM/IMM to active myeloma. Methods: We carried out a Phase II clinical trial of IL-1Ra (Anakinra) in patients with SMM/IMM to determine the biologic activity, progression-free rate, and toxicity of IL-1Ra. Since IL-1beta induces paracrine IL-6, we hypothesized that IL-1Ra would inhibit IL-6 production and myeloma cell growth. 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. Non-progressors were allowed to continue on therapy with IL-1Ra until they converted to active myeloma. IL-1beta levels were measured in a bioassay with a read out of IL-1 inducible IL-6 production. CRP levels served as a surrogate for IL-6 production. Results: Thirty-six patients are included for analysis based on intent to treat at diagnosis. At baseline, twenty-nine patients had elevated functional IL-1beta levels consistent with progressive disease and 12 patients had radiologic evidence of disease on bone survey. The median TTP for the entire group was 1 year and 2 patients exhibited a minor response based on M-protein reduction. A proportional hazards analysis was performed and the variables examined were: % bone marrow plasma cells, plasma cell labeling index (PCLI), circulating plasma cells, albumin, M-protein level, IgA subtype, CRP, CRP % reduction ≥ one-third, beta-2 microglobulin, creatinine, calcium, hemoglobin, urine total protein, presence of lytic bone disease, and IL-1 level. Univariate Cox model results showed that % BMPC, PCLI, circulating plasma cells, CRP % reduction, presence of lytic disease, and IL-1 level were all statistically significant (p < .05) variables. However, only the CRP % reduction from baseline remained significant in the multivariate analysis (p < 0.01). The median TTP for patients without (n=18) and with (n=18) a decrease in CRP was 6 months and > 2 years, respectively (p < .0001). Toxicities included injection site reactions during the first month of therapy and asymptomatic neutropenia necessitating a reduction in therapy to every other day. Five patients in whom the CRP decreased and the baseline PCLI was > 0 also demonstrated a parallel decrease in the PCLI. Several of the patients with progressive disease on IL-1Ra alone could later be rescued with the addition of low dose dexamethasone (20 mg once a week) suggesting that the endogenous IL-1beta levels were too high to inhibit with IL-1Ra alone. Conclusion: In summary, IL-1Ra can prolong the TTP to active myeloma in responsive SMM/IMM patients through inhibition of IL-6 production (decrease in CRP) and myeloma cell growth. Figure Figure

Abstract Hyperdiploid myeloma (H-MM) affects about 50% of MM. These patients exhibit significant karyotypic and clinical heterogeneity. In this study, we addressed possible biological heterogeneity within H-MM by gene expression profiling of CD138-enriched plasma-cell RNA from 53 H-MM patients using the Affymetrix U133A chip (Affymetrix, Santa Clara, CA). Analysis was performed using GeneSpring 7 (Agilent Technologies, Palo Alto, CA). Unsupervised hierarchical clustering performed using the top 100 most variable genes (generated by ANOVA) identifies 4 putative patient clusters. These clusters were reproduced using principal component analysis. Cluster 1 was characterized by high expression of a large group of cancer testis antigens and mitosis/proliferation related genes (TOP2A, NEK, ASPM, CENPA). Cluster 2 was characterized by high expression of genes involved in IL-6 and HGF signaling (MET, IL6R, SOCS3, SPINT1). Cluster 3 was characterized by high expression of genes involved in TNF/NF-KB signaling and anti-apoptosis (NFKB2, CFLAR, BIRC3, TNFAIP3, RRAS2). Cluster 4 was characterized by high expression of genes involve in angiogenesis (protocadherin, EDNRB). Unsupervised hierarchical clustering using the same set of genes in an independent cohort of H-MM patients (n=60) yielded the same 4 patient clusters over-expressing similar genes. The gene expression profile of these clusters were not driven by differences in trisomies (only about 25% of genes that define the clusters were located on the commonly trisomic chromosomes). Association between the 4 clusters and clinical parameters such as survival, chromosome 13 deletion (Δ13), presence of IgH translocations, PCLI, RAS mutation and p16 methylation was analyzed. Cluster 1 tumors were more proliferative (median PCLI 3.8, p<0.05). Cluster 2 was associated with presence of Δ13 (56%, p<0.05) although none of the genes that defined this cluster falls on chromosome 13. p16 methylation was also less common in cluster 2 (13%, p=0.06). Cluster 3 was associated with low PCLI (median 0.2, P<0.05). Most of the patients with p16 methylation also belonged to this cluster (67%, p=0.06). There was a complete absence of Δ13 in Cluster 4. Patients in the 4 clusters also had significantly different survival (log-rank p=0.002.). The difference in survival was independent of Δ13 since Δ13 has no impact on survival in this patient cohort. The molecular profiles of these subclasses may explain some of these associations. CTA expression is associated with proliferative tumors with poor prognosis. IL-6 is an important survival factor and HGF signaling has been associated with poor survival in MM which may explain the relative poor prognosis of this group. Cluster 3 may have better survival as it is associated with an anti-apoptotic signature rather than proliferative signature. In summary, gene expression profiling identified 4 sub-classes within H-MM (validated on an independent dataset and using different clustering techniques) with distinct clinical and biological associations. The gene signature associated with each sub-classes provide a molecular basis for the different clinical behaviour and further insights into deregulated pathways in H-MM.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. For selected patients high dose chemotherapy with peripheral blood stem cell support is effective, but even in those patients, only 50% derive organ responses. Other patients are too sick to undergo that therapy. Thalidomide has limited utility in this disease, largely because of its toxicity profile in patients with AL. Lenalidomide, Celgene’s lead clinical compound in a new group of drugs called IMiDs®, is highly active in patients with multiple myeloma, especially in conjunction with dexamethasone. We sought to determine the toxicity and efficacy of lenalidomide in patients with AL. Methods: Patients with symptomatic AL who had a measurable plasma cell disorder (defined as serum M-spike ≥ g/dL urine M-spike >200 mg/24 hours; or involved immunoglobulin free light chain (FLC) ≥10 mg/dL and an abnormal FLC ratio) and adequate organ reserve defined as a creatinine ≤3 mg/dL, absolute neutrophil count ≥1000, platelet count ≥75000, and a hemoglobin ≥8 g/dL were eligible. Patients were started on lenalidomide 25 mg/day for 21 days followed by a 7 day rest (1 cycle). Dose modifications were made based on toxicity. If there was evidence of progression before 3 months or no evidence of hematologic response after 3 cycles, dexamethasone 40 mg p.o. days 1–4 and 15–18 was added. Results: Twenty-three patients were enrolled between 10/28/04 and 4/7/05; 14 were previously treated. Patient characteristics are shown in Table. Organ involvement was as follows: cardiac (61%); renal (70%), hepatic (22%); nerve (13%). Nine patients withdrew from study before completing 3 months of therapy. The reasons were: cancel (1); death (4); adverse events (2); and progression (2). At the time of our preliminary analysis in July 2005, an additional 3 patients have withdrawn from study: death (1) and patient refusal (2). Of the 5 patients who died, 4 had severe cardiac involvement and at least 3 organs involved by amyloid. The median follow-up for the eleven patients remaining on study is 6.2 months. Of the 12 patients who have crossed the 3 month treatment landmark, there are 7 hematologic partial responses (4 confirmed and 3 unconfirmed), two renal responses and one liver response. Of these same 12 patients, all but one has had dexamethasone added to their treatment program. The most common grade 3–4 adverse advents at least possibly attributable to lenalidomide were neutropenia (43%), thrombocytopenia (26%), rash (17%), dyspnea (9%), fatigue (9%), and edema (4%). Expansion of the trial is planned to accrue an additional 10 evaluable patients. Conclusions: Early results suggest that lenalidomide ± dexamethasone has activity in patients with primary systemic amyloidosis. Supported in part by the Caliguiri Fund for Amyloidosis Research, Robert A. Kyle Hematologic Malignancies Program, and Celgene. Patient Characteristics Median Range Age 64 44–88 Major Organs 2 0–3 Involved FLC, mg/dl 23 4.1–278 Serum alb, g/dl 2.8 1.2–3.7 Urine protein, g/24 hrs 3.7 0.02–14.3 Creatinine, mg/dl 1.3 0.7–2.6 Alkaline phos IU/l (nml <115) 99 57–1729 NY Heart Class 1 1–3 Troponin T, mcg/l 0.03 0.01–0.55 NT-proBNP, ng/l 1419 109–42844 LV Septum, mm 13 9–24 LV EF, % 63 22–72

Abstract Background: Multiple myeloma (MM) is an incurable disease with a anticipated overall survival (OS) ranging from months to decades. Modest improvements in OS have been made with high-dose chemotherapy with peripheral blood stem cell transplant (PBSCT), but to date prognostic factors have a greater impact on OS than do individual therapies. Patients with adverse risk factors such as elevated beta-2 microglobulin (B2M), plasma cell labeling index, deletions of the long arm of chromosome 13 by metaphase cytogenetics (del 13q) require innovative new treatment strategies. Bortezomib has significant activity in patients with both newly diagnosed and relapsed/refractory MM, but its specific role in patients with adverse features has not yet been defined. Methods: Patients with newly diagnosed “high-risk” myeloma (B2M ≥ 5.5., PCLI ≥ 1, or del 13q) and adequate organ and functional status were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients were scheduled to receive bortezomib 1.3 mg/m2 every other week indefinitely. Elective peripheral stem cell mobilization (growth factor alone) was allowed after 4 cycles of bortezomib. Patients relapsing on maintenance schedule were to have the full induction schedule resumed. Responses were by the EBMT criteria but a very good partial response category was included. The primary end-point was the response rate in these high-risk patients (90% power to detect a response rate of 50% or higher). The study decision rule requires that 16 or more responses, among 39 eligible patients, are seen in order to declare this treatment effective. Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled on study. Among the 43 eligible patients, median age was 63; 51% were male. All patients had high risk disease: del 13q (6/41); plasma cell labeling index ≥1% (16/34); and B2M≥5.5 (34/43). Preliminary response data are available for 18 of the 44 cases enrolled, of which 7 had partial response, 1 had minimal response, 1 had no response, 2 had progressive disease, and 5 were unevaluable. Among those patients completing induction therapy and with response information, the median number of cycles of therapy administered is 5, range (0,8). The most common non-hematologic adverse events (AEs) of grade 3 or higher included hyponatremia (9 patients) and diarrhea (6 patients). Mild sensory peripheral neuropathy was common: grade 1, 16 patients; grade 2, 2 patients. Only 1 patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses bortezomib due to heart block and asystole. Two patients had a grade 4, 25 patients had grade 3, and 13 had grade 1 or 2 as the worst grade non-hematologic adverse event. Based on data received by August 1, 2005, 18 patients have gone off study: AEs (2); death (1); progressive disease (9); and other reasons (6). Updated results on the full study population along with FISH data for IgH translocations and deletions of 13q and 17p will be presented at the meeting. Conclusions: Preliminary results suggest that upfront bortezomib has activity in patients with high-risk MM, but further follow-up is required.