Advanced Multiple Myeloma Research Articles

Adjusting for Patient Crossover in Clinical Trials Using External Data: A Case Study of Lenalidomide for Advanced Multiple Myeloma

ObjectivesIn some trials, particularly in oncology, patients whose disease progresses under the comparator treatment are crossed over into the experimental arm. This unplanned crossover can introduce bias in analyses because patients who crossover likely have a different prognosis than those who do not cross over; for instance, sicker patients not responding to standard therapy or those expected to benefit the most may be selectively chosen to receive the experimental treatment. Standard statistical methods cannot adequately correct for this bias. We describe an approach designed to minimize the impact of crossover, and illustrate this by using data from two randomized trials in multiple myeloma (MM). MethodsThe MM-009/010 trials compared lenalidomide and high-dose dexamethasone (Len+Dex) with dexamethasone alone (Dex). Nearly half (47%) of the patients randomized to Dex crossed over to Len with or without Dex (Len+/-Dex) at disease progression or study unblinding. Data from these trials was used to predict survival in an economic model evaluating the cost-effectiveness of lenalidomide. To adjust for crossover, the prediction equations were calibrated to match survival with Dex or Dex-equivalent therapies in trials conducted by the Medical Research Council (MRC) in the United Kingdom. To adjust for differences between the MM and MRC trial populations, a prediction equation was developed from the MRC data and used to predict survival by setting predictors to mean values for patients in the MM-009/010 trials. The expected survival with Dex without crossover was then predicted from the calibrated MM-009/010 equation (i.e., adjusted to match survival predicted from the MRC equation). ResultsThe adjusted median overall survival predicted by the MRC equation was 19.5 months (95%CI, 16.6–22.9) for patients with one prior therapy, and 11.6 months (95% CI, 9.5–14.2) for patients with >1 prior therapy. These estimates are considerably shorter than was observed in the clinical trials: 33.6 months (27.1-NE) and 27.3 months (95% CI, 23.3–33.3) as of December 2005. ConclusionThe calibration method described here is simple to implement, provided that suitable data are available; it can be implemented with other types of endpoints in any therapeutic area.

ATP Site-Directed Inhibitors of Protein Kinase CK2: An Update

CK2 denotes a pleiotropic, constitutively active protein kinase whose abnormally high level in many cancer cells is held as an example of "non oncogene addiction". A wide spectrum of cell permeable, fairly specific ATP site-directed CK2 inhibitors are currently available which are proving useful to dissect its biological functions and which share the property of inducing apoptosis of cancer cells with no comparable effect on their "normal" counterparts. One of these, CX-4945, has recently entered clinical trials for the treatment of advanced solid tumors, Castelman's disease and multiple myeloma. The solution of a wide range of 3D structures of inhibitors bound to the catalytic subunits of CK2 reveals that their efficacy substantially relies on hydrophobic interactions within a cavity which is smaller than in other protein kinases. Accordingly the potency of tetra-halogenated benzimidazoles increases upon replacement of chlorine by bromine and, even more, by iodine, and decreases if two unique bulky side chains on CK2 (Val66 and Ile174) are mutated to alanines. Many CK2 inhibitors have been tested on a panel of more than 60 kinases providing Promiscuity Scores useful to evaluate their selectivity, the lowest value (9.47), denoting highest selectivity, being displayed by quinalizarin. The observation that CK2 inhibitors with medium/high promiscuity scores share the ability to inhibit a group of protein kinases as effectively as CK2 discloses the possibility of using their scaffolds for the rational development of selective inhibitors of these kinases, with special reference to PIMs, DYRKs, HIPK2, PKD and ERK8.

The effect of elotuzumab on natural killer (NK) cell function against multiple myeloma (MM).

2572 Background: Elotuzumab (Elo), an anti-CS1 monoclonal antibody (mAb) in development for MM, exerts anti-MM effects via NK cell-mediated ADCC. CS1 is also expressed on NK cells. We provide data to suggest that Elo may enhance NK cell cytotoxicity via mechanisms beyond ADCC. Methods: Primary cells were procured under IRB-approved protocols. Interferon-gamma (IFN-g) and granzyme B (GrB) production were measured by ELISPOT, NK92 cytotoxicity was determined by chromium release. Flow cytometry characterized NK cell subsets and effects of Elo on NK cell activation. Elo, Elo-G2M3 (non-CD16 binding), and isotype mAbs were from Abbott Biotherapeutics Results: Pts with advanced MM have proportionally fewer cytotoxic CD56dim NK cells in peripheral blood (22%+/-2) vs. pts with early MM (69%+/-10, n=8, p=0.005). While Elo increased CD69 expression on healthy donor NK cells (22.8%+/-7) vs. isotype (4.8% +/- 3, n=5, p = 0.01), no increase in NK cell cytotoxicity against autologous NK cells was observed. Across a rang...

A phase I study evaluating GDC-0941, an oral phosphoinositide-3 kinase (PI3K) inhibitor, in patients with advanced solid tumors or multiple myeloma.

3021 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent inhibitor of class I PI3K and demonstrates broad activity in preclinical xenograft models. Methods: A 2-stage phase I study of GDC-0941 was initiated (GDC4254g). Stage 1 utilized a 3+3 escalation design in patients (pts) with advanced solid tumors. Stage 2 is an expansion phase including pts with multiple myeloma, PIK3CA mutant (mt) tumors, and tumors evaluable by magnetic resonance imaging (MRI) methods. A single dose of GDC-0941 was administered followed by a 1-week washout and then QD dosing on a 21/28- or 28/28-day dose schedule. Objectives include: safety, pharmacokinetics, pharmacodynamic (PD) endpoints in tumor and platelet rich plasma (PRP); evaluating the use of imaging modalities (FDG-PET and functional MRI studies); and examining any relationship of PIK3CA mt status and PTEN expression and clinical activity. Results: Stage 1 has been completed with 42 pts enrolled in 11 cohorts (15-450 mg QD, 21/28-day schedule). Drug-related adverse events (AEs) reported in ≥ 10% of pts were nausea, diarrhea, fatigue, vomiting, dysgeusia, and decreased appetite. The MTD was exceeded at 450 mg with DLT of Grade (Gr) 3 maculopapular rash in 2 pts. Other drug-related AEs ≥ Gr 3 have been Gr 3 fatigue at 450 mg, Gr 3 neutropenia at 330 mg, and Gr 4 hyperglycemia at 130 mg. GDC-0941 displays dose-proportional PK. Decreased levels of pAKT in PRP correlated with GDC-0941 plasma concentrations. Signs of clinical activity include a partial response by RECIST in a pt with melanoma (V600E RAF mt) treated at 330 mg on-study for > 9 mo; a small bowel GIST (cKIT exon 9 mt) pt treated at 450 mg with 49% decrease by FDG-PET on-study for >7 mo; and an ovarian cancer (PTEN negative) pt treated at 100 mg with 30% decrease by FDG-PET, 56% decrease in pS6 staining in paired biopsies, and 80% decrease in CA-125 who was on study for ~5 months. Conclusions: GDC-0941 is generally well tolerated below 450 mg QD with signs of anti-tumor activity. Decreases in the PD markers pAKT and pS6 are consistent with downstream modulation of the PI3K pathway. The potential phase II dose is under evaluation.

Abstract 4569: Cell death-inducing ICAM-1 antibody has broad and potent anti-myeloma activity in vivo

Abstract We previously developed combined target and drug discovery methodology enabling isolation of tumor cell death-inducing antibodies from the human antibody library n-CoDeR®. Among several antibodies targeting different tumor cell associated receptors with documented cell death-inducing properties, antibodies specific for intercellular adhesion molecule-1 (ICAM-1) – a receptor not previously associated with tumor cell death- were obtained. We here characterize the ICAM-1 specific antibody BI-505 with respect to in vivo anti-tumor activity in different well-established tumor disease models, and explore mechanisms underlying its anti-tumor activity. We demonstrate in different tumor xenograft models that BI-505 is equally or more efficacious in preventing CD20 positive B cell tumor growth and in pro-longing tumor-bearing mouse survival compared to CD20 mAb Rituximab in vivo. Moreover, BI-505 showed significant anti-tumor activity against a panel of CD20 negative myeloma tumors in vivo, and BI-505 conferred enhanced mouse survival compared to the proteasome inhibitor bortesomib – approved for treatment of relapsed refractory multiple myeloma – in an experimental model of advanced multiple myeloma. Preliminary data indicate that the BI-505 epitope is highly expressed on myeloma cells in patients with multiple myeloma. The differential in vitro and in vivo anti-tumor activities of BI-505 Fc-variants correlated with binding to recombinant human FcγRIIIa and mouse FcγRIV receptors, respectively. These differences could not be explained by altered antigen-binding properties as all Fc-variants retained near identical EC50 values for binding to recombinant or cell surface expressed ICAM-1 protein. These observations are consistent with cell death and FcγR-dependent anti-tumor immunity being important mechanisms underlying BI-505 therapeutic activity. Collectively, our results demonstrate proof-of-principle for our human antibody based combined target and drug discovery methodology, and provide a rationale for further pre-clinical and clinical evaluation of BI-505 in the treatment of MM. An open multicenter phase I dose-escalation clinical trial with BI-505 in relapsed/refractory MM has recently started in the United States and Sweden. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4569. doi:10.1158/1538-7445.AM2011-4569

Lenalidomide is effective as salvage therapy in refractory or relapsed multiple myeloma: analysis of the Spanish Compassionate Use Registry in advanced patients

We evaluated the clinical results of lenalidomide (Len) as a compassionate salvage therapy in refractory/relapsed multiple myeloma (MM) patients. A nationwide multi-centre, retrospective research study was performed to evaluate clinical data from patients with advanced MM for which compassionate use of lenalidomide was requested. The primary endpoints were the overall response rate (ORR) and the time to progression (TTP). Secondary objectives included safety and overall survival (OS) since starting of lenalidomide therapy. Data collected from the Spanish Compassionate Use Registry included 111 patients treated in 2006-2008. The median (range) number of previous treatment lines was 3 (1-8). The median duration of lenalidomide treatment while on study was of 4.9months (1-18). Dexamethasone was given concomitantly with Len in 89% of patients. The ORR was 66% (4% of patients had stringent complete, 11% complete and 11% very good partial responses). Median TTP and OS were 13.0 and 17.4months, respectively. The depth of response was significantly associated with a longer OS. Toxicity, mainly myelosuppression, was predictable and manageable with Len dose adjustments and cytokine support. Lenalidomide as salvage compassionate therapy in refractory/relapsed MM showed, in this series of heavily pre-treated patients, similar efficacy to that reported in pivotal clinical trials with acceptable tolerance.

Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma

This study compared denosumab, a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand antibody, with zoledronic acid (ZA) for delaying or preventing skeletal-related events (SRE) in patients with advanced cancer and bone metastases (excluding breast and prostate) or myeloma. Eligible patients were randomly assigned in a double-blind, double-dummy design to receive monthly subcutaneous denosumab 120 mg (n = 886) or intravenous ZA 4 mg (dose adjusted for renal impairment; n = 890). Daily supplemental calcium and vitamin D were strongly recommended. The primary end point was time to first on-study SRE (pathologic fracture, radiation or surgery to bone, or spinal cord compression). Denosumab was noninferior to ZA in delaying time to first on-study SRE (hazard ratio, 0.84; 95% CI, 0.71 to 0.98; P = .0007). Although directionally favorable, denosumab was not statistically superior to ZA in delaying time to first on-study SRE (P = .03 unadjusted; P = .06 adjusted for multiplicity) or time to first-and-subsequent (multiple) SRE (rate ratio, 0.90; 95% CI, 0.77 to 1.04; P = .14). Overall survival and disease progression were similar between groups. Hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred at similarly low rates in both groups. Acute-phase reactions after the first dose occurred more frequently with ZA, as did renal adverse events and elevations in serum creatinine based on National Cancer Institute Common Toxicity Criteria for Adverse Events grading. Denosumab was noninferior (trending to superiority) to ZA in preventing or delaying first on-study SRE in patients with advanced cancer metastatic to bone or myeloma. Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.

A new combination for advanced multiple myeloma

A new combination for advanced multiple myeloma

Sudden significant total protein concentration change: not an analytical problem

Sudden and significant total protein concentration changes in multiple myeloma (MM) can be associated with new treatment regimens. We present an example of a 66-year-old male with a total protein concentration of 74 g/L, albumin 27 g/L, and a monoclonal IgG concentration of 22.2 g/L before commencing lenalidomide treatment. The patient represented 8 days later and the total protein concentration was 66 g/L, albumin 32 g/L with a monoclonal IgG concentration of 10.3 g/L. The total protein and albumin measurements were performed on Beckman DxC800 analysers using bieuret and bromcresol purple methods, respectively (Beckman Coulter Diagnostics, Fullerton, CA). The IgG was performed on Beckman Image analyser (Beckman Coulter Diagnostics). It is regularly observed that patients with the new drug treatments have total proteins, more accurately the specific immunoglobulin decreasing significantly in a matter of days. Generally, the remaining biochemical profiles undergo minimal change. To laboratorians such a major significant change in total protein concentration will trigger alarms (including possibly delta check flags) of possible analytical errors: sampling accuracy or possible assay interference. This leads to additional investigations by laboratorians, which would include sample integrity checks (sufficient volume, microclots, bubbles), possible re-analysis, running additional quality control samples, changing total protein reagents, withholding of results until communication with other professionals including the clinical unit occur, and leading to delay in reporting of the results and added costs. MM is currently an incurable hematological malignancy. Monoclonal gammopathy, a common predisposing disease, occurs in 3% of persons 50 years of age or older (1). It is characterized by the clonal expansion of monoclonal immunoglobulin-secreting plasma cells within the bone marrow. The overall median survival for patients with MM without treatment is approximately 3 years. It is the second most common hematologic malignancy, and the most common cancer to involve bone. The cause of MM is unclear. Exposure to radiation, herbicides, insecticides, benzene, and other organic solvents may play a role. Until recently the standard treatment involved a combination of oral melphalan and prednisolone. Allogeneic transplantation was first attempted in the early 1980s, and it became routine therapeutic practice in the 1990s (2), but is not widely used due to high treatment-related mortality. Autologous stem cell transplant (ASCT) has become the treatment of choice. For patients unable to undergo ASCT, including elderly patients (465 years), or patients relapsing after ASCT there have been few treatment options. Singhal et al. in 1999 (3) indicated that thalidomide, an oral agent with anti-angiogenic and immunomodulatory properties, was able to induce objective responses in 30% of patients with refractory and advanced MM. In 2006, thalidomide was approved by the US FDA, and more recently lenalidomide (approved by FDA in 2006, European Union in June 2007), a thalidomide analog with up to 50,000-fold increased potency, (4) and bortezomib, a proteasome inhibitor (approved by US FDA in May 2003), have been added and used as salvage agents for the treatment of relapsed and refractory MM. Trials of these agents as frontline therapy are underway with very promising initial results. These new drugs are cytotoxic to MM cells in the bone marrow. Therefore, rapid and significant changes in total protein concentrations, globulin or specific immunoglobulin are expected.

Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma

Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma

Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma

Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma

Transcriptional Silencing of the Wnt-Antagonist Dickkopf-1 (DKK1) by Promoter Methylation Unleashes Aberrant Wnt Signaling In Advanced Multiple Myeloma

AbstractAbstract 1919Aberrant activation of the Wnt/β-catenin pathway is implicated in driving the formation of various human cancers. Recent studies indicate that the Wnt pathway plays at least two distinct roles in the pathogenesis of multiple myeloma (MM): i) Aberrant, presumably autocrine, activation of canonical Wnt signaling in MM cells promotes tumor proliferation and metastasis; ii) Overexpression of the Wnt inhibitor Dickkopf1 (DKK1), contributes to osteolytic bone disease by inhibiting osteoblast differentiation. Since DKK1 itself is a target of TCF/β-catenin mediated transcription, these findings suggests the presence of a negative feedback loop in MM, in which DKK1 acts as a potential tumor suppressor. In line with this hypothesis, we show here that DKK1 expression is lost in most MM cell lines and in a subset of patients with advanced MM. This loss is correlated with activation of the Wnt pathway, as demonstrated by increased nuclear accumulation of β-catenin. Analysis of the DKK1 promoter revealed CpG island methylation in several MM cell lines as well as in MM cells from patients with advanced MM. Moreover, demethylation of the DKK1 promoter restores DKK1 expression, which results in inhibition of β-catenin/TCF-mediated gene transcription in MM lines. Taken together, our data identify aberrant methylation of the DKK1 promoter as a cause of DKK1 silencing in advanced stage MM, which may play an important role in the progression of MM by unleashing Wnt signaling. Disclosures:No relevant conflicts of interest to declare.

Updated Results of a Phase I Study of RAD001 In Combination with Lenalidomide In Patients with Relapsed or Refractory Multiple Myeloma with Pharmacodynamic and Pharmacokinetic Analysis

AbstractAbstract 3051 Background:Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (MM) patients following ≥1 prior therapy. RAD001, an mTOR inhibitor has been studied as a single agent in MM, and although well tolerated, did not have single agent activity. Informed by our previous studies demonstrating synergistic anti-MM activity of mTOR inhibitors when combined with Len, we studied this combination to evaluate its safety and activity as a non-steroid containing oral regimen in advanced MM. Methods:Patients with relapsed and refractory MM were assigned to Len and RAD001 to be taken for 21 days of a 28 day cycle (NCT00729638) in a standard 3+3 design. Patients were allowed to continue therapy until disease progression or unacceptable toxicity and were required to receive concomitant anti-thrombotic (aspirin 81 or 325 mg/day) therapy. Peripheral blood and bone marrow samples were collected before and after treatment for pharmacokinetic and pharmacodynamic studies. Results:Twenty-eight patients were registered on the trial between December 2008-December 2009. Two patients were inevaluable because of either rapidly progressive disease or failure to meet eligibility criteria on day 1. Data on 26 patients are therefore available. Pts had received a median of 4 prior lines of treatment.14 pts had received Len previously of which 11 pts had relapsed disease and 3 pts had relapsed/refractory disease. Both cohort 1 (Len: 10mg/day and RAD001: 5mg/every other day ×21 days of 28 day cycle) and 2 (Len: 15mg/day and RAD001: 5mg daily ×21 days of 28 day cycle) required expansion because of grade 3 neutropenia and grade 4 thrombocytopenia. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 patients in cohort 3 (Len: 20mg and RAD001: 5 mg × 21 days). The maximum tolerated dose (MTD) was therefore declared at 15 mg of len and 5mg of RAD001 for 21 days with a 7 day rest period. Most common (≥10%) Grade 1/2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which proved manageable with supportive care. One patient developed RAD related non-infectious pneumonitis requiring therapy discontinuation. Grade 3/4 adverse events (≥ 5%) included thrombocytopenia (11%) and neutropenia (22%). Nineteen patients completed 2 cycles and were evaluable for response. Median follow up is currently 8.7 months and median PFS is 4.3 months, with 12 patients receiving treatment at MTD. Overall response rate was 68% (13/19) (90% CI: [30-76%]) including CR(1) PR(2), MR(8) and SD(2). Four patients continue on the combination at 13, 14, 15 and 17 months respectively.Pharmacokinetic and pharmacodynamic data including immunohistochemistry for phosphorylated AKT, cytokine profiles, T cell subsets and transcription profile on MM cell pre and post treatment as well as correlation of response with pharmacodynamic studies will be presented. Conclusions:The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. Promising responses were noted in this heavily pretreated patient population with advanced MM. This combination thus provides an oral steroid free combination treatment strategy which warrants future evaluation in phase II studies. Disclosures:Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Adams:Novartis: Employment. Makrides:Celgene: Employment. Munshi:Millennium Pharmaceuticals: Honoraria, Speakers Bureau. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Raje:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Astra Zeneca: Research Funding; Acetylon: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide and RAD 001 for treatment of relapsed and refractory multiple myeloma.

Elotuzumab In Combination with Lenalidomide and Dexamethasone In Patients with Relapsed Multiple Myeloma: Interim Results of a Phase 2 Study

AbstractAbstract 986 Introduction:Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, an antigen highly and uniformly expressed on multiple myeloma (MM) cells but with restricted expression on normal cells. Elotuzumab exhibits significant antimyeloma activity in vitro and against MM xenografts, and its antitumor activity is enhanced independently by both lenalidomide and dexamethasone. In a dose-escalation phase 1 study that evaluated the combination of elotuzumab (5, 10, and 20 mg/kg), lenalidomide, and dexamethasone, the maximum tolerated dose was not reached, and the combination showed encouraging clinical activity (82% response rate) in patients with advanced MM. The most frequent infusion-related adverse events (AEs) were headache (21%), nausea (21%), and dizziness (11%), with 7% (2/28) of patients experiencing 3 serious infusion-related AEs during cycle 1 (1 with a grade 4 hypersensitivity reaction and 1 with 2 grade 3 stridor events). Key objectives of this dose randomized, open-label, multicenter, phase 2 study in patients with relapsed MM were to select the optimum dose of elotuzumab and to evaluate an enhanced premedication regimen to minimize the occurrence of infusion reactions. Methods:Patients with confirmed relapsed and/or refractory MM who had received 1–3 prior therapies were enrolled; prior lenalidomide therapy was excluded. Patients were randomized 1:1 to receive elotuzumab either 10 or 20 mg/kg (IV infusion on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles and then days 1 and 15 of subsequent cycles), along with lenalidomide 25 mg PO daily on days 1 to 21 and dexamethasone 40 mg PO weekly. Patients were treated until disease progression or unacceptable toxicity, if earlier. To control potential infusion reactions, patients received methylprednisolone (50 mg IV), diphenhydramine (25–50 mg PO or IV) or equivalent, ranitidine (50 mg IV) or equivalent, and acetaminophen (650–1000 mg PO) 30 to 60 minutes prior to each elotuzumab infusion. Objective responses (OR) were assessed according to the International Myeloma Working Group (IMWG) criteria. Results:As of July 8, 2010, a total of 59 patients were randomized (intent to treat population); 47 patients received at least 1 dose of study medication (safety population); and 26 patients completed or progressed prior to completing 2 cycles of treatment (efficacy population). Median age was 64 years; 36 (61%) had received ≥2 prior therapies; 28 (48%) and 31 (53%) had received bortezomib or thalidomide, respectively, and 40 (68%) had undergone transplantation. Among efficacy evaluable patients, 22/26 (85%) had a confirmed or an unconfirmed response (≥ PR) including 31% VGPR/CR. The remaining 4/26 (15%) had stable disease (Table). Treatment-emergent AEs were reported in 36/47 patients (77%); the most common events were fatigue (26%) and nausea (21%). Serious treatment-emergent AEs were reported in 22% of patients; 2 events, nausea and febrile neutropenia with thrombocytopenia, were considered to be related to elotuzumab and lenalidomide. The most common infusion-related AEs within 24 hours of elotuzumab infusion were dizziness (15%), nausea (15%), and headache (9%). These decreased in frequency after the first treatment cycle. There were no severe AEs associated with infusion reactions. Conclusion:The combination of elotuzumab, lenalidomide, and dexamethasone resulted in a high response rate in patients with advanced MM and was generally well tolerated. These results are consistent with the results previously reported from the phase 1 study. The revised premedication regimen appeared to be more effective in controlling infusion reactions, which were generally mild to moderate with no severe infusion reactions reported to date. Updated response and safety data on all patients by dose level will be presented at the meeting. Disclosures:Richardson:Millennium, Celgene, Johnson & Johnson, Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide. Moreau:Celgene, Facet, Bristol-Myers Squibb: Honoraria. Jakubowiak:Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson Ortho-Centocor: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor-Ortho Biotech: Speakers Bureau. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Millennium, Takeda Pharm, Janssen: Honoraria. Vij:Bristol-Myers Squibb: Honoraria; Celgene: Research Funding; Celgene, Bristol-Myers Squibb: Speakers Bureau. Reece:Celgene: Honoraria, Research Funding. Rossi:Sanofi-Aventis, Celgene: Consultancy, Honoraria. Tsao:Facet Biotech: Employment. Fry:Facet Biotech: Employment. Berman:Bristol-Myers Squibb: Employment. Singhal:Facet Biotech: Employment. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

Cig-FISH-Analysis of Extramedullary Myeloma Manifestations Shows Similar Incidence of Prognostic Genetic Aberrations Compared to Bone Manifestations or Soft Tissue Involvement

AbstractAbstract 4993 Introduction:Extramedullary organ impairment in patients with multiple myeloma (MM) is a very rare event, mostly occurring during disease relapse after high-dose chemotherapy with autologous or allogeneic stem cell transplantation. Recent data reported by different authors suggest a very unfavorable outcome and rapid clinical course for patients with extramedullary relapses. Often the extramedullary manifestations are associated with special biological features, such as loss of CD56 expression or plasmablastic cell morphology.In this context, only one FISH study of 9 MM patients reported that the incidence of TP53 deletions in the bone marrow of those MM patients with central nervous system (CNS) involvement was about 75% higher than in the MM patient without CNS involvement. However, there is a lack of genetic data for specific extramedullary manifestations. We herein report the first cytogenetic investigation of extramedullary organ infiltrations compared to bone lesions or consecutive soft tissue impairment of MM patients using cIg-FISH on paraffine embedded sections. Material and method:We investigated paraffin-embedded sections of different extramedullary organ manifestations of 13 MM patients and 11 MM patients with bone or soft tissue impairment originating from a bone lesion. Extramedullary organ involvements comprised biopsies from skin, pleura, pleural effusion, uterus, liver, CNS, subcutaneous soft tissue, lymph node, and thyroid gland, attained at different stages of the disease. The second group consisted of bone lesions or surrounding soft tissue, like muscle, which was infiltrated per continuitatem. For investigation of paraffine-embedded samples, we further developed the conditions of the well known cIg-FISH method to utilize all the advantages of this very sensitive method. We evaluated the most important prognostic chromosomal regions in MM using the following FISH-probes:13q14 (D13S25), 17p13 (TP53), 8q24 (MYC), t(4;14) (FGFR3/MMSET;IGH). Results:The incidences in the group of extramedullary organ involvement vs. bone and soft tissue were as follows:deletion of TP53: 23% vs. 18%MYC-overrepresentation: 36% vs. 36%deletion of 13q14: 18% vs. 36%t(4;14) 42% vs. 30%The incidence of TP53 deletions in organ infiltrations by malignant plasma cells was similar to bone or soft tissue involvement. Our result for MYC-overrepresentation is in line with the findings of recent analysis of bone marrow aspirates from patients with advanced multiple myeloma (32%) and showed again no difference between the two groups. Incidences of 13q14 deletion and t(4;14) varied slightly between the two groups, but are in range with other cIg-FISH-analyses on bone marrow plasma cells. Discussion:In this first cytogenetic investigation of extramedullary manifestations in MM patients, we showed similar frequencies of the chromosomal regions analyzed in the group of organ infiltrations by malignant plasma cells compared to bone or soft tissue involvement. All in all we could not detect differences in the incidence of the most relevant genetic aberrations of the investigated tissue probes compared to already well known bone marrow cytogenetics. Interestingly, this is in contrast to the findings of bone marrow probes in the study with patients with MM and CNS involvement, who showed a higher incidence of TP53 deletions. Concerning the group of soft tissues, originating from bone lesions this is not astonishing, maybe even expected. However, this work analyzed bone marrow of the MM patients and not the extramedullary manifestation, as we did. Further investigations or larger patient samples are needed to proof if these or other genetic aberrations are associated to the aggressive course of extramedullary manifestations of MM. Disclosures:No relevant conflicts of interest to declare.

Elotuzumab In Combination with Lenalidomide and Low-Dose Dexamethasone In Patients with Relapsed/Refractory Multiple Myeloma: Interim Results of a Phase 1 Study

AbstractAbstract 1936 Background:Elotuzumab is a humanized monoclonal IgG1 antibody targeting CS1, which is highly and uniformly expressed on multiple myeloma (MM) cells, and important to myeloma cell survival. Elotuzumab exerts significant antitumor activity against primary myeloma cells via NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), regardless of sensitivity or resistance to conventional therapies. In preclinical studies, the activity of elotuzumab is independently enhanced by lenalidomide and dexamethasone. We present the results of an ongoing phase 1 study evaluating the maximum tolerated dose (MTD), safety, clinical response, and pharmacokinetics of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed/refractory MM. Methods:Entry criteria included patients who had measurable disease, had experienced at least 1 relapse, and had not received lenalidomide for at least 6 weeks before the first dose of elotuzumab. The study enrolled 3 escalating dose cohorts of elotuzumab (5, 10, and 20 mg/kg IV), administered on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles, and then days 1 and 15 of each subsequent cycle, along with lenalidomide 25 mg PO daily on days 1 to 21 and dexamethasone 40 mg PO weekly. At each dose level, dose-limiting toxicities (DLTs) were assessed during cycle 1 and clinical responses were evaluated with International Myeloma Working Group (IMWG) criteria during each cycle. The first 5 patients received up to 6 cycles of therapy before a protocol amendment allowed subsequent patients to be treated until disease progression. Results:Twenty-nine patients with advanced MM (median stage III) who had received a median of 3 prior MM therapies, including bortezomib (69%), thalidomide (59%), or lenalidomide (21%), were enrolled. Of these, 28 received elotuzumab; 3 patients each were treated with 5 and 10 mg/kg and 22 with 20 mg/kg. Patients received a median of 8.5 treatment cycles and 20.5 doses of elotuzumab. Sixteen patients have permanently discontinued study treatment. No DLTs were observed up to 20 mg/kg during the escalation phase and hence no MTD was established. The most frequent grade 3/4 toxicities were neutropenia (36%) and thrombocytopenia (21%); 2 patients experienced 3 serious infusion-related reactions (1 patient with a grade 4 hypersensitivity reaction and 1 with 2 grade 3 stridor events) during the first treatment cycle. Objective responses (partial response or better) were obtained in 82% (23/28) of treated patients and 96% (21/22) of lenalidomide-naïve patients. ORRs were also high in patients who had received prior thalidomide 94% (15/16) or whose disease was refractory to the most recent therapy 82% (9/11). The median time to response was 7 weeks. The proportion of patients without disease progression (Kaplan-Meier estimate) at 16 months is 53% for total patients and 66% for patients in the 20 mg/kg elotuzumab cohort, who are being treated until disease progression. The median time to progression was not reached. Conclusions:The combination of elotuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated and showed encouraging overall response rates in patients with relapsed/refractory MM who had received multiple prior therapies. A larger phase 2 study is ongoing to confirm the rate and durability of the responses observed in this phase 1 trial. Disclosures:Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding. Vij:Bristol-Myers Squibb: Honoraria; Celgene: Research Funding; Celgene, Bristol-Myers Squibb: Speakers Bureau. Harousseau:Bristol-Myers Squibb, Celgene, Janssen-Cilag, Novartis, Onyx: Honoraria; Celgene, Janssen-Cilag: Speakers Bureau. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Moreau:Celgene, Facet Biotech, Bristol-Myers Squibb: Honoraria. Leleu:Janssen-Cilag, Celgene, Chugai Pharmaceutical, Roche, Amgen, Novartis, Leo Pharma: Consultancy, Honoraria, Research Funding. Kaufman:Celgene, Millennium: Consultancy; Celgene, Merck: Research Funding. Westland:Facet Biotech: Employment. Tsao:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Jagannath:Millennium, Takeda Pharmaceutical Company, Janssen-Cilag: Honoraria.

MiR-15a and Mir-16-1 Affects the Angiogenesis of Multiple Myeloma by Targeting VEGF-A

AbstractAbstract 4039MicroRNAs (miRNAs) are non-coding small RNAs that negatively modulate protein expression at a post-transcriptional level and are deeply involved in the pathogenesis of a variety of cancers. Two miRNAs, miR-15a and miR-16, which act as putative tumor suppressor by targeting the oncogene BCL2, have been implicated in cell cycle, apoptosis and proliferation. Here we investigated the possible role of miR-15a/miR-16 in the angiogenesis of multiple myeloma (MM). Using stem-loop quantitative reverse transcription-PCR analysis, we showed that miR-15a/miR-16 are significantly underexpressed in primary MM cells as well as MM cell lines (RPMI 8226, ARH-77, OPM-2, KM3, U266 and NIH929). The aberrant expression of miR-15a/miR-16 were detected especially in advanced stage multiple myeloma. The expression of miR-15a and miR-16-1 were remarkably lower in stage III MM patients (n=23), whereas it were significantly higher in healthy individuals (n=18) and stage 2, II MM patients (n=14) (P<0.01 and P<0.001, respectively). In human MM cell lines and normal plasma cell, expression of miR-15a/miR-16 inversely correlated with the expression of vascular endothelial growth factor (VEGF). Consistently with the proposed role of miRNAs as key regulators of angiogenesis, here we identified VEGF-A as a target for miR-15a and -16. Enforced miR-15a or miR-16 expression reduced VEGF-A protein level and the luciferase reporter assays demonstrated that miR-15a and -16 specifically suppress expression of VEGF-A by directly interacting with its 3′-untranslated region. Moreover, Ectopic overexpression of miR-15a and -16 led to decreased pro-angiogenic activity of MM cells. Conditioned medium of pri-miR-15a- and pri-miR-16- transfected RPMI 8226 cells inhibited human bone marrow microvascular endothelial cell (BMEC-1) proliferation, chemotactic motility and capillary formation in vitro as compared with conditioned medium of scramble probe-transfected RPMI 8226 cells (P<0.05). Finally, miR-15a/miR-16 was shown to greatly inhibit the process of tumor formation in an animal model. Infection of lentivirus-miR-15a or lentivirus-miR-16 can significantly inhibit the xenograft tumor growth in nude mice. The average tumor volume after 4 weeks for GFP-transfected cells was 372.5 mm3. While the average tumor volume for miR-15a-transfected cells was 47 mm3 (P<0.05) and for miR-16-transfected cells was 93.6 mm3 (P<0.05). Of interest, neoangiogenesis analysis by immunohistochemistry staining of anti-CD31 showed that there were significant reductions in microvessel density present in the miR-15a group and miR-16 group as compared to control (P<0.05). Take together, our findings suggested that miR-15a and miR-16 could play a role in the tumorigenesis of MM at least in part by modulation of angiogenesis through targeting VEGF-A. These findings have therapeutic implications and may be exploited for future treatment of MM. Disclosures:No relevant conflicts of interest to declare.

Super (S)-Beam for Advanced and Refractory Multiple Myeloma (ARMM)

AbstractAbstract 4800 Background:Despite availability of novel agents, many MM patients still relapse and require salvage interventions. In the Arkansas program, we have attempted to procure initially sufficient hematopoietic precursor cells, for use in high-dose therapy salvage regimens once phase I-II trials have been exhausted. We are reporting on the efficacy in terms of response rate, EFS and OS of ARMM patients receiving S-BEAM. Patients and Methods:S-BEAM comprised standard BEAM (carmustine 300 mg/m2 on day 1, etoposide 200 mg/m2 days 1–4, cytarabine 400 mg/m2 days 1–4, melphalan 140 mg/m2 on day 5) with the addition of cisplatin (10-12.5mg/m2/d CI × 5d), bortezomib (1.3-1.5mg/m2 on days 1 + 4), thalidomide (100-200mg/d for 5 days) or lenalidomide (25-100mg/d for 5 days), DEX (40-100mg/d for 5 days) plus rapamycin (3mg d1, 1mg d2-5). Statistical methods included Cox regression modeling using significance level 0.05 and Kaplan-Meier methodology for all figures. Comparisons within figures were made using the log-rank test. Results:The characteristics of 147 patients treated included prior transplant (Tx) in 67% (2Tx, 29%; =>3Tx, 11%), and prior exposure and resistance in virtually all patients (92%) to bortezomib, thalidomide, lenalidomide applied in VTD, VRD or with chemotherapy VTD-PACE. Pre-S-BEAM high-risk features included low albumin (<3.5g/dL; 66%) high B2M (>=3.5mg/L; 32%), high LDH (>=ULN; 44%), and presence of cytogenetic abnormalities (CA) in 70%. Clinical outcomes included at least PR in 62% including 48% with n-CR and 29% with CR. Two-year estimates of EFS and OS were 29% and 33%; TRM within 60 days was 3%. At 4 years, 23% remain alive and 15% event-free. Independently significant variables affecting both OS and EFS adversely included, in a model without GEP, high B2M (>5.5mg/L), high LDH (>=ULN), low hemoglobin (<10g/dL) and CA, whereas achieving PR improved survival. Based on R2-driven independent adverse variables, B2M, LDH and CA were linked to poor outcomes, with 1-year estimates of OS/EFS of 83%/69% with 0, 63%/52% with 1, 25%/9% with 2, and 13%/0% with more than 2 high-risk parameters. Gene expression profiling (GEP)-defined high-risk was present in 55% (70 genes, R70) and in 47% (80 genes, R80); delTP53 was noted in 21% and Proliferation Index (PI) score >=10 in 42%. When GEP data were included in a subset of 103 patients, high-risk designation, high LDH and age >=65 were identified on the basis of highest R2 values (49% for OS, 41% for EFS). Among 28 patients lacking any of these 3 features, 1-year OS/EFS was 83%/67%, with 1 variable (n=36) 53%/38%, with 2 (n=31) 22%/6% and with 3 (n=8) 0%/0% (both P<0.001). Applying a cut-off of 2 adverse variables, the 60 patients with 2 or fewer enjoyed 2-year OS of 49% and EFS of 48%, as opposed to 7% and 4%, respectively, among the remaining 36 patients with more than 2 risk features. Conclusion:S-BEAM provides effective salvage therapy in ARMM with 60-day TRM of 3% and prognostic factor-dependent survival expectation. We are currently evaluating S-BEAM earlier in the disease course, with PAC-MED as induction prior to and as consolidation after S-BEAM in high-risk myeloma.Multivariate analysesOS from Super-BEAMEFS from Super-BEAMMVVariable%HRP-valueHRP-value1. SPF + GEP (n=96)Age ≥ 65 yr152.390.0022.160.004B2M > 5.5 mg/L213.42<.0013.49<.001Hb < 10 g/dL182.220.0271.810.076LDH ≥ 190 U/L571.610.1122.110.012GEP 70-gene high-risk543.36<.0013.23<.001GEP MF subgroup112.340.0431.410.406Achieved PR or better response*0.490.0240.490.0232. SPF only (n=136)Age ≥ 65 yr152.040.0212.160.004B2M > 5.5 mg/L152.96<.0012.100.011Hb < 10 g/dL161.610.0412.52<.001LDH ≥ 190 U/L542.38<.0012.020.002Cytogenetic abnormalities within 1 yr of Super-BEAM462.170.0102.26<.001Achieved PR or better response*0.510.0110.530.0103. GEP only (n=103)GEP 70-gene high-risk554.61<.0013.63<.0014. “Best 3” (R2), including GEP (n=103)Age ≥ 65 yr213.33<.0012.68<.001LDH ≥ 190 U/L421.710.0471.580.071GEP high-risk554.51<.0013.58<.0015. “Best 3” (R2), no GEP (n=136)B2M > 5.5 mg/L163.23<.0012.94<.001LDH ≥ 190 U/L462.080.0011.980.001Cytogenetic abnormalities within 1 yr of Super-BEAM682.70<.0012.66<.001Overall survival by number of non-GEP risk factors (B2M, LDH, CA), selected based on maximum R2 value (38% for OS, 33% for EFS) [Display omitted] Overall survival by number of risk factors (age, LDH, GEP high-risk), selected based on maximum R2 values (49% for OS, 41% for EFS) [Display omitted] Disclosures:No relevant conflicts of interest to declare.

First-In-Human Phase I Dose Escalation Study of a Humanized Anti-CD200 Antibody (Samalizumab) In Patients with Advanced Stage B Cell Chronic Lymphocytic Leukemia (B-CLL) or Multiple Myeloma (MM)

AbstractAbstract 2465 Background:The immunosuppressive molecule CD200 is upregulated on B-CLL and MM cells which may contribute to tumor immune evasion. Samalizumab is a novel first-in-class recombinant humanized monoclonal antibody that specifically binds CD200 and blocks CD200-CD200R interactions. Preclinical data suggest that CD200 blockade may inhibit CD200-dependent immune suppression, enabling a more efficient immune response against CD200+ tumor cells. A first-in-human phase I/II trial was initiated to evaluate safety, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamic (PD) activity of samalizumab. Methods:In this 3+3 design, dose-escalation trial, pts with advanced stage B-CLL or MM (with or without prior therapy) received a single IV dose of samalizumab. Pts could receive additional 28-day cycles (1 dose/cycle) if first dose was tolerated and pts exhibited at least stable disease (SD). Assessments performed throughout cycle 1 and then every 2 wks included standard safety measures, HAHA, PK, PD, CBC, and CT scans (at cycle 4 and every other cycle thereafter). Results:Results are reported as of 20-Jun-10. Enrollment is complete with 26 pts (18M; median age 67 yrs, range 41–87) including 3 MM pts (2 at 500 mg/m2, 1 at 600 mg/m2) and 1 pt with SLL (500 mg/m2). Four pts had no prior chemotherapy; the other 22 had received a median of 2 regimens (range 1–9). Twenty pts (1 MM) received multiple (2–14+) cycles of samalizumab (86+ cycles in total); safety and efficacy data are available for 25 pts through the 500 mg/m2 cohort. Adverse events were mostly mild or moderate and manageable; the most common events were fatigue (48%), fever (20%) and rash (20%). Grade 3–5 events included neutropenia (12%) and infections (12%); no events were indicative of a cytokine storm. One non-drug-, non-CLL-related death occurred. Three pts developed HAHA. Although preliminary PK analyses (Table 1) indicate high variability due to the limited number of pts and differences in tumor burden, the median AUC of serum drug levels after the first dose (300–500 mg/m2) are consistent with a linear relationship between dose and AUC. AUC in the low dose cohorts (50–200 mg/m2) is unreliable as most PK values were below the level of quantification. PD effects consistent with inhibition of CD200-dependent immune suppression by samalizumab were observed. Out of 21 pts with sufficient peripheral immune cells to evaluate, 18 (86%) showed 81–98% reductions in peripheral CD200+CD4+ T cells and 14 (67%) demonstrated 64–75% CD200 loss on B-CLL cells following the first dose. These responses were transient at lower doses (50–200 mg/m2) and sustained at higher doses (300–500 mg/m2), indicating a dose-dependent immunoregulatory effect. Eight of 21 evaluable pts (38%) showed an increase in CD200R+ CD4+ T cells. Regulatory T cell (Treg) levels decreased 20–57% (median = 38%) in 4/7 (57%) pts whose clinical disease stabilized or improved, whereas only 5/17 (29%) pts whose disease progressed clinically showed a similar decrease (13–62%; median = 18%). Modest first-dose Th1 cytokine responses were noted in 10/25 pts. Two pts who received ≥ 9 cycles showed reduction in tumor burden by CT scan (including 1 pt with a 58% reduction and near normalization of absolute lymphocyte cell count), associated with a reduction in Tregs and increase in activated T cells over time. No MTD was identified. Conclusion:Samalizumab appears to be well tolerated and exhibits a dose-dependent linear increase in serum AUC, dose-dependent changes in CD200+ B-CLL and CD4+ T cells, and modest Th1 cytokine responses. These PD effects are consistent with the predicted immunomodulatory mechanism of action. Anti-tumor activity is evident in some pts receiving multiple cycles. Treatment is ongoing with plans for additional studies of samalizumab to explore other dosing regimens.Table 1:Dosing, Safety, PK & PD Parameters by CohortSamalizumab Dose (mg/m2)No. pts (n = 25)PKEnrolledDosed ≥4 cyclesAE grade ≥3HAHA1st-dose Th1 CytokinesSystemic Clearance L/h median (range)Distributional Clearance L/h median (range)AUC mg h/mL median (range)50413120.01 (0.006–0.27)0.03 (0.0008–2.5)–100552000.04 (0.005–0.11)0.002 (0.001–0.003)–200310220.03 (0.007–0.06)0.02 (0.002–6.13)–300322010.01 (0.01–0.01)0.05 (0.02–0.6)28.13 (19–36)400321000.02 (0.01–0.02)0.13 (0.12–22.2)35.64 (30–38)500701050.02 (0.01–0.04)0.04 (0.02–0.41)45.09 (25–74) Disclosures:Mahadevan: Alexion Pharmaceuticals, Inc: Honoraria, Speakers Bureau. Whelden: Alexion Pharmaceuticals, Inc: Employment, Equity Ownership. Faas: Alexion Pharmaceuticals, Inc: Employment, Equity Ownership. Ulery: Alexion Pharmaceuticals, Inc: Employment, Equity Ownership. Kukreja: Alexion Pharmaceuticals, Inc: Employment, Equity Ownership. Li: Alexion Pharmaceuticals, Inc: Employment, Equity Ownership. Bedrosian: Alexion Pharmaceuticals, Inc: Employment, Equity Ownership. Heffner: Alexion Pharmaceuticals, Inc: Research Funding.

The efficacy and safety of bortezomib and dexamethasone as a maintenance therapy in patients with advanced multiple myeloma who are responsive to salvage bortezomib‐containing regimens

Although treatment for multiple myeloma (MM) has considerably improved in the past decade, MM continues to be an incurable hematological malignancy that causes most patients to eventually relapse and die from their illness. Thus, the identification of effective salvage strategies remains a priority. In this trial, the authors evaluated the safety and efficacy of bortezomib and dexamethasone [V: on days 1 and 15 (1.3 mg/mq); D: on days 1-2 and 15-16, every 28-day cycle until progression (20 mg/d)] as maintenance therapy (MT) in patients with advanced MM who responded to salvage therapy that used a bortezomib-containing regimen. Forty-nine MM patients were enrolled in this study between October of 2004 and April of 2008. All patients who were included in this study were responsive to a prior salvage therapy with bortezomib and had a measurable disease. The bortezomib and dexamethasone MT improved the quality of responses to complete remission in 4 patients and very good partial response in 3 patients. In addition, 10 patients experienced at least a 50% improvement in their symptoms. The median time to progression (TTP) was 16 months with a progression-free survival of 61% after 1 year. The overall response after 1 year was 76%, and the cumulative incidence of death due to disease progression, which was adjusted for competitive risk events, was 14%. Non-dose-limiting toxicities included neuropathy (predominantly grade 1), herpes zoster reactivation, pneumonia, and gastrointestinal affections (constipation and diarrhea). Three patients developed grade 2 neuropathy, which required a bortezomib dose reduction to 1.0 mg/mq. No grade 3 or 4 toxicities were recorded. The use of bortezomib and dexamethasone as MT in advanced MM was effective and well tolerated. The twice-monthly bortezomib infusion appeared to reduce the incidence of grade 3 and 4 neuropathies in comparison to similar experiences in other settings.