Untreated Multiple Myeloma Research Articles

Phase 1/2 Study of Oral MLN9708, A Novel, Investigational Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM)

Abstract 479 Background:MLN9708 is an investigational, oral, potent, reversible, and specific 20S proteasome inhibitor, which immediately hydrolyzes to MLN2238, the biologically active dipeptidyl leucine boronic acid. In preclinical studies, MLN2238 has shown faster proteasome dissociation and greater tissue penetration than bortezomib. Current phase 1 data indicate that oral administration of single-agent MLN9708 was generally well tolerated, with no grade ≥3 peripheral neuropathy, and showed signs of antitumor activity in some patients with relapsed and/or refractory MM. Bortezomib in combination with lenalidomide and dexamethasone demonstrated a 100% partial response or better (≥PR) rate in patients with previously untreated MM, providing the rationale for evaluating oral MLN9708 in place of bortezomib in this combination. Here we report phase 1 data from the first combination study of MLN9708 (ClinicalTrials.gov: NCT01217957). Methods:Primary phase 1 objectives were to determine the safety, tolerability, and maximum tolerated dose (MTD) of weekly MLN9708 in combination with lenalidomide and dexamethasone; secondary objectives included characterization of the pharmacokinetic (PK)/pharmacodynamic (PD) profile of MLN9708, assessment of PK interaction and response. Adults aged ≥18 years with ECOG performance status of 0 to 2, and adequate renal, hepatic, and hematologic function were eligible. Patients with grade ≥2 peripheral neuropathy or prior/concurrent deep vein thrombosis (DVT)/pulmonary embolism were excluded. Patients received oral MLN9708 weekly on days 1, 8, and 15, lenalidomide 25 mg on days 1–21, and dexamethasone 40 mg on days 1, 8, 15, and 22, for up to twelve 28-day cycles. Patients received thromboprophylaxis with aspirin or low molecular weight heparin. Transplant-eligible patients could undergo stem cell transplant after six cycles. MLN9708 dose escalation, from a starting dose of 1.68 mg/m2, followed a 3+3 scheme based on the occurrence of dose-limiting toxicities (DLTs) in cycle 1. Adverse events (AEs) were evaluated according to NCI-CTCAE v4.0. Response was assessed according to modified EBMT criteria. Results:At data cut-off (June 29, 2011), 10 patients have been enrolled and treated: three each at 1.68, 2.23, and 2.97 mg/m2 and one at 3.95 mg/m2; median age was 66 years (range 59–77). Patients completed a median of 3 cycles (range 1–6), with three having received 6 cycles; treatment is ongoing in six patients. A DLT of grade 3 fainting was observed in a patient treated at 3.95 mg/m2. The MTD has not yet been reached; the current cohort is receiving 3.95 mg/m2. Drug-related AEs included rash in four patients (two maculopapular, two erythematous); vomiting and fatigue in three patients each; and diarrhea, constipation, and nausea in two patients each. Grade 1 treatment-related peripheral neuropathy was reported in one patient. Serious AEs were seen in four patients: one at 3.95 mg/m2 (DLT of grade 3 fainting), one at 2.23 mg/m2 (grade 3 DVT) unrelated to MLN9708, and two unrelated at 1.68 mg/m2 (grade 3 hypotension; grade 3 gastrointestinal hemorrhage resulting in discontinuation). Two patients required lenalidomide dose reductions to 15 mg due to erythematous rash; no dose reductions were required for MLN9708 or dexamethasone. There were no on-study deaths. Of nine response-evaluable patients, all nine achieved ≥PR, including three very good PR (VGPR) and one complete response. Time to response was rapid; all responders achieved a ≥50% decrease in M-protein in cycle 1, and best response was reached by the end of cycle 4. No patient has progressed to date. One patient with confirmed VGPR discontinued at cycle 6 to undergo stem cell transplant. Conclusions:MLN9708 administered weekly in combination with lenalidomide and dexamethasone appears to be generally well tolerated in previously untreated MM patients at the MLN9708 dose levels studied, with evidence of antitumor activity in the dose-escalation cohorts. Evaluation continues to determine the MTD of MLN9708 in this combination. Updated results, PK data, assessment of PK interaction, and PD data will be presented. Disclosures:Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Richardson:Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Celgene: 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. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding. Hui:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding.

Lenalidomide Plus Low-Dose Dexamethasone Compared with Thalidomide Plus Low-Dose Dexamethasone: A Randomised Phase III Study

Abstract 2932 Background:We prospectively studied the efficacy and safety of Lenalidomide and Thalidomide in conjugation with low-dose dexamethasone in previously untreated symptomatic multiple myeloma (MM) patients. The results from an interim analysis of this on-going trial are presented. Methods:Between 1st March 2009 and 30th June 2011, 56 patients with previously untreated symptomatic MM were enrolled to receive 4 cycles of either Lenalidomide 25 mg daily from day 1 to 21 of a 28-day cycle (Arm A) or Thalidomide 100 to 200 mg daily (Arm B). Patients in both arms received dexamethasone 20 mg from day 1 to 4 and 9 to 12 along with monthly zoledronic acid. EORTC quality of life questionnaire C-30 version 3.0 was answered by all the patients at the start of treatment and at the end of 4 cycles. Data from 38 patients who have completed 4 cycles treatment is being analysed. Responses were assessed by International Myeloma Working Group (IMWG) criteria. Adverse events were graded according to CTCAE version 3.0. Results:Patients' characteristics are similar in both arms with respect to age, sex, stage and myeloma subtype. Median age (range) of patients is 54 yr (40 to 65) in arm A and 48 yr (37 to 65) in arm B. Gender: male/female 12/7 in arm A and 13/6 in arm B. ISS stage: I/II/III - 5/7/7 and 9/4/6. with Durie-Salmon stage: IIA/IIIA/IIIB - 1/14/4 and 2/13/4. Myeloma subtype included IgG/IgA/light chain: 11/2/6 and 14/3/2 in arms A and B, respectively.Currently 38 patients are evaluable for response (19 in each arm), 17 and 19 patients responded (PR or higher) in arms A (74%) and B (84%) respectively. Arm A: sCR-1, VGPR-5, PR-8, stable (SD)-3, progressive disease-2. Arm B: VGPR-5, PR-11 and SD-3 (p=0.46). Two patients have been lost to follow up in both arms. Two and 1 patients died of progressive disease in arms A and B respectively. The median time to response was 4 weeks in arm A compared with 11 weeks in arm B (p<0.002).Ten patients have undergone autologous stem cell transplantation and are currently on maintenance therapy.Grade 3 / 4 toxicities in Len/dex arm included: neutropenia-2 (10.5%), thrombocytopenia-2 (10.5%) and anemia in 2 (10.5%) patients. Other common adverse reactions included URTI, dryness of mouth and dysguesia. One patient developed autoimmune thrombocytopenia.Patients in the Thal/dex group had constipation, grade 3 in 1 (5%) patient, tremors-2 (10.5%) and grade 1 sensory neuropathy occurred in 9 (47%) patients.Analysis of quality of life data revealed significant improvement in all the scores in both arms after 4 cycles compared to baseline. Improvement in global QOL score was similar in both arms (p=0.37). Median baseline global QOL score was 25 (range, 0–66.67) and 33.33 (range, 16.67–50) in arms A and B, respectively. Post 4 cycles, median global QOL score was 50 (range, 0–83.33) and 50 (range, 33.33 to 100) in arms A and B, respectively. Conclusion:Patients in Lenalidomide and low-dose dexamethasone had a more rapid response than those treated with Thalidomide and low-dose dexamethasone. Myelosuppression was the major toxicity in Len/dex arm while sensory neuropathy was the prominent adverse effect noted with Thalidomide. Disclosures:No relevant conflicts of interest to declare.

Influence of Genetic Polymorphisms in CYP1A2, CYP2C19, CYP3A4, GSTP1, MDR1 and PSMB5 Genes in Toxicity and Response to Induction Therapy in Multiple Myeloma Patients Included in the Trial of the Spanish PETHEMA/GEM 05 for Newly Diagnosed MM Elderly Patients (Age 65 or More)

Abstract 1412Over the last decade, numerous new drugs have been incorporated in the treatment armamentarium of multiple myeloma (MM). However, there is not much information on the role of single nucleotide polymorphisms (SNPs) regarding toxicity and efficacy of the new myeloma therapies. Aims: to analyze the influence of genetic polymorphisms on toxicity and outcome of induction therapy on patients included in the trial of the Spanish PETHEMA/GEM 05 for newly diagnosed MM elderly patients (age 65 or more, “GEM05mas65”). (Lancet Oncol 2010; 11: 934). Patients and Methods: Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of botezomib plus melphalan and prednisone VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy. Genetic studies were performed in blood samples from 169 patients among the 260 included in the original trial (VMP: 84 patients; VTP: 85 patients). Toxicity and outcome parameters were analyzed and related to the genotype of polymorphisms in genes involved in bortezomib (CYP1A2 *1C, CYP1A2 *1F, CYP3A4), thalidomide (CYP2C19 *2, CYP2C19 *17) and melphalan metabolism (GSTP1 I105V) as well as bortezomib transport (MDR1 −3435C>T) and drug target (PSMB5 1042G>A). Results: Clinical results in our cohort reproduced those of the 260 patients of the original trial already published. The most frequent non haematological toxicity was peripheral neuropathy, similar in both arms. Among the 169 patients included in our study CYP2C19 *17 T carriers had worse overall response (p=0.033). Likewise, MRD1 −3435TT carriers presented less incidence of grade 3–4 neutropenia (p=0.041) meanwhile patients AA for CYP2C19 *2 genotype presented more grade 3–4 thrombopenia (p=0.009). The impact of the different genotypes among the two arms and inside each one was also analyzed. Wild type patients for MRD1 −3435T SNP displayed higher rate of severe neutropenia only in the VMP arm and in a genetic load depending manner (CC=71%, CT=38%, TT=22%; p= 0.012). Conclusions: Our results suggest that polymorphisms in genes involved in the metabolism of thalidomide, (CYP2C19 *17 y *2) or bortezomib transport (MDR1 −3435C>T) may result in a thalidomide modified metabolism rate or in a lower efficacy in the bortezomib transport, suggesting a potential influence in the haematological toxicity (neutropenia and thrombopenia) and overall response rates in MM patients treated with VMP or VTP. These results together with the relative elevated frequency of these SNPs in this population (>20%) justifies the interest of studying the genetic profile since it can become a step forward on the individualized management of MM patients. Disclosures:Mateos:Celgene: Honoraria; Janssen: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.

Once Weekly Bortezomib Plus Dexamethasone in Newly Diagnosed Multiple Myeloma: A Preliminary Study in Chinese Patients

Abstract 5128 Introduction:Bortezomib has become a cornerstone in the management of multiple myeloma (MM) and the currently accepted practice is a twice weekly administration at 1.3mg/m2. Recently, several studies have demonstrated a successful treatment with the modified Bortezomib schedule in refractory or elderly newly diagnosed MM. These previous studies suggest that, given at weekly intervals, Bortezomib remains equally efficacious and may even improve tolerability. We here present our institution's experience where we retrospectively compare the efficacy and toxicity parameters between once weekly (1.6mg/m2) and twice weekly (1.3mg/m2) schedule of Bortezomib plus Dexamethasone in newly diagnosed, untreated MM patients. Methods:The once weekly schedule consisted of 5-week cycle of which Bortezomib plus Dexamethsone was administered during the first 4 weeks as follows: Bortezomib 1.6mg/m2 intravenously on days 1, 8, 15, 22 and Dexamethsone 20mg intravenously on days 1–2, 8–9, 15–16 and 22–23 followed by a 12-day rest period. The twice weekly schedule consisted of 3-week cycle as follows: Bortezomib 1.3mg/m2 intravenously on days 1, 4, 8, 11 and Dexamethsone 20mg intravenously on days 1–2, 4–5, 8–9 and 11–12 followed by a 9-day rest period. We retrospectively collected data from Jan 2009 to Dec 2010 of 37 patients with newly diagnosed MM who were either treated with once weekly schedule (n =13) or twice weekly schedule (n = 24). Allocation of patients to their respective treatment group was not randomized but rather on the basis of their means, after they were made fully aware that the once weekly schedule was still under evaluation. Results:The median age was similar between two schedules (53 years vs. 54.5 years, P=0.674). Both treatment groups received a median number of two cycles of chemotherapy. The median follow-up was also similar, being 12 months (range, 4–19) in the once weekly treatment group and 10.5 months (range, 2–19)in the twice weekly treatment group. In the standard twice weekly schedule, the overall response rate of 74.9% including 2(8.3%) CR, 8(33.3%) VGPR and 8(33.3%) PR, while 2(8.3%) patients had stable disease (SD) and 3(12.5%) had progressive disease (PD). Among the patients in the weekly schedule, 10 of 13 patients (77.0%) achieved at least PR with 30.8% at least VGPR. In addition, SD was observed in 1 patient (7.7%) and PD in another 1 patient (7.7%). The responses to treatment were not found to be statistically significant different in our study when comparing the once weekly schedule to the twice weekly schedule. The median time to the best response was 2 cycles (range,2–4) in the once weekly schedule as compared with 2.5 cycles (range,2–4) in the twice weekly schedule (P=0.564). The median survival was not reached in either schedule since the follow-up was not long enough. The median progression free survival (PFS) and duration of response (DOR) of the weekly schedule did not differ significantly from that of the twice weekly schedule (8 months vs. 10 months, P=0.545 and 6 months vs. 7 months, P=0.467; respectively). After a median follow-up of 12 months (range, 2–19), 2 patients (15.4%) in the weekly schedule and 4 patients (16.6%) in the twice weekly schedule had died (P=0.723) thus mortality in the two groups did not differ significantly. Over grade 3 of gastrointestinal symptoms were similar in the once weekly (16%) and twice weekly (20.5%) schedules. Peripheral sensory neuropathy was reported more frequently in the twice weekly schedule, including grade 1 in 4 patients (17%), grade 2 in 4 patients (17%), grade 3 in 3 patients (12.5%), and grade 4 in 1 patient (4%). While grade 1 neuropathy in 2 patients (15%), grade 2 in 1 patient (8%), grade 3 in 1 patient (8%) were reported in the weekly schedule and all had resolved within two months. All grade 3 and 4 hematologic toxic effects were more frequent in the twice- weekly schedule than in the weekly schedule (75% vs. 54%), as was over grade 2 of herpes zoster (16.5% vs. 8%). Incidence of over grade 2 rash remained low and was similar in the two schedules (both 8%). However the difference between the two schedules was not statistical significantly. Conclusions:Our study provides additional evidence that the once weekly Bortezomib (1.6mg/m2) plus Dexamethasone schedule is active and well tolerated in the treatment of patients with newly-diagnosed multiple myeloma, with the similar efficacy and lesser toxicity compared with the twice weekly schedule. Disclosures:No relevant conflicts of interest to declare.

Patients with POEMS Syndrome Have High Bone Turnover and Increased Circulating Angiogenic Cytokines; Should Angiopoietin-2 and Bone-Specific Alkaline Phosphatase Be Used As Minor Criteria for the Diagnosis of the Disease?

Abstract 806▪FN2▪This icon denotes a clinically relevant abstractPOEMS syndrome is defined by the presence of peripheral neuropathy (P), monoclonal plasma cell disorder (M), organomegaly (O), endocrinopathy (E) and skin changes (S). The majority of patients have sclerotic bone lesions, although the underlying mechanisms are still unclear. Increased circulating vascular endothelial growth factor (VEGF) is another feature of the disease. However, there is almost no information on the role of other angiogenic molecules in POEMS biology. The aim of the study was to evaluate bone metabolism and angiogenic cytokines in POEMS and compare the results with multiple myeloma (MM) and osteosclerotic patients of other etiology.We retrospectively studied 61 POEMS patients (40M/21F, median age 52 years) who were diagnosed between 1996 and 2010 and were treated and followed in Mayo Clinic Rochester (MN, USA), Hôpital Saint-Louis, Paris (France) and in Alexandra Hospital, Athens (Greece). We evaluated the following indices of bone remodeling and angiogenesis in all patients at diagnosis and in 22 of them one month after front-line treatment: i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)]; ii) osteoblast inhibitor dickkopf-1 (Dkk-1); iii) bone resorption marker CTX; iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin]; and v) angiogenic cytokines [VEGF, angiogenin (ang), angiopoietin (angp)-1 and -2]. These molecules were also measured in 60 newly diagnosed, untreated MM patients (34M/26F, median age: 54 years) and 44 healthy controls. Bone markers were also evaluated in 24 patients with HbS/beta-thalassemia (10M/14F, median age: 43 years) who presented with osteosclerosis, defined as osteosclerotic bone lesions in plain radiography and high T-score of lumbar spine DXA (median: +3.6, range: +2 to +7.9).All POEMS patients presented with P and M, while 90% had E, 83% had S, 61% had O and 32% had papilloedema. One or more documented sclerotic bone lesions in plain X-rays were observed in 78% of patients (diffuse lesions in 44%), while 43% of patients had also an osteolytic component. Seven patients had Castleman disease.At diagnosis, compared to controls, POEMS patients had increased levels of bALP (mean ± SD: 48.3 ± 22.9 IU/L vs. 21.6 ± 8.2 IU/L; p<0.001), CTX (0.97 ± 0.94 ng/ml vs. 0.33 ± 0.24 ng/ml; p<0.001), Dkk-1 (p<0.001), sRANKL (p<0.001) and sRANKL/OPG ratio (p<0.001). Patients with diffuse osteosclerosis had increased levels of Dkk-1 compared to others (p = 0.05), suggesting a balance effect to increased formation activity. Patients with POEMS had increased levels of bALP and decreased levels of CTX compared to MM patients (p<0.001 and p = 0.03, respectively), while they had increased levels of CTX and sRANKL/OPG ratio compared to HbS/beta-thal patients (p = 0.001 for both comparisons). There were no other differences regarding bone markers among studied groups.Regarding angiogenic cytokines, at diagnosis, POEMS patients had elevated VEGF (1232 ± 565 pg/ml vs. 195 ± 211 pg/ml; p<0.001), ang (266 ± 82 ng/ml vs. 190 ± 45; p<0.001) and angp-2 (3.5 ± 2.2 ng/ml vs. 1.2 ± 0.6 ng/ml; p<0.001) and decreased angp-1 (p =0.05) and angp-1/angp-2 ratio (reflects increased angiogenic capacity; 9.1 ± 8.8 vs. 44.8 ± 76.1; p<0.001) compared to normal controls. We found no strong correlations between the levels of VEGF, ang and angps. When compared to MM patients, POEMS patients had increased circulating VEGF (p = 0.001) without any difference regarding the other angiogenic cytokines. Response to therapy was accompanied by a dramatic reduction of VEGF only (551 ± 541 pg/ml compared to baseline 1800 ± 1510 pg/ml; p = 0.003).Receiver-operating characteristic (ROC) curve analysis showed that high levels of angiopoietin-2 (≥ 2.3 ng/ml) and high bALP (≥ 38 IU/l) each have a 95% specificity for patients with POEMS syndrome.These results suggest that patients with POEMS syndrome have high bone turnover with increased bone formation as compared to healthy subjects, to MM patients, who have reduced bone formation, and to osteosclerotic HbS/beta-thal patients, who have diminished bone resorption. Importantly, our analysis supports the use of angp-2, bALP along with VEGF as minor criteria for the diagnosis of POEMS. Successful treatment reduced VEGF, which seems to be a suitable marker for the follow-up of POEMS patients. Furthermore the imbalance of angp-1/angp-2 pathway may indicate possible targets for the development of novel agents against POEMS. Disclosures:No relevant conflicts of interest to declare.

Circulating Angiogenic Cytokines Are Elevated in Patients with Smoldering Myeloma; Implications Into Disease Biology

Abstract 5059Angiogenesis is a critical step in the evolution of carcinogenesis in solid tumors and hematologic malignancies and is considered to be an early event in tumorigenesis. Multiple myeloma (MM) is a hematologic malignancy in which a preceding monoclonal gammopathy (MGUS) is considered a precursor. Asymptomatic/smoldering MM (SMM) is associated with a substantial risk of progression to MM and according to current recommendations these patients should be followed without therapy. Thus evolution from MGUS to SMM and to symptomatic myeloma is now considered as the model describing the natural history of the disease. In order to study the role and evolution of circulating angiogenesis related cytokines, we studied their levels in patients with MGUS, asymptomatic MM and symptomatic MM, before the initiation of first line therapy. We also studied possible associations of these cytokines with features of the disease in patients with SMM that could help identify possible markers of early evolution.We measured serum levels of vascular endothelial growth factor (VEGF), angiogenin, angiopoietin (angp)-1 and -2, using standard ELISA methodology (R&D Systems, Minneapolis, MN, USA). The definition of MGUS, SMM and symptomatic MM was based on the published IMWG criteria. All above cytokines were also measured in 21 individuals with MGUS, in 174 newly diagnosed, untreated MM patients (31 with SMM) and in 44 age- and gender-matched healthy controls.We focused our analysis on patients with SMM. The median age was 63.5 years (range 40–83 years) and 55% were males. The median bone marrow infiltration in trephine biopsy was 20% (range: 12%-75%). Sixty-one per cent had IgG, 29% had IgA isotype while 3% had light chain only myeloma and 6% had biclonal myeloma.The median (range) serum levels for VEGF were 406.5 pg/ml (186.3–797.6 pg/ml), for angp-1 were 31064 pg/ml (18220–50856 pg/ml), for angp-2 were 1434 pg/ml (486.1–4004.5 pg/ml), for angp-1 to angp-2 ratio were 20.8 (6.5–78.1), for angiogenin were 262732.6 pg/ml (138670–1003040 pg/ml) and for bFGF were 12.082 pg/ml (non-detected to 123.37 pg/ml). There were no significant correlations of the levels of angiogenesis related cytokines with serum beta-2 microglobulin levels, the levels of the monoclonal protein, IgA versus IgG isotype, serum LDH levels or age. Patients with extensive bone marrow infiltration (≥60%) had significantly higher levels of ang-2 (p=0.017) and significantly lower angp-1/angp-2 ratio (p=0.004) compared to all others. Compared to healthy controls, patients with SMM had higher levels of angp-1 (p=0.05) and angp-2 (p=0.03) but their respective ratio was not significantly different (p=0.272). Serum levels of VEGF were significantly higher in SMM patients than in controls (mean 429 pg/ml vs. 196 pg/ml, p<0.001). Similarly serum levels of angiogenin were significantly higher in SMM (mean 304028 pg/ml vs 190245 pg/ml, p<0.001). When patients with SMM compared to MGUS patients, there were no significant differences for any of the studied angiogenesis related cytokines. Compared to patients with symptomatic MM, patients with SMM had higher levels of angp-1 (p<0.001) and lower level of angp-2 (p<0.001) resulting in a significantly lower angp-1/angp-2 ratio, indicating a switch to increased vessel-formation activity, while the levels of VEGF were similar.The above results indicate that early in the evolution of the disease (MGUS to SMM to Symptomatic MM) there is an angiogenic switch which is manifested by an increase in the levels of angiogenic cytokines that promote neovasculogenesis (such as VEGF, angp-2 and angiogenin) and a gradual suppression of cytokines that balance their effects (such as angp-1). A possible prognostic significance of the circulating levels of angiogenic cytokines in patients with SMM that could help identify patients at higher risk for progression to symptomatic MM needs further study. Disclosures:No relevant conflicts of interest to declare.

Annexin II Interactions with the Annexin II Receptor Enhance Multiple Myeloma Cell Adhesion and Growth in the Bone Marrow Microenvironment,

Abstract 3942 Background:Multiple myeloma (MM) is an incurable B-cell malignancy that develops in the bone marrow. The marrow microenvironment plays a critical role in supporting homing, lodging, and growth of MM cells by activating signaling pathways in both MM and bone marrow stromal cells (BMSC). We previously showed that annexin II (AXII) is involved in prostate cancer cell lodgment to the bone marrow via the annexin II receptor (AXIIR) expressed on prostate cancer cells. We hypothesized that MM cells use a similar mechanism to lodge and grow in the bone marrow. In support of this hypothesis, we found that MM cell lines and primary MM cells from 8 MM patients express the AXIIR protein, and that MM cells adhered significantly better to BMSC from AXII+/+ mice than from AXII−/− mice. Further, knockdown of AXIIR by siRNA in MM1.S and ANBL-6 MM cells decreased AXII binding and decreased adherence of MM cells to human stromal cells and BMSC from AXII+/+ mice. Furthermore, addition of an anti-AXII antibody to MM1.S cells, did not effect MM cell growth demonstrating that AXII expressed by MM cells does not support MM cell growth. Importantly, soluble AXII was released by osteoclasts into their conditioned media which stimulated the growth of MM cells via ERK1/2 and AKT phosphorylation. In the further study, we further characterized the role of AXIIR in MM-BMSC interactions. Methods:AXIIR expression in MM cells was determined by RT-PCR, Western blotting, and immunocytochemistry. Adhesion and growth assays were performed between MM cells and BMSC or AXII to determine the contribution of the AXII/AXIIR axis in supporting adhesion and growth of MM cells. In addition, MM cells or CD138+ cells from MM patients were treated with AXII to determine AXII-dependent MM cell growth. Further, adhesion and growth assays were performed on MM cells expressing either siAXIIR or shAXIIR. Phosphorylation assays were performed to determine the pathways stimulated by AXII in MM cells. Since OCL secrete large amount of AXII, MM cell growth assays were performed with OCL-CM from AXII+/+ and AXII−/− mice in the presence of an AXII antibody. Results:We now report that in addition to MM1.S and ANBL-6 cells, other MM cell lines, including U266, H929, and OPM2 also express AXIIR, and that AXII stimulated the growth of RPMI8226, ANBL-6 and U266 in addition to MM1.S cells. Finally, an AXIIR antibody prevented adhesion of MM1.S cells to AXII, and that AXII upregulated the adhesion molecule, RhoA in MM cells. Additionally, AXII did not stimulate the proliferation of MM1.SshAXIIR cells compared to MM1.SshControl or untreated MM cells, demonstrating that AXII specifically acts through its receptor, AXIIR on MM cells to promote proliferation. More importantly, AXII stimulated the growth of CD138+ cells obtained from MM patients. Conclusions:Based on our results, we conclude that the interaction between AXII and AXIIR in the bone marrow microenvironment supports adhesion via RhoA and growth of MM cells by stimulating the Erk1/2 and Akt pathways, AXII produced by MM cells does not act in an autocrine manner on MM cell growth. Thus, AXII and AXIIR are key players in MM and targeting the AXII/AXIIR axis may be a novel therapeutic approach for MM. Disclosures:Roodman:Amgen: Consultancy; Millennium: Consultancy.

The Nestin Expression in Monoclonal Gammopathies

Abstract 5111 Background.Monoclonal gammopathies (MG) are the most common plasma cell disorders characteristic by a presence of clonal plasma cells (PCs). The nestin is considered to be a marker of multipotent proliferative precursors, but recently its expression was found in PCs of multiple myeloma (MM) as well. Consequences of the nestin expression still remain unclear. Aim.Phenotypic analysis of the nestin expression in the most frequent MGs and its correlation with other markers. Patients and Methods.Total of 45 samples was analyzed [31 newly diagnosed untreated MM patients, 14 untreated monoclonal gammopathy of undetermined significance (MGUS) subjects and 5 non-MG samples]. Whole bone marrow CD38+CD138+ PCs were studied for intracellular expression of nestin and surface expression of CD19, CD20, CD27, CD28, CD33, CD56, and CD117 by flow cytometry. Results.Flow cytometric analysis shown the nestin expression in 21.4 % (3/14) of MGUS and 45.2 % (14/31) of MM patients, on the other hand no expression of nestin was found in non-MG controls. Expression of the nestin was relatively homogeneous, but not highly intensive. The nestin positive PCs did not express CD19 and/or CD20, but expression of CD27 was found in 29.4 % (5/17) cases, CD28 in 11.8 % (2/17), CD33 in 5.9 % (1/17), CD44 in 35.3 % (6/17), CD56 in 88.2 % (15/17), and CD117 in 29.4 % (5/17) cases. Statistical analysis did not found any significant correlation and/or difference in phenotype when compared the nestin positive and negative samples, although the nestin negative samples expressed CD56 less frequently then the nestin positive samples [46.4 % (13/28) vs. 88.2 % (15/17)], respectively. Summary/Conclusion.Our result showed difference in the nestin expression when compared bone marrow of MGUS subjects with MM patients. Although there was no correlation between the nestin positivity and phenotype of PCs, we suppose that the nestin could associate with unfavorable prognosis but further studies are needed to elucidate its clinical implication in MGs. Disclosures:No relevant conflicts of interest to declare.

A Score Model for Predicting Unsuccessful or Sub-Optimal Peripheral Blood Stem Cell Collections in Multiple Myeloma Based on a Retrospective Analysis of 1,039 Patients Receiving Novel Agents As Induction Therapy and Cyclophosphamide Plus G-CSF As Mobilizing Regimen,

Abstract 4044Induction therapy with the so-called “novel agents” (bortezomib or IMIDs) followed by autologous stem cell transplantation (AuSCT) is considered the current standard therapeutic approach for younger patients with multiple myeloma (MM). However, a variable proportion of these patients still fails to mobilize and to collect a number of CD34+ peripheral blood stem cells (PBSC) sufficient for a safe transplant procedure or, as required in selected patients, for double or salvage AuSCTs. The aim of this study was to analyze, in a large number of MM initially treated with novel agents and homogeneously mobilized, the role of some potential risk factors on PBSC collection in patients eligible for AuSCT.To this purpose, the impact of age > 60 years, baseline cytopenia at diagnosis (Hb< 10 g/dl and/or neutrophil count < 1,000/μl and/or platelet count < 100,000/μl), initial use of lenalidomide and grade 3–4 hematological toxicity during induction therapy were retrospectively evaluated in 1,337 previously untreated MM patients enrolled in five consecutive clinical trials finalized to AuSCT and conducted by GIMEMA cooperative Group and MM Italian Network. In all cases, the mobilizing regimen was cyclophosphamide + G-CSF. In four of these studies, including 1,039 patients, induction regimens had comprised novel agents: thalidomide (TD, 296 patients), bortezomib (PAD, 121 patients), thalidomide plus bortezomib (VTD, 219 patients), lenalidomide (RD, 403 patients). 298 patients treated with a VAD-modified induction regimen (DAV) were also evaluated. Data were retrospectively extracted from two different databases of the coordinating Centers (Torino and Bologna) using a single, dedicated excel file. Total amounts of less than 2 and less than 5 × 10e6/kg CD34+ PBSC after a single mobilizing procedure were considered as “unsuccessful ” or “sub-optimal” results, respectively.Overall, 917 patients (68.6%) showed the presence of at least one risk factor: 615 patients (46%) had only 1 parameter, 302 a combination of 2 (n. 237, 17.7%), 3 (n. 56, 4.2%) or 4 (n. 9, 0.7%) parameters, respectively. After a single PBSC mobilization, 413 patients (30.9%) had a sub-optimal result, including 256 patients (19.1%) with unsuccessful collection. Any single parameter negatively influenced PBSC collection vs absence of parameters (p < 0.000). At multivariate analysis, however, grade 3–4 hematological toxicity (p < 0.000) and the use of lenalidomide (p < 0.013) during induction showed the most powerful negative effects on mobilization. The number of present risk factors (from 4 to 0) significantly paralleled the ineffective procedures, both in terms of absolute median amount of CD34+ PBSC collected (from 1.2 to 10.6 × 10e6/kg) or percentage of unsuccessful/sub-optimal collections (from 78% to 13% and from 89% to 24%, respectively) (p < 0.000). On these basis, we constructed a predictive score where the four parameters were pooled and weighted according to their relevance as single or combined variables, attributing the value of 3 for grade 3–4 hematological toxicity, 2 for the use of lenalidomide and 1 each for age > 60 and baseline cytopenia. Applying this model, we found that the risk of collecting less than 2 (27.5% vs 17.3%) and less than 5 (41% vs 28.6%) × 10e6/kg CD34+ PBSC, was significantly higher in patients with a total score equal or >3 than in patients scored <3 (p < 0.000 for both comparisons). These data did not differ significantly when the patients who had not received novel agents as induction therapy were excluded from the analysis.In conclusion, our score model provides a simple and effective method to predict unsatisfactory PBSC collections in MM patients eligible for AuSCT who have received novel agents as induction therapy and a combination of chemotherapy plus G-CSF as mobilizing treatment. Disclosures:Musto:Genzyme: Honoraria. Grossi:Genzyme: Consultancy. Sarli:Genzyme: Honoraria. Cavo:Genzyme: Honoraria. Boccadoro:Genzyme: Honoraria. Palumbo:Genzyme: Honoraria.

Bortezomib- and Thalidomide-Induced Peripheral Neuropathy (PN) in Multiple Myeloma (MM): Clinical and Molecular Analysis of 474 Patients Treated with Thalidomide-Dexamethasone (TD) or Bortezomib-TD (VTD)

Abstract 1821 Introduction: PN is an important complication of MM and its incidence has been further increased after the introduction of the novel agents thalidomide and bortezomib. In a phase 3 trial comparing TD with VTD as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation for previously untreated MM patients, the VTD arm was significantly superior over TD in terms of improved rates of complete or near-complete response (CR/nCR) (the primary study endpoint) and progression free survival (PFS). Toxicity of VTD and TD regimens, including PN, was a secondary study endpoint. Methods: We performed a subanalysis of the study to assess the frequency, reversibility, risk factors and molecular markers associated with treatment-emergent PN. PN was graded by use of National Cancer Institute9s Common Toxicity Criteria (NCI CTCAE) version 3.0. Since grade 1 PN could be misinterpreted and does not interfere with the daily activities, only patients who developed PN of at least grade 2 were evaluated. A total of 474 patients (of whom, 236 randomized to the VTD arm and 238 to TD) were stratified according to the development or not of grade ≥2 neurological adverse events (NAEs). Gene expression profiles (GEP) of pre-treatment CD138+ bone marrow plasma cells (BMPCs) were analyzed in a subset of 127 VTD-treated patients for whom biological samples taken at diagnosis were adequate for genomic analysis. GEP experiments were performed using the Affymetrix HG-U133 Plus 2.0 platform and class comparison of groups of array was done with one-way ANOVA Partek Genomic Suite (version 6.4). Results: Occurrence of PN throughout the entire treatment program was significantly higher in the VTD arm compared with TD. In particular, the rate of grade ≥2 PN was 35% vs 10% (p Conclusions: Although VTD incorporated into double ASCT was associated with a higher incidence of grade ≥2 PN compared with TD, the probability of complete resolution or improvement to at least grade 1 was comparable in both VTD- and TD-treated groups. Importantly, NAEs did not adversely affect the rate of CR/nCR, and TTP and PFS. No relationship between development of PN and both patient demographics and disease characteristics was observed. Conversely, GEP analysis of BMPCs from patients with VTD-induced PN showed the significant deregulated expression of genes involved in the nervous system function. Disclosures: Off Label Use: Bortezomib and Thalidomide as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation in newly diagnosed multiple myeloma. Tosi:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Baccarani:Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Bristol-Mayers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Boccadoro:Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria. Cavo:Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Renal Function Measures Improve on Lenalidomide and Dexamethasone and Compete with Patient Characteristics to Predict Lenalidomide Dose Density and Hematologic Toxicity: An E4A03 Analysis

Abstract 1882 Introduction:Lenalidomide (L) with dexamethasone (D) has demonstrated activity in untreated symptomatic multiple myeloma (MM) (Rajkumar et al. Lancet Oncol 2010; 11: 29–37). Neutropenia may occur, requiring dose reductions, interruptions, or G-CSF support in up to 20% of patients. Renal clearance accounts for 67% of L elimination, and renal insufficiency is associated with an increased risk of cytopenias. Product information recommends the use of the Cockcroft-Gault (C-G) equation for creatinine clearance (CrCL) estimation for initial dosing; however, other estimates including the Modification of Diet in Renal Disease (MDRD) method may be more accurate. We evaluated the impact of renal function on L dosing, cytopenias, and response in patients on the Eastern Cooperative Group (ECOG) E4A03 study. Methods:All patients (n=445) enrolled on E4A03 were included in this analysis. Clinical data at baseline and after 4 cycles was reviewed. Renal function over the first 4 treatment cycles was estimated using both last reported on cycle 4 and last ever reported serum creatinine (SCr) as the former method resulted in a loss of 70 more patients. Patients were classified by CrCL (mL/min) stage: (1) ≥90 (2) 60–89 (3) 30–59 (4) 15–29 (5) <15. Patients were further categorized into CrCL groups collapsing stages 3–5 while maintaining division of normal status. Demographic and disease data of age, ECOG performance status (PS), sex, race, ISS stage, and complete blood counts were included. Percent of planned L dose and dose interruptions were calculated. Descriptive statistics were used to assess measures at each timepoint. Associations between baseline MDRD, C-G, SCr and patient characteristics were assessed by chi-square testing, and logistic regression models of L dose modification, cytopenias, and response status with renal function measures were created. Results:Mean SCr improved in 361/445 (81%) by 0.23 mg/dL following treatment initiation. Mean MDRD CrCL improved in 264/445 (59%) by 24.3 mL/min. Because only initial weight was captured, C-G estimates over time were not available. ISS stage II/III was associated with baseline elevated SCr (> 1.5 mg/dL) and low CrCL (p<0.001). Dose modification of L occurred in 44% of patients over 4 cycles (Table 1). In adjusted analyses, C-G predicted L dose modifications, p<0.001 [stage 3–5 vs 1 OR 2.09 (1.23-3.55)] along with ECOG PS. Similarly, in adjusted analyses, grade 2–5 cytopenias were better predicted by C-G stage, p<0.001 [stage 3–5 vs 1 OR 5.08 (2.18-11.84)], over MDRD stage, p=0.025 [stage 3–5 vs 1 OR 2.66 (1.07-6.61)]. No association between baseline or change in renal function and ≥ VGPR after 4 cycles was noted.Table 1Baseline Characteristics Associated with Lenalidomide Dose ModificationsVariableOR (95% CI)p-valueAge (≥ 65 vs < 65y)1.57 (1.08, 2.29)0.019SCr (> 1.5 vs ≤ 1.5 mg/dL)1.83 (1.06, 3.15)0.031ISS Stage II/III vs I2.04 (1.33, 3.12)0.004ECOG PS 1/2 vs 01.80 (1.23, 2.64)0.002MDRD (Stage 3–5 vs Stage 1)1.97 (1.10, 3.51)0.041C-G (Stage 3–5 vs Stage 1)2.59 (1.59, 4.21)< 0.001 Conclusion:Renal function improvement in patients receiving LD warrants regular CrCL monitoring and L dose increases in patients on reduced doses without cytopenias. Baseline MDRD is not superior to C-G for CrCL estimation for predicting L dosing and cytopenia development. Optimizing L exposure through pharmacokinetic modeling or other methods may further refine dosing. Disclosures:Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

A Phase I/II Study of Bortezomib in Combination with Melphalan and Prednisolone in Japanese Patients with Newly Diagnosed Multiple Myeloma

Abstract 5132BACKGROUND AND PURPOSE: Although bortezomib is widely used both in newly diagnosed and in relapsed/refractory multiple myeloma (MM) patients (pts), it is only approved for relapsed/refractory MM in Japan. To evaluate safety, pharmacokinetics (PK) and efficacy of bortezomib combined with melphalan and prednisolone (MPB) therapy, we conducted a phase I/II study in untreated Japanese MM pts who were ineligible for hematopoietic stem cell transplant (HSCT). METHODS: This was a dose-escalation study designed to determine the recommended dose (RD) of bortezomib in combination with melphalan and prednisolone by estimating the maximum tolerated dose based on dose-limiting toxicity (DLT) in the phase I portion, and to investigate the overall response rate (ORR; CR+PR) and safety of MPB therapy in the phase II portion. Particularly, a continuity of treatment was historically compared with a global phase III study (VISTA trial), and the incidence of interstitial lung disease was assessed. Pts were planned to receive 9 cycles (6-week/cycle) of bortezomib (days 1, 4, 8, 11, 22, 25, 29, and 32 in cycles 1 to 4; and days 1, 8, 22, and 29 in cycles 5 to 9) plus melphalan (9 mg/m2) and prednisolone (60 mg/m2) administered on days 1 to 4 of each cycle. RESULTS: A total of 101 pts were enrolled and 99 received at least one dose of the study treatment. The median age was 72 years (range: 48–84), and 5 were under 65 years. The most common type of MM was IgG (66%), followed by IgA (25%). In the phase I portion, each 6 pts were assigned to receive 0.7 mg/m2 and 1.0 mg/m2, and no DLTs were observed in either dose level. In 1.3 mg/m2 group, 2 events of DLTs (enterocolitis infections and ileus) occurred in 1 of the 6 pts. Therefore, 1.3 mg/m2 was determined as RD for the subsequent phase II portion. In the phase I portion, PK parameters, Cmax (120 ng/mL), tmax (0.078 h) and AUC24 (74.1 ng·h/mL) in plasma bortezomib at RD, were similar to those in VISTA trial and no apparent drug-drug interaction was observed in the PK of bortezomib in the MPB therapy. The response was evaluated in 17 pts in the phase I portion, and in 86 pts in the phase II portion (including 5 pts receiving 1.3 mg/m2 in the phase I portion). In the phase I portion, all 6 pts in 0.7 mg/m2 achieved partial response (PR). In 1.0 mg/m2, 3 pts achieved complete response (CR), and 2 pts achieved PR out of 6 pts. In 1.3 mg/m2, 2 pts achieved CR, and 2 pts achieved PR out of 6 pts. In the phase II portion, 17 pts achieved CR, and 43 pts achieved PR. The ORR was 70% (60/86) with the two-sided 90% confidence interval of the ORR was 61% to 78%. This ORR (70%) was comparable with the ORR (71%) in the MPB group of VISTA trial. The median time to response was 51 days (range: 43–82). In the phase II portion, the frequent (≥50%) adverse events (AEs) were hematologic toxicities (neutropenia, lymphopenia, thrombocytopenia and anemia), diarrhea, nausea, constipation, rash, elevated c-reactive protein, elevated lactate dehydrogenase, weight loss, anorexia, hyponatremia, peripheral neuropathy, leukocytosis and hepatic dysfunction. The incidence of AEs was generally higher and AEs were generally more severe in this study compared with the MPB group of VISTA trial, but most of the AEs were clinically manageable. Incidence of interstitial lung disease (interstitial pneumonia, pneumonitis and hypoxia) was 10% (9/87) in the phase II portion (with chest X-ray and oximeter analysis periodically and arterial oxygen partial pressure and chest CT as needed) and 1% (4/340) in the MPB group of VISTA trial, respectively. There was no death due to lung disorder in this study. Only rare cases of grade 3 events (pneumonitis and hypoxia) or serious events were reported, and all of the events were clinically manageable. Whereas the incidence of peripheral neuropathy (grade 3 and 4), the median number of treatment cycles (range) and the median dose intensity for bortezomib in the first 4 cycles were 10% (9/87), 5 cycles (1–9) and 6.86 mg/m2/cycle in the phase II portion of this study, those in the MPB group of VISTA trial were 14% (46/340), 9 cycles (1–9) and 8.32 mg/m2/cycle, respectively. CONCLUSION: This phase I/II study in Japan suggests that the RD of bortezomib in MPB therapy is 1.3 mg/m2 and MPB therapy in newly diagnosed Japanese MM pts ineligible for HSCT is effective as well as those in VISTA trial. Further investigation is needed to refine the administration schedule of this combination in Japanese pts. Disclosures:No relevant conflicts of interest to declare.

Phase II Trial of Intravenously Administered AMD3100 (Plerixafor) for Stem Cell Mobilization in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation Following a Lenalidomide-Based Initial Therapy

Abstract 2992 Background:Patients with myeloma receiving initial therapy with lenalidomide-based regimens can have difficulty collecting adequate stem cells for an autologous transplant. Stem cell collection in these patients can be significantly enhanced by addition of the CXCR-4 antagonist plerixafor to the mobilization regimen. Plerixafor is typically given subcutaneously (SQ), with collection approximately 11 hours after injection to obtain maximum yield. Intravenous administration can potentially allow more rapid and predictable mobilization compared to the SQ route. We designed this trial to prospectively assess the efficacy of intravenous plerixafor administration in patients undergoing lenalidomide therapy. Patients and methods:Patients who were receiving initial therapy with a lenalidomide-based regimen and were undergoing stem cell collection within 12 months of their myeloma diagnosis were enrolled. Patients received GCSF at 10 μg/kg/day for 4 days followed by addition of plerixafor at 0.24 mg/kg/dose starting on day 5. Plerixafor was administered intravenously early morning (6–7 am) followed by apheresis beginning 4–5 hours later. Plerixafor was administered for a maximum of 4 days; but patients could continue apheresis beyond the 4th day at treating physician discretion. The aims of the study were to determine the proportion of patients reaching a stem cell yield of at least 3 million CD34 cells/kg by second day of apheresis, the safety and tolerability of intravenously administered plerixafor, and the overall rate of failure to mobilize (defined as less than 2.5 million CD34 cells/kg in 4 collections). Results:Thirty-seven patients were accrued between December 2009 – April 2011, and 36 were eligible for analysis. The median age was 61 years (range; 28–73); 61% were male. The median time from start of initial therapy to enrollment was 4.6 months (range; 2.6 to 11.1) and the median cycles of lenalidomide were 4 (range; 3–11). Thirty-four (94%) of the patients achieved at least 3 million CD34 cells/kg within 2 days of apheresis. The median CD34 cells/kg after 1 day of collection was 3.9 million (range; 0.7 to 9.2) and after two days of collection was 7.02 million (range: 1.1–16.5). Two patients failed the mobilization (<2.5 million CD34 cells/kg). There were no grade 3 or 4 non-hematological adverse events and one patient experienced grade 4 thrombocytopenia. The most common grade 1 or 2 adverse events seen were gastrointestinal, namely nausea, diarrhea and abdominal pain or bloating. Grade 1 dizziness was reported in 8 patients. Overall, the infusion was well tolerated. Conclusion:Intravenously administered plerixafor is an effective strategy for mobilization in this patient group with low rate of failure to mobilize. It is well tolerated with toxicity comparable to the SQ administration. It also offers flexibility in patient scheduling with a convenient schedule for early morning infusion followed by apheresis later in the day. Disclosures:Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Lacy:Celgene: Research Funding.

Continued Overall Survival Benefit After 5 Years' Follow-up with Bortezomib-Melphalan-Prednisone (VMP) Versus Melphalan-Prednisone (MP) in Patients with Previously Untreated Multiple Myeloma, and No Increased Risk of Second Primary Malignancies: Final Results of the Phase 3 VISTA Trial

Abstract 476▪FN2▪This icon denotes a clinically relevant abstract Background:Data from the initial report of the international, multicenter, phase 3 VISTA trial demonstrated that VMP was superior to MP across all efficacy endpoints, including response rates, time to progression, and overall survival (OS), in previously untreated multiple myeloma (MM) patients ineligible for high-dose therapy. Following this report, centralized assessment of response/progression was stopped and, per protocol, patients were followed for up to 4.5 years post-last patient in date for survival and the use of subsequent anti-MM therapy only. An updated analysis, conducted after a median follow-up of 36.7 months, demonstrated a continued significant OS benefit with VMP. Here we report the final updated OS analysis of VISTA after 5 years of follow-up, including an exploratory analysis of the risk of second primary malignancies (SPMs), an important issue for MM patients receiving long-term therapy. Methods:Patients were randomized (1:1) to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1–4, days 1, 8, 22, and 29, cycles 5–9; melphalan 9 mg/m2 days 1–4, prednisone 60 mg/m2, days 1–4, all cycles) or MP (N=338) alone. Patients were followed at least every 12 weeks for survival and subsequent therapy use. Data on SPMs were collected during February 2011 by surveying all study sites to capture information for 655 (96%) patients. Results:After median follow-up of 60.1 months, with only 5% of patients lost to follow-up, median OS was 56.4 versus 43.1 months for patients randomized to VMP compared to MP (HR 0.695, p=0.0004), reflecting a 31% reduced risk of death with VMP (Figure); 5-year OS rates were 46.0% and 34.4%, respectively. This compares favorably with the 6.6-month increase in median OS in a meta-analysis of six phase 3 trials of MP-thalidomide vs MP (Fayers et al, Blood 2011). The OS benefit with VMP was seen across patient subgroups, including those aged ≥75 years (median 50.7 vs 32.9 months, HR 0.71), patients with ISS stage III MM (median 42.1 vs 30.5 months, HR 0.67), and those with creatinine clearance <60 mL/min (median 56.8 vs 36.7 months, HR 0.70), but no significant difference was observed in the small subgroup of patients with documented high-risk cytogenetics (n=46). At data cut-off (March 24, 2011), 63% of VMP and 73% of MP patients had received subsequent MM therapies; use of subsequent therapies was generally similar between arms, except for a higher proportion of MP patients receiving subsequent bortezomib (43% vs 22%). Time to next treatment (median 27.0 vs 19.2 months; HR 0.557, p<0.0001) and treatment-free interval (median 16.6 vs 8.3 months, HR 0.573, p<0.0001) were superior with VMP vs MP. Among all patients who had received subsequent therapies, OS was superior with VMP vs MP (median 55.7 vs 46.4 months; HR 0.745, p=0.0162). A 30-month landmark OS analysis demonstrated superior survival from landmark among all VMP patients (median not reached) and among VMP patients who had received any subsequent therapy (median 28.2 months) vs MP patients who had received subsequent bortezomib (median 23.0 months). Taking into account the longer observation period due to prolonged survival on the VMP arm, analyses of SPM risk (Table) showed no difference in incidence proportions or ‘exposure’-adjusted incidence rates between arms. Rates on both arms (VMP 0.0166, MP 0.013 per patient-year) were consistent with background incidence rate in the general population aged 65–74 years (0.019, SEER database). Conclusions:VMP resulted in a substantial long-term OS benefit vs MP (13.3-month increase in median), which was seen across patient subgroups and regardless of extensive subsequent therapy. There was no increased risk of SPMs identified with VMP vs expected background rates. [Display omitted] SPMs: relative risk (RR)VMPMPRR (95% CI)*Incidence proportionPatients with data collected, N327328Hematologic**, n (%)3 (1)3 (1)1.003 (0.204, 4.933)Fatal2 (1)3 (1)0.669 (0.113, 3.976)Non-hematologic, n (%)16 (5)10 (3)1.605 (0.739, 3.484)Fatal6 (2)6 (2)1.003 (0.327, 3.078)Incidence ratePatient-years for which data collected, N11671004Hematologic, n per patient-year0.00260.0030.862 (0.174, 4.269)Fatal0.00170.0030.574 (0.096, 3.436)Non-hematologic, n per patient-year0.01400.0101.389 (0.630, 3.061)Fatal0.00520.0060.859 (0.277, 2.664)*RR <1 favors VMP;**Acute leukemia, n=2 both arms, 1 MDS (VMP), 1 B-cell lymphoma (MP) Disclosures:San Miguel:Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc: Consultancy. Dimopoulos:Millennium Pharmaceuticals, Inc.: Honoraria; Ortho Biotech: Consultancy, Honoraria. Kropff:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Spicka:Janssen-Cilag: Honoraria; Celgene: Honoraria. Petrucci:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria. Dmoszynska:Janssen-Cilag: Research Funding. Delforge:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Anderson:Celgene: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Esseltine:Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Liu:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Deraedt:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. de Velde:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Richardson:Celgene: Consultancy; Janssen Research & Development: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy.

Phase I Trial of a Novel Combination of An HDAC Inhibitor (LBH589) and An mTOR Inhibitor (RAD001) in Lymphoid and Plasma Cell Malignancies

Abstract 2682 Background:The PI3K-Akt pathway is critical to tumor growth in lymphoid malignancies and mTOR inhibitors have shown promising activity in lymphoid malignancies. However, alternate signaling pathways allow cells to escape the effect of mTOR inhibition. Pre-clinical studies have shown that the combination of LBH589, an HDAC inhibitor, with the mTOR inhibitor RAD001 results in potent synergy. We then explored this combination in a phase I/II clinical trial. Patients and Methods:Patients with relapsed multiple myeloma (MM), non-Hodgkin lymphoma (NHL) or Hodgkin Lymphoma (HL) were enrolled into a phase I trial of escalating doses of LBH589 and RAD001. The doses are shown in the table. The study utilized a 3+ 3 design with MTD defined as the maximum dose resulting in less than 2 dose limiting toxicities (DLT) during the first cycle among 6 patients treated at that dose. DLT was defined as a grade 4 neutropenia or thrombocytopenia lasting >= 7 days, febrile neutropenia or any other grade >=3 non-hematologic toxicity considered possibly related to the drugs. Once MTD was determined, patients were enrolled into two separate phase 2 studies, one for relapsed MM and another for relapsed NHL or HL. Results:Twenty-six patients were enrolled to the phase 1 study; 23 were eligible for MTD analysis. There were 16 patients with NHL, 4 with HL and 3 with MM. Median age was 61 (range, 24–73) and 17 were male. The median number of prior therapies was 4 (range 2–11), including a prior stem cell transplant in 11 (48%). No DLT was observed at any of the doses tested in the trial (See below). Hematological toxicities were the most common AEs observed, with a grade 3 or 4 hematologic AE in 15 patients and grade 3 or 4 non-hematologic AEs in 6 patients across all cycles administered. Grade 3 and 4 hematologic AEs included 10 patients with neutropenia and 8 patients with thrombocytopenia. Grade 3 and 4 non-hematologic AEs included hyperglycemia, hypertriglyceridemia, hypophosphatemia, diarrhea, pneumonia and mucositis in one patient each. Overall, 10 responses (43%) were seen (Table). Conclusions:The combination of LBH589 and RAD0001 is tolerated at the doses tested, with hematological toxicities being the most common adverse events. The recommended phase II dose is LBH 40 mg MWF every other week along with 5 mg RAD001 every day in 4-week cycles. Clinical efficacy was seen in all diseases tested with partial responses seen in NHL and HL as well as a minor response in a patient with refractory myeloma, who had previously failed single agent RAD001. Phase 2 trials are ongoing in both disease groups.TableDose LevelNumber of DLTsResponseLevelLBH doseRAD001 dose010 mg MWF every week5 mg every day0/31 MR (MM), 1 PR (NHL)1A15 mg MWF every week5 mg every day0/32 PR (NHL)1B15 mg MWF every week10 mg every day0/32 PR (NHL, HL)2A20 mg MWF every week5 mg every day0/52 PR (NHL)330 mg MWF every other week5 mg every day0/31 PR (NHL)440 mg MWF every other week5 mg every day0/61 CR (NHL) Disclosures:Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Lacy:Celgene: Research Funding. Reeder:Celgene: Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Novartis: Research Funding.

A Better Mobilization Regimen for Newly Diagnosed Multiple Myeloma Patients,

Abstract 4051 Introduction:What constitutes an acceptable mobilization regimen for collecting CD34+ cells depends on whether the goal of collection is to obtain a minimum number versus optimal number of cells. When treating patients with high-risk myeloma it may be important to obtain an optimal number. Here we compare retrospectively our earlier mobilization regimen, VTD-PACE, with MVTD-PACE in newly diagnosed, previously untreated multiple myeloma patients. Materials and Methods : We reviewed data for all patients who collected hematopoietic progenitor cells on Total Therapy protocols TT3a/TT3b with VTD-PACE (n=394) from February 2004 to September 2008 (138 females and 256 males, median age 59y; range 31–75), and on TT4/TT5 with MVTD-PACE (n=188) from August 2008 to May 2011 (78 females and 110 males, median age 61y, range 30–76). Based on their predicted first day collection with a large volume leukapheresis (30L processed), using our center’s predictive formula (Blood 2010; 116(21):1182a), patients were stratified into 4 mobilizer types: poor (<2×106 CD34+ cells/kg), intermediate (≥2 to 10×106), good (>10 to 20×106) and excellent (>20×106). Variables examined included number of CD34+ cells/μl blood on day 1 and day 2 of collection (we have a minimum 2 day collection requirement), number of collection days to reach our minimum goal of 20×106 CD34+ cells/kg, and total CD34+ cells/kg collected for both chemotherapy groups. Variables for both groups stratified by mobilizer type were compared using two-tailed student’s t-tests, except for the poor mobilizer group, where population size was too small for formal statistical analyses (VTD-PACE n=7, MVTD-PACE n=4), although averages were calculated. Results : There was no significant difference between VTD-PACE and MVTD-PACE for CD34+ cells/μl blood on day 1 of collection among the excellent [mean 368.9 (n=184) vs. 434.6 x106 (n=92); p-value 0.07], good [mean 138.6 (n=102) vs. 128.6 x106 (n=40); p-value 0.19], and intermediate [mean 60.1 (n=100) vs. 55.9 x106 (n=52); p-value 0.39] groups. A statistically significant difference between VTD-PACE and MVTD-PACE was found for CD34+ cells/μl blood on day 2 of collection for excellent mobilizers [mean 333.8 (n=184) vs. 460 ×106 (n=92); p-value <0.001], but not for the good [mean 165.7 (n=102) vs. 189.5×106 (n=40); p-value 0.21] and intermediate [mean 80.1 (n=101) vs. 102.3 ×106 (n=52); p-value 0.07] groups. When CD34+ cell/kg collection totals with VTD-PACE and MVTD-PACE were compared, a significant difference was seen for the intermediate mobilizer group only [mean 23.6 (n=101) vs. 26.3 ×106 (n=52); p-value 0.03]. For the poor mobilizer group, VTD-PACE had an average CD34+ cells/μl blood of 13.5×106 for day 1 of collection and 17.0 ×106 for day 2, with a total of 14.5×106 CD34+cells/kg collected; while MVTD-PACE had an average of 13.2×106 CD34+ cells/μl blood for day 1 of collection, 24.9×106 for day 2, with a total of 24.2×106CD34+ cells/kg collected. The number of collection days was similar between VTD-PACE and MVTD-PACE in the excellent mobilization group (2 days), but was slightly more for VTD-PACE compared to MVTD-PACE for the good (2.1 vs. 2 days), intermediate (3.2 vs. 2.9 days), and poor (6.1 vs. 5.8 days) groups. Conclusion : Both regimens allow more than minimum collections, but MVTD-PACE provides a higher peak number of CD34+ cells/μl blood, resulting in a slightly lower mean number of days of collection than VTD-PACE to reach an optimal collection. Disclosures:No relevant conflicts of interest to declare.

Bortezomib-Dexamethasone or Vincristine-Doxorubicin-Dexamethasone as Induction Therapy Followed by Thalidomide as Maintenance Therapy in Untreated Multiple Myeloma Patients

This randomized, retrospective study evaluated the effect of thalidomide combined with bortezomib-dexamethasone (TBD) or vincristine-doxorubicin-dexamethasone (T-VAD) on 46 patients with multiple myeloma. Newly diagnosed patients were randomly allocated to receive TBD (n = 24) or T-VAD (n = 22). The high-quality response rate (complete response plus very good partial response) was 62.5% in the TBD group and 45.4% for T-VAD. The complete response rate was 29.2% for TBD and 13.6% for T-VAD. Overall survival at 2 and 3 years, respectively, was 91.7% and 62.5% for TBD versus 86.4% and 54.5% for T-VAD. Most of the toxic effects of treatment were well tolerated. Both regimens were effective in the treatment of newly diagnosed multiple myeloma patients. Further studies are required to determine the role of thalidomide in these two regimens.

A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients

The combination of pegylated liposomal doxorubicin (PLD), bortezomib and dexamethasone has shown efficacy in the treatment of multiple myeloma (MM) patients. Our earlier retrospective study suggested that modification of the doses, schedules and route of administration of these drugs appears to reduce toxicity without compromising anti-MM activity. As a result, we evaluated this modified drug combination in the frontline setting in a prospective multicentre phase II trial. Thirty-five previously untreated MM patients were enrolled. Dexamethasone IV 40 mg, bortezomib 1 mg/m(2) and PLD 5 mg/m(2) were administered on days 1, 4, 8 and 11 of a 4-week cycle. Patients were treated to their maximum response plus two additional cycles. The treatment regimen was discontinued after a maximum of eight cycles. Our modified schedule and dosing regimen achieved a high overall response rate of 86%, while showing a marked decrease in the incidence and severity of peripheral neuropathy, palmar-plantar erythrodysesthesia and myelosuppression compared to the standard dosing on a 3-week cycle using these drugs. This modified regimen of dexamethasone, bortezomib and PLD shows improved tolerability and safety while maintaining a high response rate when compared to standard treatment with these agents in the frontline setting.

Bortezomib for previously untreated multiple myeloma

Introduction:The paradigm of antimyeloma treatment has rapidly changed since the introduction of the first-in-class proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide.Areas covered:This manuscript discusses the most recent data on the frontline use of bortezomib and bortezomib-based combinations in multiple myeloma. Preclinical data, pharmacokinetics and pharmacodynamics of bortezomib are summarized, as well as published clinical trials of its use as a first-line treatment for transplant-eligible and elderly myeloma patients. Additionally, the use of bortezomib in particular myeloma subgroups, including patients with high-risk cytogenetics and renal insufficiency, is discussed. Finally, the prevention and management of bortezomib-induced side effects, including the latest data on weekly dosing for untreated elderly patients, is focused on.Expert opinion:Bortezomib has become an important backbone of frontline myeloma treatment. Nevertheless, continued efforts to implement newer dosing regimens and to identify new partner drugs for bortezomib remain an important challenge.

Early versus delayed autologous transplantation after immunomodulatory agents‐based induction therapy in patients with newly diagnosed multiple myeloma

Early versus delayed autologous stem cell transplantation (SCT) results in comparable overall survival in patients with multiple myeloma (MM) who receive alkylator-based therapies. It is not clear whether this paradigm holds true in the context of new therapies, such as immunomodulatory drugs (IMiDs). The authors studied 290 patients with untreated MM who received IMiD-based initial therapy, including 123 patients who received thalidomide-dexamethasone (TD) and 167 patients who received lenalidomide-dexamethasone (LD) induction before SCT. Patients who underwent a stem cell harvest attempt were considered transplantation-eligible and were included. SCT within 12 months of diagnosis and within 2 months of harvest were considered early SCT (n = 173; 60%). SCT >12 months after diagnosis was considered delayed SCT (n = 112; 40%). In the delayed SCT group, 42 patients had undergone SCT at the time of the current report, and the median estimated time to SCT was 5.3 months and 44.5 months in the early SCT and delayed SCT groups, respectively. The 4-year overall survival rate from diagnosis was 73% in both groups (P = .3) and was comparable in those who received TD (68% vs 64%, respectively) and those who received LD (82% vs 86%, respectively) as initial therapy. The time to progression after SCT was similar between the early and delayed SCT groups (20 months vs 16 months; P value nonsignificant). The current results indicated that, in transplantation-eligible patients who receive IMiDs as initial therapy followed by early stem cell mobilization, delayed SCT results in similar overall survival compared with early SCT. It is noteworthy that an excellent 4-year survival rate of >80% was observed among transplantation-eligible patients who received initial therapy with LD regardless of the timing of transplantation.