Lenalidomide Dexamethasone Research Articles

Continuous Lenalidomide and Low-Dose Dexamethasone for the Treatment of Patients with Newly Diagnosed Multiple Myeloma and Renal Impairment in the First Trial

Background: Second ASCT (ASCT2) is a safe and feasible for relapsed MM patients (pts), who have had durable remission from first ASCT (ASCT1). Long term stability of cryopreserved stem cells (SCs) has become an important issue in pts who require ASCT2 after a long period of disease remission. Our study aims to evaluate the engraftment ability of long term cryopreserved SCs for salvage ASCTs in a larger number of pts. Patients /Methods: We retrospectively reviewed 102 relapsed MM pts who underwent salvage ASCT2 using SCs from first collection at our institution between January 2003 to June 2013. Patient demographics, disease characteristics, chemotherapy and ASCT details were obtained from medical charts and transplant database. Neutrophil engraftment was defined as the first of 3 consecutive days that neutrophil counts were >0.5x109/L. Platelet engraftment was defined as day of platelet counts >20x109/L without supportive transfusion. Paired simple T-test was used to compare time to engraftment between ASCTs. Results: One hundred and two pts (65 males, 64%) underwent salvage ASCT for relapsed MM. Median age at diagnosis, ASCT1 and ASCT2 were 56, 57 and 61 years, respectively. Majority (98%) of pts received high dose cyclophosphamide followed by G-CSF for SCs mobilization and melphalan 200 mg/m2 for conditioning. All collected SCs were cryopreserved in 10%DMSO. Median SCs storage times were 1.9 (0.4-24.7) and 47.2 (15-131) months for ASCT1 and ASCT2, respectively. Median time duration between two ASCTs was 45 (14-128) months. Median numbers of CD34+ cells infused at ASCT1 were 6.43x106/kg (2.6-33.2) and 5.7x106/ kg (1.2-16.9) at ASCT2. There was no significant difference in median time to engraftment between ASCT1 and ASCT2; 12 (616) vs 11 (10-15) days for neutrophil engraftment (p1⁄40.33) and 11 (10-20) vs 11 (10-20) days for platelet engraftment (p1⁄40.26). There was no delayed engraftment (>21days) in any pts. We further investigated the stability of SCs based on years of cryopreservation at ASCT2. There was no difference in time to neutrophil (p1⁄40.06) and platelet engraftment (p1⁄40.74) between pts who were given short ( 6years) term cryopreserved SCs. Conclusion: Long term cryopreserved SCs can be safely used in salvage ASCT in relapsed MM pts. Cryopreservation of SCs >6 years results in no loss of viability as determined by comparable times to engraftment in both upfront and salvage ASCTs. PO-105 Continuous Lenalidomide and Low-Dose Dexamethasone for the Treatment of Patients with Newly Diagnosed Multiple Myeloma and Renal Impairment in the First Trial M. Dimopoulos, M. Cheung, M. Roussel, T. Liu, B. Gamberi, B. Kolb, H.G. Derigs, H. Eom, K. Belhadj, P. Lenain, R. van der Jagt, S. Rigaudeau, R. Hall, A. Jaccard, A. Tosikyan, L. Karlin, W. Bensinger, R. Schots, G. Chen, J. Marek, A. Ervin-Haynes, T. Facon National and Kapodistrian University of Athens, Athens, Greece; Odette Cancer Centre, Toronto, Canada; CHU Purpan/IUCT Oncopole, Toulouse, France; West China Hospital of Sichuan University, Chengdu, China, China; Arcispedale S. Maria Nuova, Reggio Emilia, Italy; Hopital Robert Debre, Paris, France; Staedtische Kliniken Frankfurt am Main Hochst, Frankfurt, Germany; National Cancer Center, Goyang, Korea, Republic Of; Hopital Henri Mondor, Creteil; Centre Henri Becquerel, Rouen, France; Ottawa Hospital, Ottawa, Canada; Hopital de Versailles, Le Chesnay, France; Royal Bournemouth Hospital, Dorset, United Kingdom; CH Hopital Dupuytren, Draveil, France; Hopital du Sacre-Coeoeoeur de Montreal, Montreal, Canada; Centre Hospitalier Lyon Sud, Pierre-Benite, France; Fred Hutchinson Cancer Center, Seattle, United States; University Hospital VUBeMyeloma Center Brussels, Brussels, Belgium; Celgene Corporation, Summit, United States; Service des Maladies du Sang, Hopital Claude Huriez, Lille, France

Lenalidomide and low-dose dexamethasone (Ld) is equivalent to Ld plus autologous stem cell transplant (ASCT) in newly diagnosed multiple myeloma (NDMM): Results of a randomized, phase III trial.

8530 Background: Upfront ASCT is the current standard of care for transplant-eligible NDMM. However, its use has come into question with the emergence of novel agents such as lenalidomide. This ran...

A phase I/II trial of very low to low-dose continuous azacitidine in combination with standard doses of lenalidomide and low-dose dexamethasone in patients with relapsed or refractory multiple myeloma.

8584 Background: Azacitidine (AZA) may overcome drug resistance of relapsed or refractory multiple myeloma (RRMM).Continuous administration should maximize epigenetic effects and safety. Methods: Lenalidomide (len) 25mg (10mg if GFR 30-59 ml/min) d1-21 every 28d and dexamethasone (dex) 40mg weekly (len-dex) were combined with escalating doses of AZA from 30mg/m2 SC weekly to 50mg/m2SC twice a week. Dose limiting toxicity (DLT) was assessed during cycle 1. IMWG uniform response criteria (partial response, PR) and adapted EBMT criteria (minor response, MR) were used. Plasma activity of the AZA inactivating enzyme cytidine deaminase (CDA) was measured by HPLC at Zymo Research Corp., CA. Results: Forty patients (pts) with relapsed (n = 3) or refractory (n = 37) MM were enrolled after a median of 4 prior regimens (range 1-10). Their disease was refractory to len (n = 32), bortezomib and / or carfilzomib (n = 32), or both len and proteasome inhibitors (n = 28). The target phase II dose of 50mg/m2 SC twice a wk ...

Downregulation of myeloma-induced ICOS-L and regulatory T cell generation by lenalidomide and dexamethasone therapy

Multiple myeloma (MM) produces significant cellular and humoral immune defects. We have previously reported that MM induces CD4+CD25+FoxP3+ cells (TRegs), via tumour expression of the immune checkpoint regulator, ICOS-L. We sought to define what impact the immunomodulatory drug lenalidomide, alone or with dexamethasone, has on TReg cell generation. Lenalidomide pre-treatment of MM cell lines reduced TReg generation and the concomitant TReg:TEff (CD4+CD25+FoxP3−: effector T cells) ratio, as a consequence of reduced ICOSL transcription. Dexamethasone did not affect surface ICOS-L expression but did induce TReg cell apoptosis without impacting on TEff cell survival. Combined lenalidomide and dexamethasone significantly reduced both TReg induction and the TReg:TEff cell ratio. In vivo, serial analysis of the TReg:TEff ratio in MM patients on lenalidomide–dexamethasone therapy revealed a progressive reduction towards age-matched control values, though not complete correction. Our data demonstrate for the first time immune synergism to explain the observed immune-modulation associated with lenalidomide–dexamethasone therapy.

Steven-Johnson Syndrome (SJS) in a Multiple Myeloma patient treated with lenalidomide and low dose dexamethasone regimen: a rare Case Report

Lenalidomide is an immunomodulatory drug (IMiD), a derivative of thalidomide used in the treatment of multiple myeloma. Stevens-Johnson syndrome (SJS) is a rare but life-t hreatening cutaneous adverse reaction, at a rate of 1.1 to 7.1 cases per million person-years, mortality rate between 1% to 3% and 10% to 70% when it is associated with TIN. Very few cases of Lenalidomide induced SJS has been reported. We describe a case of Stevens-Johnson syndrome induced by induction therapy lenalidomide-low dose Dexamethasone regimen in a 56 year-old male who underwent induction therapy for multiple myeloma.

The investigational proteasome inhibitor ixazomib for the treatment of multiple myeloma.

Ixazomib is an investigational, reversible 20S proteasome inhibitor. It is the first oral proteasome inhibitor under clinical investigation in multiple myeloma (MM). Under physiological conditions, the stable citrate ester drug substance, ixazomib citrate (MLN9708), rapidly hydrolyzes to the biologically active boronic acid, ixazomib (MLN2238). Preclinical studies have demonstrated antitumor activity in MM cell lines and xenograft models. In Phase I/II clinical studies ixazomib has had generally manageable toxicities, with limited peripheral neuropathy observed to date. Preliminary data from these studies indicate ixazomib is active as a single agent in relapsed/refractory MM and as part of combination regimens in newly diagnosed patients. Phase III studies in combination with lenalidomide-dexamethasone are ongoing.

Phase 1 Study of the Investigational Proteasome Inhibitor Ixazomib Alone or in Combination with Lenalidomide–Dexamethasone (Rd) in Japanese Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Background Ixazomib is the first oral proteasome inhibitor to be investigated clinically for the treatment of MM. Phase 1 studies have shown single-agent activity and manageable toxicities in RRMM (Kumar et al. Blood 2014) and phase 1/2 studies have suggested the feasibility and activity of weekly oral ixazomib plus Rd in previously untreated MM (Kumar et al. ASH 2012; Richardson et al. ASH 2013). These findings have led to ongoing phase 3 trials of weekly ixazomib 4 mg + Rd in RRMM and previously untreated MM. However, the early-phase studies were conducted in Western pts. This phase 1, open-label multicenter study aimed to determine the safety, tolerability, and pharmacokinetics (PK) of weekly ixazomib alone or with Rd in Japanese pts with RRMM (Japic Clinical Trials Information no. 121822). Methods Primary objectives were to evaluate the safety and tolerability, including dose-limiting toxicities (DLTs) and adverse events (AEs), and the PK of ixazomib alone or with Rd. A secondary objective was evaluation of antitumor activity. Japanese pts aged ≥20 years with RRMM who had received at least 2 prior regimens, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. All had measurable disease and ECOG performance status of 0–2. Pts with grade ≥2 peripheral neuropathy or grade ≥2 diarrhea at study entry were excluded. Pts received ixazomib 4 mg on days 1, 8, and 15 of 28-day cycles, alone or with Rd (lenalidomide 25 mg on days 1–21, dexamethasone 40 mg on days 1, 8, 15, and 22), per the regimen used in the ongoing phase 3 trials. AEs were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points prior to and after dosing on days 1 and 15 of cycle 1. Responses were assessed per IMWG uniform response criteria. Results Fourteen pts were enrolled; 8 (57%) were male, median age was 62.5 yrs (range 53–71), 4 pts were aged ≥65 yrs, median number of prior therapies was 7. Seven pts received single-agent ixazomib and 7 received ixazomib + Rd. One pt in each cohort was excluded from the DLT-evaluable population. Two patients experienced DLTs in cycle 1: 1 pt receiving single-agent ixazomib had grade 4 thrombocytopenia and grade 3 diarrhea, hypertension, hypokalemia, hyponatremia, and nausea; 1 pt in the ixazomib + Rd cohort had grade 4 thrombocytopenia and neutropenia. All events were considered treatment-related. At data cut-off (Jan 6 2014), 6 pts remained on treatment and 8 had discontinued due to: progressive disease (PD; n=3), AEs (n=3), symptomatic deterioration, and protocol violation (each n=1). At data cut-off, pts (n=14) had received a median of 6 cycles of ixazomib (range 1–21); the 7 pts in the ixazomib + Rd cohort had received a median of 4 cycles (range 1–12) of ixazomib + Rd. Thirteen (93%) pts experienced treatment-related AEs; the most common were neutropenia (71%), thrombocytopenia (71%), leukopenia (64%), lymphopenia (57%), and diarrhea (50%). There were no cases of peripheral neuropathy. Nine (64%) pts had grade ≥3 AEs; the most common were lymphopenia (50%), neutropenia (43%), and thrombocytopenia (36%). Two (14%) pts (single-agent cohort) had serious AEs (grade 2 bronchitis in 1 pt, and grade 4 thrombocytopenia and grade 3 hypokalemia in 1 pt). Three pts discontinued due to AEs; 1 due to diarrhea in the single-agent cohort, and 1 due to neutropenia and 1 due to thrombocytopenia in the ixazomib + Rd cohort. There were no deaths. PK data showed ixazomib was rapidly absorbed with a Tmax at 1.08–1.83 hrs. Terminal half-life (geometric mean) was 5.7 days for single-agent ixazomib and 5.2 days for ixazomib + Rd. There were no substantial differences in the ixazomib PK profile between the two cohorts. Thirteen pts were response-evaluable. One pt (ixazomib + Rd cohort) had a partial response; at data cut-off, this pt remained in response with a 100% M-protein reduction (unconfirmed VGPR) and duration of response of ~10.8 months. Seven pts had stable disease (including 3 with M-protein reductions of 25–50%), 2 had PD, and 3 were not assessable. Conclusions These data suggest that ixazomib 4 mg alone or with Rd is feasible and tolerable in Japanese pts with RRMM. The AEs were manageable, reflecting the AE profile seen in Western populations, supporting the use of this dose and schedule in Japanese pts. Disclosures Handa: Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding. Off Label Use: Investigational agent ixazomib for the treatment of Japanese patients with relapsed and/or refractory multiple myeloma.. Matsushima:Takeda Pharmaceutical Company Limited : Employment.

Treatment of Non-Transplant Patients with Multiple Myeloma: Routine Treatment by Office-Based Haematologists in Germany - Data from the Prospective Tumour Registry Lymphatic Neoplasms (TLN)

SummaryBackground: Various treatment options exist for patients with multiple myeloma (MM). Clinical registries provide insight into routine treatment and identify changes in treatment over time. Patients and Methods: The Tumour Registry Lymphatic Neoplasms (TLN) prospectively collects data on the treatment of patients with lymphoid B cell neoplasms as administered by office-based haematologists in Germany. Data on patient and tumour characteristics, comorbidities, systemic treatments and outcome parameters are recorded. Results: 371 non-transplant patients with MM were recruited between 2009 and 2011. At the start of first-line (second-line) treatment, the median age was 73 (75) years; 67% (74%) of the patients had stage III MM (classification of Durie and Salmon) and 19% (28%) had renal insufficiency. In the first line, 40% of the patients received bortezomib + melphalan + prednisone (VMP), 25% received bortezomib ± dexamethasone (V±D) and 8% were treated with melphalan + prednisone + thalidomide (MPT). While use of bortezomib-based regimens increased from 67% (2009) to 85% (2011), use of melphalan-based regimens decreased from 68% to 48%. The overall objective response rate of treatment was 82%. In the second line, 34% of the patients received V±D and 16% lenalidomide + dexamethasone (LD). Conclusion: Bortezomib-based regimens dominate the first- and second-line treatment of MM. Future analyses will investigate outcome data, e.g. effectiveness of bortezomib retherapy compared to other second-line treatments.

Lenalidomide and Dexamethasone in Transplant-Ineligible Patients with Myeloma

BackgroundThe combination melphalan–prednisone–thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches.MethodsWe randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide–dexamethasone versus MPT.ResultsThe median progression-free survival was 25.5 months with continuous lenalidomide–dexamethasone, 20.7 months with 18 cycles of lenalidomide–dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide–dexamethasone vs. MPT and 0.70 for continuous lenalidomide–dexamethasone vs. 18 cycles of lenalidomide–dexamethasone; P<0.001 for both comparisons). Continuous lenalidomide–dexamethasone was superior to MPT for all secondary efficacy end points, including overall survival (at the interim analysis). Overall survival at 4 years was 59% with continuous lenalidomide–dexamethasone, 56% with 18 cycles of lenalidomide–dexamethasone, and 51% with MPT. Grade 3 or 4 adverse events were somewhat less frequent with continuous lenalidomide–dexamethasone than with MPT (70% vs. 78%). As compared with MPT, continuous lenalidomide–dexamethasone was associated with fewer hematologic and neurologic toxic events, a moderate increase in infections, and fewer second primary hematologic cancers.ConclusionsAs compared with MPT, continuous lenalidomide–dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. (Funded by Intergroupe, Francophone du Myélome and Celgene; FIRST ClinicalTrials.gov number, NCT00689936; European Union Drug Regulating Authorities Clinical Trials number, 2007-004823-39.)

In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone.

The development of resistance to therapy is unavoidable in the history of multiple myeloma patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclinical models, especially those mimicking acquired resistance. Here we present an in vivo model of acquired resistance based on the continuous treatment of mice bearing subcutaneous MM1S plasmacytomas. Xenografts acquired resistance to two generations of immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide) in combination with dexamethasone, that was reversible after a wash-out period. Furthermore, lenalidomide-dexamethasone (LD) or pomalidomide-dexamethasone (PD) did not display cross-resistance, which could be due to the differential requirements of the key target Cereblon and its substrates Aiolos and Ikaros observed in cells resistant to each combination. Differential gene expression profiles of LD and PD could also explain the absence of cross-resistance. Onset of resistance to both combinations was accompanied by upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway and addition of selumetinib, a small-molecule MEK inhibitor, could resensitize resistant cells. Our results provide insights into the mechanisms of acquired resistance to LD and PD combinations and offer possible therapeutic approaches to addressing IMiD resistance in the clinic.

Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma

Cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide. However, the clinical implications of CRBN in MM patients are unclear. Using immunohistochemical (IHC) staining on paraffin-embedded bone marrow sections, the expression of CRBN protein in myeloma cells (MCs) was assessed in 40 relapsed/refractory MM (RRMM) patients who received lenalidomide/dexamethasone (LD) and 45 and 22 newly diagnosed MM (NDMM) patients who received thalidomide/dexamethasone (TD) and melphalan/bortezomib/prednisolone (MVP), respectively. IHC staining were scored on a scale representing the diffuseness and intensity of positive-staining MCs (range, 0–8) and a score ≥4.5 was used for CRBN positivity (CRBN+) on a cut-point analysis of all possible scores and response of TD and LD. Compared to CRBN+ NDMM patients, CRBN− NDMM patients had more international staging system (ISS) III (26 vs. 61 %, respectively; P = 0.006). In the LD and TD cohorts, the response rate (RR) was higher in CRBN+ patients than CRBN− patients (LD 79 vs. 33 %, respectively; P = 0.005) (TD 75 vs. 29 %, respectively; P = 0.005); however, this trend was not observed in the MVP cohort. In the LD and TD cohorts, the positive and negative prediction value of CRBN+ for treatment response was 79 and 67 % and 75 and 71 %, respectively. Multivariate analysis showed that CRBN+ was a significant factor associated with superior RR for LD and TD. The data suggest that expression of CRBN protein in MCs assessed using the IHC is a feasible approach to predict the response of IMiDs in MM patients.

Follow-Up Study of a Multiple Myeloma Patient Successfully Treated with Clarithromycin (CAM), Low-Dose Lenalidomide and Low-Dose Dexamethasone: Significance and Possible Mechanism of Action of CAM as an Add-On Therapy

Background: Recently, high efficacy of the chemotherapeutic regimen combining clarithromycin (CAM) with lenalidomide (Len) and dexamethasone (Dex) (BiRD) in treating multiple myeloma (MM) patients has been reported. However, the exact mechanism of added CAM has not been fully elucidated. This case report will provide helpful information for understanding the significance and the mechanism of action of CAM as an add-on therapy. Patient: A 78-year-old female patient with IgA-λ type MM was treated with low-dose Len coupled with low-dose Dex (low Rd), and excellent response was achieved for long term, but she later became refractory to this treatment. Then, CAM was added to low Rd (low Rd-CAM, i.e., modified BiRD therapy). This add-on-therapy was found to be effective, but later suspended because of pneumonitis. Then, low-dose Len coupled with CAM (low R-CAM) treatment was applied; but effect of this Dex-free treatment was insufficient. Thus, low Rd-CAM was reapplied and satisfactory reduction of IgA was achieved. This fact suggests that low Rd-CAM is the favorable combination, Dex is requisite and CAM might have enhanced the effect of Dex. In this case, various serum cytokines were examined during the course of illness. Only interleukin-6 showed apparent increase, and tumor necrosis factor-α, transforming growth factor-β, soluble IL-2 receptors and C-reactive protein showed the slight increase during low Rd-CAM treatment. The results seem somewhat conflicting, but it seems that intricate cytokine response due to immune activation might have occurred during low Rd-CAM treatment.

Initial treatment of transplant-ineligible patients in multiple myeloma

Over two-thirds of newly diagnosed multiple myeloma are over 65 years. The treatment goals for the non-transplant-eligible patients should be to prolong survival by achieving the best response, while ensuring quality of life. New upfront treatment combinations based on first generation of novel proteasome inhibitors and immunomodulatory drugs plus alkylating agents, the historical platform, have significantly improved outcomes in the past 10 years. Other non-alkylator induction regimens, essentially lenalidomide plus low-dose dexamethasone are also available and provide a novel backbone that may be combined with novel second- and third-generation drugs. Data indicate that prolonged treatment extends the progression-free survival. In summary, this group requires individualized and dose-modified regimens to improve tolerability and efficacy, while maintaining their quality of life.

AT‐101 downregulates BCL2 and MCL1 and potentiates the cytotoxic effects of lenalidomide and dexamethasone in preclinical models of multiple myeloma and Waldenström macroglobulinaemia

Multiple myeloma, the second most common haematological malignancy in the U.S., is currently incurable. Disruption of the intrinsic apoptotic pathway by BCL2 and MCL1 upregulation is observed in >80% of myeloma cases and is associated with an aggressive clinical course. Remarkably, there is no approved drug with the ability to target BCL2 or MCL1. Thus, we investigated the anti-tumour effects of a pan-BCL2 inhibitor, AT-101, which has high binding specificity for BCL2 and MCL1 in preclinical models of plasma cell cancers (Multiple myeloma and Waldenström macroglobulinaemia). Gene expression and immunoblot analysis of six plasma cell cancer models showed upregulation of BCL2 family members. AT-101 was able to downregulate BCL2 and MCL1 in all plasma cell cancer models and induced apoptotic cell death in a caspase-dependent manner by altering mitochondrial membrane permeability. This cytotoxic effect and BCL2 downregulation were further potentiated when AT-101 was combined with lenalidomide/dexamethasone (LDA). NanoString nCounter mRNA quantification and Ingenuity Pathways Analysis revealed differential changes in the CCNA2, FRZB, FYN, IRF1, PTPN11 genes in LDA-treated cells. In summary, we describe for the first time the cellular and molecular events associated with the use of AT-101 in combination with lenalidomide/dexamethasone in preclinical models of plasma cell malignancy.

Bendamustine, Bortezomib and Dexamethasone (BVD) In Elderly Patients With Multiple Myeloma In First Relapse: Final Analysis Of The Intergroupe Francophone Du Myelome (IFM) 2009-01 Trial

BackgroundPrognosis of relapses is severe in elderly multiple myeloma (MM). In recent studies, median survival at progression after 1st line therapy was between 9 and 13 months (T. Facon, Lancet 2007; C. Hulin, J Clin Oncol 2009). Bortezomib (V) plus dexamethasone (D) is a major regimen in the treatment of relapses. Bendamustine (B) demonstrated to be highly active in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly patients with progressive MM on or after 1stline treatment. MethodsPhase 2 IFM 2009-01 trial was dedicated to patients older than 65 years in 1st relapse or refractory to 1st line therapy. Inclusion criteria were measurable disease, PS ECOG 0-2, ANC > 1.5x109/l, platelets > 100x109/l, serum creatinine level < 250 mcmol/l, AST and ALT < 3xULN. Pts with prior exposure to bortezomib were excluded. Treatment regimen was B 70 mg/m2 day 1-8, V 1.3 mg/m2 day 1-8-15-22 and D 20 mg day 1-8-15-22 every 28 days. 6 cycles were administered. Responders were assigned to receive maintenance treatment with 6 additional cycles administered 1 month out of 2. Response was evaluated according to IMWG criteria. Response rate was the primary objective. Progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. ResultsFrom 03/2010 to 07/2011, 73 pts were included. Median age was 75.8 years (range 66-86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior line of therapy: Melphalan-Prednisone (MP) in 12, MP-Thalidomide in 42, Lenalidomide-Dexamethasone (LD) in 14, other IMiD-based regimen in 5. Median treatment cycles administered was 7 (1-12). 51 pts (69.8%) achieved at least partial response [best response CR: 10 pts (13.6%), VGPR: 12 pts (16.5%), PR: 29 pts (39.7%), MR: 4 pts (5.5%), SD: 5 pts (6.8%), progression: 12 pts (16.5%), unrelated early death: 1 pt (1.3%)]. Median PFS was 10.8 months (95%CI: 7-18.2 months) and median OS 23 months (15.4-27.5). Adverse prognostic factors for PFS were PS ECOG 2 (p=0.0002), beta 2 microglobulin level > 3.5 mg/l (p=0.0006) and del17p (p=0.01). 26 pts (35.6%) completed the planned 12 cycles of treatment. Cause of treatment discontinuation was progressive MM in 30 pts (41.1%), failure to achieve PR in 5 pts (6.8%), adverse event in 10 pts (13.6%), patient refusal and unknown 1 pt (1.3%) each. 37 pts (50.6%) had died at time of final analysis. Cause of death was MM in 30 pts, sepsis in 5 pts, renal failure in 1 pt and unrelated in 1 pt. Grade 3-4 adverse events were neutropenia: 14 pts (19.1%), thrombocytopenia: 8 pts (10.9%), sepsis: 14 pts (19.1%), gastro-intestinal: 6 pts (8.2%), anaphylaxis: 2 pt (2.7%). Grade 2 peripheral neuropathy occurred in 8 pts (10.%) and grade 3 in 3 pts (4.1%). ConclusionsIn this elderly population with poor prognosis MM, BVD combination provides a high overall response rate and manageable toxicity. These results compare favourably with those achieved with VD or LD. Disclosures:Roussel:CELGENE: Honoraria; JANSSEN: Honoraria. Leleu:CELGENE: Honoraria; JANSSEN: Honoraria. Cony-Makhoul:BMS: Honoraria. Avet-Loiseau:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Moreau:Janssen: Honoraria; Janssen and Millennium: Membership on an entity's Board of Directors or advisory committees.

Interference Of The Tumor Supportive Effects Of BCL2 and MCL1 Sensitize Malignant Plasma Cells To The Lethal Effects Of Lenalidomide and Dexamethasone Regimen: An Important Clinical Path For BCL2 Targeting Drugs

BackgroundMultiple myeloma (MM) is the second most common hematologic malignancy in the U.S. and is characterized by increased immunoglobulin production and infiltration of the bone marrow by malignant plasma cells. Myeloma cell growth is supported by both the elements present in the bone marrow microenvironment as well as deregulation of internal cellular systems associated with proliferation and apoptosis. Defective programmed cell death by BCL2 or MCL1 upregulation is observed in >80% of myeloma cases and is associated with an aggressive clinical course. Remarkably, there is no approved drug with the ability to target BCL2 or MCL1. Various strategies to mitigate the effects of increased BCL2 functionality, via small molecule inhibitors or BCL2-specific antisense oligonucleotides have been previously examined in MM. These studies revealed that 1) apart from BCL2, additional anti-apoptotic members belonging to the BCL2 family (i.e. MCL1, BCL-xL) play integral roles in maintenance of the myeloma cell phenotype, 2) drugs, which target only BCL2 offer limited therapeutic advantage and 3) given that survival factors engaged in MM are multifactorial, perhaps isolated targeting of the BCL2 pathways may not be sufficient. We therefore hypothesized that the clinical development of drugs that target various antiapoptotic BCL2 family members will require a partnership with established anti-MM regimens whose activity can potentially be further enhanced with correction of the apoptotic response system. AimSince lenalidomide and dexamethasone (LD) is an established therapy for plasma cell cancers, we investigated if the pan-BCL2 inhibitor AT-101 (BH3 mimetic), which has high binding specificity for BCL2, MCL1 and BCL-xL, can be an effective therapeutic partner to enhance anti-MM effects of LD. MethodsHuman MM (KMS11, U266, OPM2) and WM (BCWM.1) cell lines along with their corresponding bortezomib resistant (BR) clones, (KMS11/BR, U266/BR, OPM2/BR and BCWM.1/BR) which were developed in our laboratory were used in this study. For gene expression profiling, the Illumina HumanHT-12 v3 whole-genome gene expression array and Nanostring nCounter mRNA quantification assays (NanoString, Seattle, WA) were utilized. Statistical analysis was conducted using R-based packages and the MeV software (TIGR). Apoptosis was measured by annexin-v/PI staining, and mitochondrial membrane permeability (MOMP) was assessed using TMRM followed by flow cytometry. Protein profiles were ascertained by western blot. ResultsGene expression and immunoblot analysis of six plasma cell cancer models showed upregulation of various BCL2 family members, notably MCL1 and BCL-xL. In a dose-dependent manner, AT-101 was able to downregulate BCL2 and MCL1 and induced apoptotic cell death in MM and WM cells in a dose dependent manner. Tumor cell death was associated with caspase and PARP-1 cleavage accompanied by an increase in MOMP. This cytotoxic effect and BCL2 downregulation were further potentiated when AT-101 was combined with lenalidomide/dexamethasone (LDA). Nanostring nCounter mRNA quantification and IPA analysis revealed differential changes in the CCNA, FRZB, FYN, IRF1, PTPN11 genes in LDA treated cells. IPA canonical pathway analysis demonstrated the p53 signaling and the cyclins and cell cycle regulation pathways to be the most significantly activated by LDA therapy. SummaryIn summary, we describe for the first time the cellular and molecular events associated with the use of AT-101 in combination with lenalidomide/dexamethasone in preclinical models of plasma cell malignancy. This study lays the rationale for engaging and handicapping the intrinsic apoptotic system through the pan-BCL2 targeting capabilities of AT-101; thus enhancing the anti-MM effects of lenalidomide/dexamethasone. Disclosures:Foran:Celgene: Research Funding.

Retrospective Study Of Incidence Of Thromboses In Chinese Versus African Americans With Multiple Myeloma

BackgroundRisk of arterial (ATE) and venous thromboembolic events (VTE) is increased in multiple myeloma (MM). Immunomodulator therapy (Imid) concurrent with steroids further increases this risk. Retrospective single arm studies suggest that Asian patients with MM may have a lower risk of TE than in other ethnicities. We performed a retrospective study comparing Chinese (C) and African American (AA) patients in two centers, the Department of Clinical Oncology, Prince of Wales Hospital, the Chinese University of Hong Kong (PWH) and the University hospitals, Case Medical Center, Cleveland, Ohio (CMC), for ethnic differences in incidence of TE in MM. Methods120 Chinese patients from PWH and 100 AA patients from CMC fulfilling IMWG consensus criteria for MM diagnosis between Jan 1st 2000 and Dec 31st 2011 were identified and selected for analysis. Data regarding demographics, comorbidities, myeloma characteristics, therapy and thrombotic complications were collected by electronic and paper chart review. Data collection was censored as of Dec 31st 2012. ResultsThe Chinese cohort comprised more men, lower baseline incidence of diabetes (DM), hypertension (HTN) and non-myeloma related renal failure (CRF), advanced myeloma at diagnosis and more IgA subtype than AA. Over 90% of patients of both groups received chemotherapy. 72% of Chinese and 80% of AA received Imid based treatment. Lenalidomide with steroids was used more often in AA (36.8% AA vs 3.6%C, p<0.0001), Chinese received more thalidomide with steroids. (62.2% C vs 42.1%, p:0.004) Use of thromboprophylaxis (TP) is not routine in PWH, less Chinese were on TP during the disease course (11.7% vs 68%, p<0.0001) or during Imid based treatment. (16% vs 85%, p: 0.0001) Relative rates of aspirin, low molecular weight heparin and warfarin usage for TP were similar across both groups.Despite lower TP rates, a significantly lower rate of symptomatic VTE was observed in the Chinese. (3.3% vs 22%, p:0.001) The difference in VTE detection persisted on correction for number of imaging studies performed, 24 imaging tests in Chinese and 145 in AA. (16.7% vs 48.3%, p:0.004). Amongst the Chinese, all 4 events (100%) occurred on thalidomide dexamethasone (TD), 3 events (75%) in the absence of TP. In the AA, 21 of 26 events (81%) occurred on Imid based treatment. 12 events (46%) occurred in the absence of TP. On binary logistic regression using race, gender, prior venous thrombosis, any TP, TD and lenalidomide dexamethasone therapy as covariates, AA race (OR: 5.022, 95% CI:1.3- 19.4) and TD therapy (OR: 4.07, 1.26- 3.13) emerged as significant risk factors for VTE. Overall incidence of VTE on TD treatment was 4.5% in Chinese versus 22% in AA. (p:0.002)An increased number of arterial events were seen in the Chinese (9.2% vs 3% in AA) but the difference did not reach statistical significance. Of the 11 arterial events in Chinese, 5 (46%) occurred on Imid based therapy, 9 events (82%) were in the absence of TP. 7 were cardiac and 4 cerebrovascular. Of the 3 arterial events in AA, 1 (33.3%) occurred on Imids and all patients were receiving TP. 1 was cardiac, 1 abdominal and 1 upper limb. ConclusionOur study suggests that the Chinese have a lower risk of VTE than AA in the setting of MM. However , despite lower prevalence of most vascular risk factors in Chinese, ATE rates in Chinese were higher than AA, while not statistically significant. Larger studies are necessary to further elucidate these differences in thrombosis risk and to develop specific guidelines for TP in Asian patients with MMTable 1Characteristics of AA and Chinese patients with MM (*: p value <0.05, NS: not significant)CharacteristicAA (n=100)Chinese (n=120)pAgeMean age at MM diagnosis64.7 (SD:12.6)65.7 (SD:10.8)NSGender, n (%)Male gender n (%)43 (43%)69 (57.5%)*Blood group, n (%)O36 (36%)44 (36.7%)NSNon O42 (42%)62 (51.7%)Comorbidities, n (%)DM31 (31%)28 (23.3%)NSHTN63 (63%)57 (47.5%)*Lipids32 (32%)10 (8.3%)*Gout2 (2%)12 (10%)*Atrial fibrillation4 (4%)7 (5.8%)NSActive smoking8 (8%)10 (8.3%)NSCRF22 (22%)5 (4.2%)*Pre myeloma arterial thrombosis13 (13%)18 (15%)NSPre myeloma venous thrombosis5 (5%)1 (0.8%)NSMyeloma characteristics, n (%)DSS 1 or 237 (37%)20 (16.7%)*DSS 363 (63%)100 (83.3%)IgG73 (73%)56 (46.7%)*IgA19 (19%)37 (30.8%)IgM1 (1%)0 (0%)Light chain/non secretory/ IgD7 (7%)27 (22.5%)TE events, n (%)VTE after MM diagnosis22 (22%)4 (3.3%)*ATE after MM diagnosis3 (3%)11 (9.2%)NS Disclosures:No relevant conflicts of interest to declare.

Bendamustine, Bortezomib and Dexamethasone (BVD) in Elderly Patients with Multiple Myeloma in First Relapse: Updated Results of the Intergroupe Francophone Du Myelome (IFM) 2009-01 Trial

AbstractAbstract 4044 Background:Prognosis of relapse is severe in elderly multiple myeloma (MM). In recent studies, median survival at progression after 1st line therapy was between 9 and 13 months (T. Facon, Lancet 2007; C. Hulin, J Clin Oncol 2009). Bortezomib (V) plus dexamethasone (D) is a major regimen in the treatment of relapses. Bendamustine (B) demonstrated to be highly active in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly patients with progressive MM on or after 1st line treatment. Methods:Phase 2 IFM 2009-01 trial was dedicated to patients older than 65 years in 1st relapse or refractory to 1st line therapy. Inclusion criteria were measurable disease, PS ECOG 0–2, ANC > 1.5×109/l, platelets > 100×109/l, serum creatinine level < 250 mcmol/l, AST and ALT < 3xULN. Pts with prior exposure to bortezomib were excluded. Treatment regimen was B 70 mg/m2 D1–8, V 1.3 mg/m2 D1–8-15–22 and D 20 mg D1–8-15–22 every 28 days. 6 cycles were administered. Responders were assigned to receive maintenance treatment with 6 additional cycles administered 1 month out of 2. Response was evaluated according to IMWG criteria. Response rate was the primary objective. Progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Results:The present analysis is restricted to the 6 monthly cycles. From 03/2010 to 07/2011, 73 pts were included. Median age was 75.8 years (range 66–86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior line of therapy: melphalan-prednisone (MP) in 12, MP-Thalidomide in 44, Lenalidomide-Dexamethasone (LD) in 14, other IMiD-based regimen in 3. 49 pts (67.1%) achieved at least partial response [best response CR: 9 pts (12.3%), VGPR: 12 pts (16.5%), PR: 28 pts (38.3%), MR: 6 pts (8.2%), SD: 4 pts (5.5%), progression: 13 pts (17.8%), early discontinuation: 1 pt (1.3%)]. Adverse prognostic factors for response were 1st line regimen with IMiD (p=0.006) and del17p (p=0.036). At 6 months, PFS was 67.1% and OS 80.8%. Cause of death was MM in 9 pts, sepsis in 4 pts and renal failure in 1 pt. Grade 3–4 adverse events were neutropenia: 16 pts (21.9%), thrombocytopenia: 7 pts (9.6%), sepsis: 14 pts (19.2%), gastro-intestinal: 9 pts (12.3%), anaphylaxis: 1 pt (1.3%). Grade 2 peripheral neuropathy occurred in 10 pts (13.6%) and grade 3 in 2 pts (2.7%). At 6 months, treatment was discontinued in 33 pts (45.2%). Cause of discontinuation was progressive MM in 18 pts (24.6%), failure to achieve PR in 5 pts (6.8%), adverse event in 8 pts (10.9%), patient refusal or lost to follow-up 1 pt (1.3%) each. Conclusion:In this elderly population with poor prognosis MM, BVD combination provides a high overall response rate and manageable toxicity. These results compare favorably with those achieved with VD or LD. Disclosures:Hulin:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Kolb:janssen: Honoraria; celgene: Honoraria. Roussel:celgene: Honoraria; janssen: Honoraria.

PCN58 A Comprehensive Cost-Effectiveness Analysis of Lenalidomide for Multiple Myeloma Patients who Have Received at Least One Prior Therapy

Guidelines preferred (category 1) salvage therapies for relapsed/refractory multiple myeloma typically include bortezomib (BTZ) and lenalidomide. Since no randomized controlled trials (RCT) or relative effectiveness assessments comparing both drugs exist a comprehensive assessment of the cost-effectiveness of lenalidomide+dexamethasone (LEN/DEX) was performed in different drug sequencing (≥1 prior vs. 1 prior therapy) using indirect comparison. A Markov-type model was designed to assess long-term cost-effectiveness of LEN/DEX vs BTZ (indirect), using patient-level data from the MM-009/MM-010 RCTs (LEN/DEX vs. DEX) and published APEX trial data (BTZ vs. DEX). Due to potential crossover-induced bias, overall survival (OS) was estimated using a quantitative relationship between time-to-progression/progression-free-survival and OS (censored normal weighted Tobit regression model, based on 153 studies containing 230 treatment arms and 22,696 MM patients). The indirect comparison was based on a mixed treatment comparison of time-to-progression from the aforementioned trials. The Portuguese societal perspective was assumed. Effectiveness was measured in life years (LY) and quality-adjusted life years (QALY). Annual discount rates were set at 5%. Probabilistic sensitivity analysis was conducted with Monte-Carlo simulations. LEN/DEX is estimated to add substantial clinical benefits to BTZ. In patients with ≥1 prior therapy incremental LY, QALY and costs with LEN/DEX were 1.1 LY (95%CI: 0.4;2.0), 0.8 QALY (95%CI: 0.3;1.5) and 49,266€ (95%CI: 37,730€;67,342€) and in patients with only 1 prior therapy 1.4 LY (95%CI: 0.4;2.9), 1.1 QALY (95%CI: 0.3;2.1) and 57,293€ (95%CI: 39,303€;84,809€), respectively. Corresponding ICERs (LEN/DEX vs BTZ) ranged from 39,770€/LY to 61,649/QALY. Lenalidomide plus dexamethasone can be regarded as a cost-effective choice compared to bortezomib monotherapy for relapsed/refractory multiple myeloma patients in Portugal.

Bendamustine, bortezomib, and dexamethasone (BVD) in elderly patients with relapsed/refractory multiple myeloma (RRMM): The Intergroupe Francophone du Myélome (IFM) 2009-01 protocol.

8014 Background: Bortezomib (V) plus dexamethasone (D) is a treatment of choice of RRMM. In small series, the addition of an alkylator was beneficial. Bendamustine (B) showed a high activity in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly pts with MM progressive on or after 1st line therapy. Methods: We conducted a phase 2 trial combining B 70 mg/m2 D1-8, V 1.3 mg/m2 D1-8-15-22 and D 20 mg D1-8-15-22 every 28 days. 4 cycles were administered. In responders (PR or better), 2 additional cycles were provided followed by a maintenance phase with 6 cycles given every 2 months. Inclusion criteria were progression on or after 1 prior line of therapy, measurable disease, PS ECOG &lt;3, ANC &gt; 1.5x109/l, platelets &gt; 100x109/l, creatinine &lt; 250 mcmol/l, AST and ALT &lt; 3xULN. Pts with prior exposure to bortezomib were excluded. Response was evaluated according to IMWG criteria. Primary end point was response at end of cycle 4, secondary objectives overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Results: The present analysis was restricted to the first 4 cycles. From 03/2010 to 07/2011, 73 pts were included, median age 75.8 years (range 66-86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior therapy: MP in 12, MP-thalidomide in 44, lenalidomide-dexamethasone (LD) in 14, other in 3. 42 pts (57.5%) were responders at end of cycle 4 [CR: 8 (10.9%), VGPR: 9 (12.3%), PR: 25 (34.2%), SD: 10 (13.6%), progression: 11 (15%), early discontinuation: 10 (13.6%)]. 6pts/10 were in PR and 1pt/10 in VGPR at time of discontinuation. ORR was 67.1% (49/73 pts). 11 pts died (MM: 6, sepsis: 4, renal failure: 1). Adverse events grade 3-4 were neutropenia: 16 pts, thrombocytopenia: 7 pts, sepsis: 12 pts, gastro-intestinal: 8 pts, anaphylaxis: 1 pt. 2 pts had DVT. Peripheral neuropathy grade&gt;1 occurred in 9 pts, all grade 2. Treatment was stopped in 20 pts (lack of efficacy: 11, toxicity: 9). Conclusions: These results compare favorably with those achieved with VD or LD. The triplet BVD combination is very effective and tolerable in elderly pts with MM in 1st progression.