Five-Year Follow-up of Randomized, Phase II Trial of Idiotype-Pulsed Dendritic Cell Vaccine with Adjuvant Cytokines In Plateau Phase and Post-Transplant Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1958-1958
Author(s):  
Yi Lin ◽  
Morie Gertz ◽  
Sumithra Mandrekar ◽  
Kristina Laumann ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine ◽  
Plateau Phase ◽  
Time To Progression ◽  
Kaplan Meier

Abstract Abstract 1958 Vaccines may offer additional benefit as consolidation therapy after plateau phase or autologous stem cell transplant (ASCT) for multiple myeloma (MM). We have reported previously the results of another phase II trial showing that using APC8020 (Mylovenge™) after ASCT improved the overall survival (OS 5.3 yrs, 95% CI 4.0 yrs – NA) compared to ASCT alone (3.4 yrs, 95% CI 2.7 – 4.6 yrs; p = 0.02; Lacy, AJH (84): 799). We now report the results from a randomized, phase II trial using the same vaccine plus adjuvant cytokines in MM patients in plateau phase after either chemotherapy or ASCT. Twenty patients were enrolled between 2001 and 2003 and were randomized to receive APC8020 and adjuvant cytokine of either interferon-g (IFNg, arm A, n = 10) or interleukin-2 (IL2, arm B, n = 10). Each cycle of treatment included five days of daily subcutaneous injections of either IFNg (106 IU, arm A) or IL2 (200 mg, arm B) followed by APC8020 injection. Each patient received a cycle of treatment every 2 weeks for 4 cycles. One patient in each arm was in plateau phase post-chemotherapy. Time from diagnosis to treatment was 11.9 mos for the patient in arm A and 16.2 mos for arm B. Time to progression (TTP) was 3.7 and 68 months respectively the patient in arm A and B. Both patients were alive at five years. For the 9 post-ASCT patients in each arm, no statistically significant differences were seen in the baseline characteristics between the 2 arms. The median time from diagnosis to treatment was 15.4 months. No grade 4 or 5 adverse events (AEs) were reported. Two patients in each arm had grade 3 AE, including lymphopenia, thrombocytopenia, hemorrhage, infection, and fatigue. One patient in arm B had grade 3 autoimmune disorder that was deemed possibly related to study treatment. The most common AEs were grade 1 fatigue (n = 7) and anemia (n = 5) in arm A and grade 1 anemia (n = 7) and injection site reaction (n = 5) in arm B. The median TTP was 9.3 months (95% CI: 3.9 – 19.3 months) for arm A and 6.6 months for arm B (95% CI: 6.3 – 29.6 months) with no statistically significant difference between the two arms (p = 0.89). The median OS had not been reached for either arm; the 5-year OS rate was 67% and 56% for arms A and B respectively (p = 1.0). Interestingly, similar to our previous study where TTP was not different while OS was improved with vaccine, when we compared the clinical outcome for all patients in this vaccine trial to that of 78 matched control patients who only received ASCT during the same time frame, we did not see significant improvement in TTP (Figure 1). However, the 5-year overall survival for all patients in this trial is significantly improved at 71% (95%CI: 51–96%) compared to ASCT control patients (41%, 95% CI: 31 – 54%; p = 0.03; Figure 1). This trial suggests improved OS with vaccine plus cytokine. It is possible that modulation of patients’ immunity may help them live longer with multiple myeloma. Further investigation is needed to compare the approach in this trial with dendritic cell vaccine alone to better understand optimal strategy for vaccine therapy in MM. Figure 1. Kaplan-Meier curves for time to progression and overall survival Figure 1. Kaplan-Meier curves for time to progression and overall survival Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Lacy:Celgene: Research Funding.

scholarly journals Efficacy and safety of Id-protein-loaded dendritic cell vaccine in patients with multiple myeloma – Phase II study results

Neoplasma ◽  
2012 ◽  
Vol 59 (04) ◽  
pp. 440-449 ◽  
Author(s):  
L. ZAHRADOVA ◽  
K. MOLLOVA ◽  
D. OCADLIKOVA ◽  
L. KOVAROVA ◽  
Z. ADAM ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dendritic Cell ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine ◽  
Efficacy And Safety ◽  
Study Results ◽  
Id Protein

A Phase II Trial of Radioimmunotherapy-Based Autologous Transplantation with I-131 Tositumomab, Cyclophosphamide and Etoposide in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5502-5502
Author(s):  
Paul S Martin ◽  
Isaac C Jenkins ◽  
Theodore A Gooley ◽  
Damian J Green ◽  
John M Pagel ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Reference Group ◽  
B Cell Lymphoma ◽  
Survival Outcomes ◽  
P Value ◽  
Cox Models ◽  
Kaplan Meier

Abstract PURPOSE: Autologous stem cell transplantation (ASCT) is the standard of care for patients with chemosensitive relapsed or refractory diffuse large B-cell lymphoma (DLBCL). However, even with this aggressive approach, 40-70% of patients will still relapse. Many conventional conditioning regimens employ a combination of chemotherapy +/- total body irradiation (TBI), with further dose escalation limited by non-hematological toxicities. CD20-targeted radioimmunotherapy (RIT) delivers high doses of tumor-localized radiation with relative sparing of vital organs and has been successfully utilized to improve the efficacy and reduce the normal organ toxicity of ASCT. Based on the radiosensitivity of DLBCL and the reduced cross-resistance with chemotherapy, we hypothesized that RIT-based ASCT would improve survival outcomes for patients with relapsed/refractory DLBCL. PATIENTS AND METHODS: We performed a prospective phase II trial utilizing RIT-based myeloablative conditioning with high-dose I-131 tositumomab (to deliver ≤25 Gy to critical normal organs), cyclophosphamide (100mg/kg) and etoposide (60mg/kg) followed by ASCT in patients with relapsed/refractory DLBCL. Additionally, based on retrospective chart review, we identified and evaluated 61 eligibility-matched control patients who underwent myeloablative conditioning with TBI (12Gy), cyclophosphamide (100mg/kg), and etoposide (60mg/kg) at our Center during the trial enrollment period. RESULTS: From October 1999 to May 2011, we treated 27 DLBCL patients on this phase II trial. Baseline patient characteristics included advanced disease (89%), IPI≥2 (52%), and a median age of 51.4 years (range 31.9-59.1). The vast majority of patients had received prior rituximab (89%), with 59% considered rituximab refractory (defined as less than partial remission (PR) following or relapse within 6 months of rituximab therapy) and 55% experiencing relapse within 12 months of rituximab-based immunochemotherapy (R-chemo). Fifteen percent of patients achieved complete remission (CR) with their last chemotherapy regimen, 37% achieved PR, 26% had stable disease (SD) and 22% had progressive disease (PD). Patients received a median I-131 activity of 540 mCi (range 285 to 797), with lung (n=21), liver (n=4), and kidney (n=2) as the critical normal organs receiving the highest absorbed dose. Engraftment of neutrophilsand platelets occurred at a median of 13 (range 9-17) and 11 (range 7-38) days after ASCT, respectively. The 100-day non-relapse mortality was 7% (n=2), with one death due to cardiac failure and one due to respiratory failure. With a median follow up of 6.6 years (range 0.2-15.5), median overall survival (OS) was not reached and median progression free survival (PFS) was 3.5 years. Median PFS in the highest-risk patients, as defined by recurrent disease within 12 months of R-chemo (n=15) or chemorefractory relapse (n=13), was 22.6 and 10.8 months, respectively. Serial annual bone marrow evaluations did not identify any cases of treatment-associated myelodysplastic syndrome or acute myeloid leukemia. In comparison to the RIT group, the 61 eligibility-matched, TBI-conditioned control group patients were less heavily pretreated (2 vs 3 average prior regimens [p=<0.001], 9 vs 11 average prior cycles of chemotherapy [p=0.01]), with a trend toward higher CR rate (34% vs. 15 %, p=0.07) and lower rate of PD (9% vs. 22%, p=0.06) prior to ASCT. Adjusting for these disparate covariates, RIT-based ASCT resulted in significantly improved survival outcomes for patients with high-risk disease (relapse within 12 months of R-chemo, rituximab refractory disease, or chemorefractory relapse [SD/PD to last salvage regimen]) when compared to standard TBI-based conditioning (Figure 1). CONCLUSION: These data suggest that myeloablative RIT-based conditioning using I-131-tositumomab, cyclophosphamide and etoposide followed by ASCT is safe, feasible and effective for relapsed/refractory DLBCL. In comparison to standard TBI-based conditioning, this RIT-based approach may yield improved survival outcomes for a subset of high-risk patients. Figure 1. Kaplan-Meier curves for RIT vs TBI-based conditioning for high-risk DLBCL patients. Results from Cox models: HR = hazard ratio (95% CI) where reference group is TBI; p = p-value. Figure 1. Kaplan-Meier curves for RIT vs TBI-based conditioning for high-risk DLBCL patients. Results from Cox models: HR = hazard ratio (95% CI) where reference group is TBI; p = p-value. Disclosures Maloney: Juno Therapeutics: Research Funding; Janssen Scientific Affairs: Honoraria; Seattle Genetics: Honoraria; Roche/Genentech: Honoraria. Cassaday:Seattle Genetics: Research Funding; Pfizer: Research Funding. Gopal:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; BMS: Research Funding; Sanofi-Aventis: Honoraria; Millenium: Honoraria, Research Funding; BioMarin: Research Funding; Emergent/Abbott: Research Funding; Piramal: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding.

scholarly journals Phase II Trial of In Vivo Purging with Daratumumab in Newly Diagnosed Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Shebli Atrash ◽  
Myra Robinson ◽  
Barry Paul ◽  
Sarah Norek ◽  
David M. Foureau ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
T Cell ◽  
Clinical Response ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Newly Diagnosed ◽  
Post Induction

Background: In multiple myeloma, induction therapy (IT) before hematopoietic progenitor cells (HPC) collection reduces the tumor burden, improves the quality of the collection, and diminishes end-organ damage. The data concerning the impact of the response to IT on progression-free survival (PFS) after autologous stem cell transplant (ASCT) remains limited. IFM 2005-01 reported better PFS in patients who achieved at least a very good partial response (VGPR) after IT (PFS post-ASCT 41 vs. 31 months, p= 0.01). Also, studies have consistently shown that minimal residual disease (MRD) negativity impacted PFS/ overall survival (OS). Currently, rates of CR and MRD-negativity post-ASCT are sub-optimal. Given the clinical activity and the safety profile of daratumumab (Dara), evaluation of this novel agent pre- and post-ASCT is warranted, as it may improve the post-ASCT ≥ CR and MRD-negativity rates. Study Design and Methods: This study is a single-arm, two-stage phase II trial to estimate the CR rate post-ASCT in newly diagnosed MM (NDMM). Transplant eligible (TE) NDMM subjects who did not achieve at least a VGPR post initial IT are eligible for the trial. Enrollment will be planned post-induction and before HPC mobilization. Subjects will receive four weekly doses of Dara prior to HPC mobilization, then another four weekly doses of Dara after HPC engraftment post-ASCT. The primary objective is to evaluate the ≥ CR rate post-ASCT in NDMM subjects who did not achieve at least a VGPR post-induction. The secondary objectives are to estimate: ≥VGPR rate, time to first response (TTFR), time to best response (TTBR), duration of response (DoR), PFS, time to progression (TTP), time to next treatment (TTNT), and OS. Also, the study will evaluate toxicities related to Dara and ASCT outcomes (HPC collection and engraftment parameters). The exploratory objectives are to explore: MRD rates of bone marrow and HPC product using Euro-flow criteria and DNA-PCR.The correlation between systemic immune profiling and the clinical response using cytokine profiling by multiplex protein assay and Blood immunotyping [including NK, NK-T, and T cell subsets distribution and activation analyses by flow cytometry.The correlation between circulating T cell receptor (TCR) repertoire immuno-sequencing by next-generation sequencing (NGS) with clinical response parameters.The changes in BM and BM plasma cells' biology before and after treatment by Whole Exome Sequencing, andThe correlation between PET/CT responses and endpoint. The main eligibility criteria are age ≥ 18 years, ECOG PS 0-2, measurable disease at the time of diagnosis, &lt; VGPR per IMWG 2016 criteria following a 3-drug IT regimen for TE-NDMM. However, patients must have achieved at least a minimal response, and treatment plan includes ASCT post-induction. Statistical methods: Post-ASCT ≥CR response is the primary endpoint for this study. For NDMM, standard therapy strategies provide ≥CR rates of approximately 50%. For this population of subjects treated with Dara-based in vivo purging, the aim is to achieve a post-ASCT ≥ CR rate of 70%. A minimax 2-stage design will be used to test the hypothesis that the ≥ CR rate post-ASCT is less than or equal to 50%. Twenty-three subjects will be enrolled in the first stage, and if at least 12 of the 23 subjects have ≥CR after ASCT, an additional 16 subjects will be enrolled (total of 39 subjects). If at least 24 of 39 subjects have ≥CR after ASCT, the null hypothesis will be rejected. Based on a one-sided, α = 0.10 significance level, this sample size will provide 90% power to reject the null, assuming the true ≥CR rate post-ASCT is 70%. The treatment schedule: Pre-mobilization Dara on days 1,8,15,22. Four weeks after the Day 22 dose of Dara, all subjects will undergo HPC mobilization with the hematopoietic growth factor G-CSF with or without the chemokine receptor type 4 (CXCR4) antagonist. Post-ASCT and after engraftment is complete, Dara will be restarted days +49, +56, +63, +70. ClinicalTrials.gov Identifier: NCT04230031 Figure 1 Disclosures Atrash: Amgen, GSK, Karyopharm.: Research Funding; Takeda, Amgen, Karyopharm, BMS, Sanofi, Cellactar, Janssen and Celgene: Honoraria; BMS, Jansen oncology, Sanofi: Speakers Bureau. Paul:Regeneron: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Other: Stock Ownership (prior employee). Symanowski:Casgen: Consultancy; Eli Lilly: Consultancy; Immatics: Consultancy; Novartis: Consultancy. Bhutani:Janssen: Other: Clinical Trial Funding to Institute; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute. Voorhees:Bristol-Myers Squibb: Other: Personal fees; Celgene: Other: Personal fees; Janssen: Other: Personal fees; Novartis: Other: Personal fees; Oncopeptides: Other: Personal fees; TeneoBio: Other: Personal fees; Levine Cancer Institute, Atrium Health: Current Employment; Adaptive Biotechnologies: Other: Personal fees. Usmani:Merck: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Research Funding; GSK: Consultancy, Research Funding; Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.

scholarly journals Randomized Phase II Trial of Combination Idiotype Vaccine and Anti-CD3/Anti-CD28 Costimulated Autologous T Cells in Patients with Multiple Myeloma Post-Autotransplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4548-4548 ◽  
Author(s):  
Muzaffar H. Qazilbash ◽  
Edward A Stadtmauer ◽  
Veera Baladandayuthapani ◽  
Heather Lin ◽  
Beryl M. Tross ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Hematopoietic Stem ◽  
Randomized Phase Ii ◽  
Significant Difference ◽  
Equity Ownership ◽  
To Receive

Abstract Background: Despite major advances in the treatment of multiple myeloma (MM) only a minority of patients achieve long-term disease control. Immunotherapy combined with autologous hematopoietic stem cell transplantation (auto-HCT) may reduce relapse rates. Immunoglobulin idiotype (Id) conjugated with a carrier protein, Keyhole limpet hemocyanin (KLH), is a tumor-specific antigen in MM. Vaccine-primed, anti-CD3/anti-CD28 costimulated adoptive T-cell transfer can augment humoral and cellular immune responses to vaccination despite cytotoxic therapy. We hypothesized that Id-KLH vaccine + the vaccine-primed costimulated T cells will result in a robust Id-specific humoral and cellular response, compared to a control vaccine (KLH only). Methods: In this randomized, phase II trial, the primary objective was to determine if Id-KLH primed, costimulated T cells will induce a more robust Id-specific immunity than KLH-primed T cells. Eligible patients had IgG monoclonal protein. Patients were randomized 1:1 to receive either Id-KLH vaccine or KLH-only vaccine, followed by auto-HCT, and then vaccine- primed costimulated T cells followed by two booster doses of the vaccine to which they were randomized. This study was supported by The MD Anderson Cancer Center SPORE in Multiple Myeloma. Results: A total of 36 patients were enrolled between 1/2013 and 5/2015. Sixteen (44%) were randomized to Id-KLH and 20 (55%) to KLH-only. The Table below summarizes the patient characteristics. There was no significant difference between the two groups in terms of age, risk status or induction therapy. No treatment-related mortality, infusion reactions or dose-limiting toxicity was seen in either arm. Five (31%) and 3 (15%) patients achieved complete remission (CR) by day+180 in the Id-KLH and KLH arms, respectively (p=0.42). Initial analysis of a subgroup of patients revealed a significantly higher mRNA expression of immune activation genes IL-2, CCR6 and CD40 by NanoString nCounter in the Id-KLH group compared with the KLH only group (Figure). Eleven (68%) and 17 (85%) went on to receive maintenance therapy with lenalidomide or lenalidomide + ixazomib in the Id-KLH and KLH arms, respectively (p=0.42). After a median follow up of 26 months, 2-year PFS was 81% and 83% in Id-KLH and KLH arms, respectively (p=0.35). Conclusion: Id-KLH vaccine and vaccine-primed costimulated T cells can be safely administered in the setting of auto-HCT.There was a more robust immune response and a trend towards higher CR rate in the Id-KLH group. Disclosures Stadtmauer: Teva: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Takada: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Garfall:Medimmune: Consultancy; Bioinvent: Research Funding; Novartis: Consultancy, Research Funding. Cohen:Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy, Research Funding. June:Johnson & Johnson: Research Funding; Immune Design: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; University of Pennsylvania: Patents & Royalties; Celldex: Consultancy, Equity Ownership; Tmunity: Equity Ownership, Other: Founder, stockholder ; Pfizer: Honoraria.

The Transcriptome of Immunomodulator-Resistant Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1772-1772
Author(s):  
Moritz Binder ◽  
S. Vincent Rajkumar ◽  
Martha Q. Lacy ◽  
Jessica L. Haug ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Overall Survival ◽  
Differentially Expressed Genes ◽  
Research Funding ◽  
Differentially Expressed ◽  
Resistant Disease ◽  
Kaplan Meier ◽  
Gene Coding ◽  
Cellular Pathways

Introduction: While the molecular target of immunomodulators such as pomalidomide (POM) and lenalidomide (LEN) has been identified, the mechanisms underlying therapeutic resistance remain incompletely understood. The uniformly emerging resistance to therapy over time in the absence of identifiable cereblon pathway mutations in the majority of patients raises questions about alternative mechanisms including aberrant gene expression. Methods: We performed gene expression profiling using an Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray on CD138+ bone marrow cells from patients with relapsed / refractory (RRMM) and newly diagnosed (NDMM) multiple myeloma prior to initiating treatment. Patients were treated on two phase II clinical trial protocols (MC0789: POM ± dexamethasone in RRMM; MC0884: LEN ± dexamethasone in NDMM) between 2007 and 2012. We categorized patients based on their IMWG response as non-responders (SD) and responders (VGPR+). We selected 15 responders and 15 non-responders from MC0789 (n = 30) and compared overall survival, gene expression patterns, and involved cellular pathways between the two groups. We selected 5 responders and 5 non-responders from MC0884 (n = 10) for targeted validation of differentially expressed candidate genes. After data quality control and normalization of gene expression values, differential gene expression was estimated using limma. Statistical significance was adjusted for multiple testing in the discovery set using a false discovery rate-based approach for genome-wide experiments (q-value). We used Gene Ontology and PANTHER pathway analysis for functional annotation of differentially expressed genes. Overall survival estimates were calculated using the Kaplan-Meier method. Computation and visualization were performed in R. Results: Median age at treatment initiation on MC0789 was 65 years (40 - 82), 65% of the patients were male. Pomalidomide resistance was associated with an increase in mortality (median overall survival 1.6 versus 6.4 years, p = 0.009, Kaplan-Meier plot). There were 1076 differentially regulated genes between responders and non-responders (521 up- and 555 down-regulated, q < 0.050 for all genes, volcano plot). Expression of CRBN was 1.5-fold down-regulated in non-responders (q = 0.005). Supervised hierarchical clustering of the top 500 differentially expressed genes demonstrated distinct patterns in pomalidomide-resistant disease (heatmap). Gene ontology analysis revealed protein synthesis as one of the most enriched biological processes (bar graph). Pathway analysis showed a 6-fold enrichment (FDR = 0.007) of the ubiquitin proteasome pathway in pomalidomide-resistant disease. Differentially expressed genes involved key protein degradation pathways, epigenetic modifiers, and transcription factors. Targeted validation in MC0884 revealed 13 common genes with at least 1.5-fold differential expression (5 up- and 8 down-regulated), 12 of which have previously been implicated in the regulation of apoptosis, tumor glucose metabolism, Rho and Wnt signaling, miRNA-driven resistance to chemotherapy, and ubiquitin-dependent protein degradation (Table and Sankey diagram). The most up-regulated gene in non-responders was MYRIP, a gene coding for a vesicle trafficking protein associated with platinum resistance and suppression of pro-apoptotic BCL-2 family members in solid malignancies. The most down-regulated gene was FRZB, a gene coding for a negative regulator of Wnt signaling, previously implicated in the progression of monoclonal gammopathy of undetermined significance to multiple myeloma. Conclusions: Overall survival of patients with pomalidomide-resistant RRMM remains poor. Pomalidomide resistance was associated with differential gene expression in several potentially targetable cellular pathways beyond the known drug target cereblon. Targeted validation of candidate genes revealed common cellular pathways in immunomodulator-resistant disease. Elucidating the exact molecular mechanisms underlying immunomodulator resistance is of considerable interest for biomarker development and the identification of novel therapeutic targets and warrants further exploration. Figure Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Research Funding; Alnylam: Research Funding; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Akcea: Consultancy; Takeda: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Lenalidomide, Adriamycin and Dexamethasone (RAD) As An Induction Regimen In Newly Diagnosed Multiple Myeloma – Interim Results From a German Multicenter Phase II Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1987-1987 ◽  
Author(s):  
Stefan Knop ◽  
Christian Langer ◽  
Monika Engelhardt ◽  
Lars O Muegge ◽  
Wolf Roesler ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Phase Iii ◽  
Line Treatment ◽  
Newly Diagnosed ◽  
First Line ◽  
First Line Treatment

Abstract Background Induction triplets utilizing at least one of the “novel drugs” and steroids with or without chemotherapy are considered current standard of care in newly diagnosed, symptomatic multiple myeloma (MM). Medically fit patients (pts) remain candidates for subsequent autologous (auto) stem cell transplant (SCT) while use of allogeneic (allo) SCT remains a matter of debate. As we had previously shown the RAD regimen to be well tolerated and highly effective in relapsed and relapsed/refractory MM, we evaluated this combination in first-line treatment. Methods The current phase II trial (DSMM XII) was designed to include a total of 190 pts up to 65 years of age with symptomatic MM. Four 4-week cycles of RAD (lenalidomide 25 mg/day, d 1-21; adriamycin 9 mg/m² as 24-hour infusion, d1-4; oral dexamethasone 40 mg, d1-4 and 17-20; pegfilgrastim 6 mg, d 6) preceded stem cell chemomobilization. Low-molecular weight heparin for prophylaxis of venous thromboembolic events (VTE) was mandatory. Pts received either tandem auto SCT (melphalan 200 mg/m²; Mel200) or auto followed by allo SCT. Allo SCT (preparative regimen: treosulfan/fludarabine) was reserved for pts featuring at least one cytogenetic or serologic risk factor who had a matched sibling or unrelated donor available. Lenalidomide maintenance was administered for one year following both tandem auto and auto/allo SCT. This is the second pre-planned interim safety and efficacy analysis. Results Eighty-nine pts with a median age of 54 (range, 30-65) years, who were recruited between August 2009 and October 2010, are evaluable. Fifty pts (56.2%) had ISS stage II/III disease and in all except three, molecular cytogenetic analysis was performed. Incidences of chromosomal abnormalities were as follows: deletion of (del) 13q, 24.7%; translocation t(4;14), 12.4%; t(14;16), 3.4%; and del 17p, 5.6%. Treatment-related mortality with RAD induction was 0% while 61.8% of pts had treatment-emergent SAEs. Seventeen pts (19%) experienced neutropenia of grades 1 to 4. Incidences of severe (grades 3/4) and febrile neutropenia were 5.6 and 1%, respectively. Seven pts each (8%) had pneumonia and VTE, respectively. Post-RAD-induction CR/sCR and at least VGPR rates were 9% and 47.2%, respectively. All 78 pts with at least stable disease successfully mobilized stem cells. Overall response rate (at least partial response, PR) following first SCT on an intention-to-treat basis was 83%. Twelve pts each (13.5%) achieved centrally confirmed complete response (CR) or stringent (s)CR, respectively, and 54 pts (60.7%) had at least very good PR (VGPR). Conclusions This interim analysis shows RAD to be very well tolerated and effective in first line treatment of symptomatic MM. Mel200 further increased rates of deep response (at least VGPR) achieved by RAD induction. We are currently comparing this regimen to bortezomib, lenalidomide and dexamethasone (VRd) in a phase III trial. Disclosures: Knop: Celgene GmbH: Honoraria. Off Label Use: Lenalidomide and doxorubicin in newly diagnosed multiple myeloma. Engelhardt:MSD, Janssen-Cilag: Research Funding. Einsele:Celgene GmbH: Consultancy, Honoraria, Research Funding. Bargou:Celgene GmbH: Research Funding.

scholarly journals Outcome of Multiple Myeloma Patients Treated with Carrd-PACE Chemomobilization: A Single-Center Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3377-3377 ◽  
Author(s):  
Andrew J. Cowan ◽  
Mehdi Karami ◽  
Edward N. Libby ◽  
Pamela S. Becker ◽  
David G. Coffey ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Median Time ◽  
Research Funding ◽  
Cardiac Toxicity ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Autologous Transplant ◽  
Kaplan Meier ◽  
Pet Ct

Abstract Background: Bortezomib was originally incorporated into DT-PACE (thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) as an intensive induction regimen (VTD-PACE) prior to high-dose melphalan and autologous transplant for multiple myeloma (MM). This regimen is effective in the induction setting, and also for patients with relapsed disease (Barlogie British Journal of Haematology 2007, Singh ASCO 2013). At our center, we examined the outcomes of MM patients undergoing chemomobilization with a regimen that substituted carfilzomib and lenalidomide for bortezomib and thalidomide (CarRD-PACE). Methods: Twenty MM patients with measureable disease received CarRD-PACE for chemomobilization. We excluded in this report patients with plasma cell leukemia, renal insufficiency, heart failure, or those patients who were refractory to carfilzomib. Results: The median age was 61.5 years (range, 35- 69). Nine of these patients were women (45%). The median left ventricular ejection fraction pre-treatment was 62% (range, 50 - 77%). Of patients with initial staging information, 8 were ISS stage I (47%), 5 patients ISS II (29%), and 4 were ISS III (24%). High risk cytogenetics, defined as presence of deletion 17p, t(4;14), t(14;16), were present in 5 patients at time of chemomobilization (25%). Fourteen patients (82%) had bulky disease (defined as having > 3 lesions, or having a single lesion > 3 cm on PET-CT or MRI) prior to treatment, assessed by MRI (n=12) or PET-CT (n= 2). The median time from diagnosis to mobilization was 9.5 months (range, 4- 44). Patients had previously received a median of 2 regimens of therapy (range, 1- 5). Fifteen patients received 1 cycle of CarRD-PACE, and 5 patients received 2 cycles. Eighteen patients response evaluable; in these patients, the overall CR/PR response rate after completion of treatment was 25% (4 PR, 1 CR), with fifteen patients (75%) having SD. A total of 18 patients (90%) collected stem cells after mobilization, requiring a median of 1 day of collection (range, 1-2), and collected a median of 18.3 x 10^6 CD34+ cells/kg (range, 4.8 - 69.88). Grade 3-4 toxicities occurred in 6 patients (30%), most common was neutropenic fever (n=4) (20%). No patients experienced a cardiac toxicity. Hospital readmission following treatment occurred in 4 patients (20%) for a median of 6.5 days (range, 3 - 15). Eighteen patients (90%) underwent a single autologous transplant, and 2 (10%) received tandem autologous-allogeneic transplant. Following autologous transplant, the median time to neutrophil engraftment was 18 days (range, 14 - 29 days), and the median time to platelet engraftment was 13 days (range, 7 - 19 days). The PFS at 6 months was 63% (95% CI, 0.382 - 1), and the OS at 6 months was 91% (95% CI, 0.754 - 1) (Figure). Discussion: CarRD-PACE is a well-tolerated and effective therapy in heavily treated multiple myeloma patients with substantial disease burden at the time of autologous transplant, and can successfully mobilize autologous PBSC. Despite the theoretical concern regarding the combination of 2 agents with cardiac toxicity (carfilzomib and doxorubicin), we did not observe any cardiac toxicities of any grade during treatment. This approach may be particularly useful in individuals with bortezomib associated neuropathy and or those with bortezomib refractory disease. Figure Kaplan-meier plots for progression free and overall survival. Figure. Kaplan-meier plots for progression free and overall survival. Disclosures Becker: GlycoMimetics: Research Funding. Shadman:Pharmacyclics: Honoraria, Research Funding; Acerta: Research Funding; Gilead: Honoraria, Research Funding; Emergent: Research Funding. Gopal:Seattle Genetics: Research Funding.

The Efficacy and Safety of RAD (Lenalidomide, Adriamycin and Dexamethasone) In Newly Diagnosed Multiple Myeloma – First Results of a Phase II Trial by the German DSMM Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1945-1945
Author(s):  
Stefan Knop ◽  
Christian Langer ◽  
Monika Engelhardt ◽  
Lars O Muegge ◽  
Albrecht Reichle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Current Phase ◽  
Newly Diagnosed ◽  
First Line ◽  
Peripheral Blood Stem Cells ◽  
First Line Therapy ◽  
Line Therapy

Abstract Abstract 1945 Background Prognosis of patients with multiple myeloma (MM) has significantly improved by the introduction of autologous (auto) stem cell transplantation (SCT). The “novel drugs” which have shown activity in relapsed MM are increasingly used in first-line therapy aiming at maximized response prior to SCT. Whether allogeneic (allo) SCT adds to further disease control remains a matter of debate. Our group has shown the RAD regimen (lenalidomide, adriamycin and dexamethasone) to be highly effective and relatively well tolerated in relapsed and refractory MM. Therefore, we decided to explore RAD in the up-front management. Patients and Methods The current phase-II trial (DSMM XII) was designed to include patients (pts) up to the age of 65 years with newly diagnosed MM requiring treatment. We chose four cycles of RAD (lenalidomide 25 mg d-21; infusional adriamycin 9 mg/m2 per day d1-4; dexamethasone 40 mg d1-4 and 17–20; pegfilgrastim 6 mg d 6) every 4 weeks for induction followed by chemomobilization of peripheral blood stem cells. Low molecular weight heparin is mandatory during RAD treatment for thromboprophylaxis. All pts are to undergo one cycle of melphalan 200 mg/m2 followed by auto SCT. A subsequent allo SCT after reduced intensity conditioning (treosulfan/fludarabin) is scheduled for pts featuring at least one previously identified (cytogenetic or serologic) risk factor. Those with very favourable risk are to proceed to a second auto SCT. All patients will receive 12 months of lenalidomide maintenance (10 mg per day) on a continuous basis. Here, we present results of a planned safety analysis. Results 75 pts with a median age of 57 (range, 35–66) years have been enrolled by 11 German centers between 9/2009 and 7/2010. Currently, 51 pts are evaluable for toxicity during RAD induction: In all, 25 severe adverse events (SAEs) were reported for 16 subjects (31%). 68% of SAEs were assessed to be drug-related. Most frequent events were venous thrombosis (VTE; n=4), pyrexia (n=3) and syncope (n=2). Neutropenia, extravasation, pleural effusion, and allergic dermatitis accounted for one SAE each. 17 patients, 10 of whom (59%) had ISS stage II/III disease, are evaluable for post-induction response. Ten subjects (59%) achieved VGPR or better: 6 pts had VGPR and 2 patients each CR and stringent CR as assessed by the investigator. Conclusions Our preliminary results suggest RAD to be a well tolerated and effective novel induction protocol in up-front treatment of MM. Notably, incidence of severe hematotoxicity observed so far is significantly lower than was in our previous study in relapsed/refractory pts. Incidence of VTE was acceptable while no neurotoxicity occurred. Updated results will be presented. Disclosures: Knop: Celgene Germany: Consultancy, Honoraria. Off Label Use: Lenalidomide in combination with doxorubicin in myeloma first-line therapy. Reichle:Celgene Germany: Research Funding. Einsele:Celgene Germany: Consultancy, Honoraria. Bargou:Celgene Germany: Consultancy, Research Funding.

scholarly journals Prognostic Implications of Multiple Cytogenetic High-Risk Abnormalities in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5615-5615
Author(s):  
Moritz Binder ◽  
S. Vincent Rajkumar ◽  
Rhett P. Ketterling ◽  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Cumulative Effect ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
Prognostic Implications

Abstract Background: Cytogenetic evaluation using fluorescence in situ hybridization (FISH) at the time of diagnosis is essential for initial risk stratification in multiple myeloma. The presence of specific cytogenetic abnormalities is known to confer a poor prognosis, less is known about the cumulative effect of multiple cytogenetic high-risk abnormalities. We aimed to evaluate the prognostic implications of the presence of multiple cytogenetic high-risk abnormalities at the time of diagnosis. Methods: We studied 226 patients who were diagnosed with multiple myeloma between July 2004 and July 2014 at Mayo Clinic Rochester, underwent FISH evaluation within six months of diagnosis, and presented with cytogenetic high-risk abnormalities. High-risk cytogenetics were defined as t(4;14), t(14;16), t(14;20), del(17p), or gain(1q). Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and evaluating up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). Kaplan-Meier overall survival estimates were calculated and the log-rank test was used to compare overall survival in patients with single and multiple cytogenetic high-risk abnormalities. A multivariable-adjusted Cox regression model was used to assess the effect of multiple cytogenetic high-risk abnormalities on overall survival adjusting for age, sex, and Revised International Staging System (R-ISS) stage. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 65 years (32 - 90), 129 (57%) of the patients were male. The median overall survival was 3.5 years (3.1 - 4.9) for the entire cohort (n = 226), 4.0 years (3.3 - 5.1) for those with one cytogenetic high-risk abnormality (n = 182, 80%), and 2.6 years (1.7 - 3.1) for those with two cytogenetic high-risk abnormalities (n = 44, 20%). There were no patients with more than two cytogenetic high-risk abnormalities. Ninety-eight patients (45%) had a high-risk translocation, 77 (35%) had del(17p), 39 (18%) had a high-risk translocation plus del(17p), and 5 (2%) had gain(1q) plus either a high-risk translocation or del(17p). Figure 1 shows the Kaplan-Meier overall survival estimates stratified by the number of cytogenetic high-risk abnormalities (n = 226). The presence of two cytogenetic high-risk abnormalities (compared to one) was of prognostic significance after adjusting for age, sex, and R-ISS stage (HR 2.01, 95% CI 1.27 - 3.19, p = 0.003, n = 205). Conclusions: Approximately one in five patients with newly diagnosed high-risk multiple myeloma presented with two high-risk abnormalities at the time of diagnosis. These patients experienced inferior overall survival suggesting a cumulative effect of multiple cytogenetic high-risk abnormalities. The relatively low number of observed gain(1q) was likely related to the fact that not all patients were evaluated for that abnormality. Therefore the presented hazard ratio represents a conservative effect estimate and may underestimate the true effect. Figure 1 Figure 1. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Kumar:Janssen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy.

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