VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

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Title: 12 Versus 8 Prophylactic Intrathecal (IT) Chemotherapy Administration Decrease Incidence of Central Nervous System (CNS) Relapse in Patients (pts) with Newly Diagnosed Philadelphia (Ph)-Positive Acute Lymphocytic Leukemia (ALL)

Blood ◽

10.1182/blood-2019-130284 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3810-3810 ◽

Cited By ~ 1

Author(s):

Shilpa Paul ◽

Koji Sasaki ◽

J Michael Savoy ◽

Adam Dipippo ◽

Nadya Jammal ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Leptomeningeal Disease ◽

High Dose ◽

Molecular Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cns Relapse ◽

Increased Risk

Introduction: The addition of tyrosine kinase inhibitors to hyperfractionated cyclophosphamide, dexamethasone, vincristine, and doxorubicin alternating with high-dose methotrexate and cytarabine (HCVAD) for the treatment of Ph-positive ALL has significantly improved outcomes. However, with the increased median survival, an increased incidence of CNS relapses were documented over time, thus suggesting an increased risk among pts with Ph-positive disease (Ravandi et al, Cancer 2015).In order to reduce this incidence, treatment protocols for Ph-positive ALL were amended in 2012 to increase prophylactic IT chemotherapy from 8 to 12 at our institution. The aim of this study is to compare the incidence of CNS relapses in pts with Ph-positive ALL treated with 8 versus 12 ITs. Methods: We conducted a retrospective chart review of 156 pts with newly diagnosed Ph-positive ALL treated with Rituximab (R)± HCVAD plus imatinib (n=35), dasatinib (n=68), or ponatinib (n=53) between July 2001 and January 2019. Pts with CNS disease at initial diagnosis were excluded. Complete molecular response (CMR) at 3 months was defined as absence of a quantifiable BCR-ABL1 transcript. CNS relapse was identified by detection of blasts or rare atypical cells in the cerebrospinal fluid (CSF) in at least 2 successive evaluations and/or findings of leptomeningeal disease on imaging. Landmark analysis was performed at 6 months at the approximate time of completion of both systemic and IT therapy. Poor risk cytogenetic abnormality was defined as the presence of +der(22)t(9;22) and/or −9/9p in the absence of high hyperdiploidy (51‐65 chromosomes). CNS relapse-free survival (RFS) was defined from the start of therapy to the time of CNS relapse. Patients who died or relapsed in bone marrow were censored at the time of death and systemic relapse, respectively. Survival was assessed with and without the censoring of allogeneic stem cell transplantation (ASCT). Results: Pt characteristics are summarized in Figure A. One hundred and twelve pts (72%) received a median of 8 ITs (range, 2-8) and 44 pts (28%) received a median of 12 (range, 9-15). There were no statistically significant differences between groups in regards to baseline characteristics with the exception that more patients in the > 8 ITs cohort received ponatinib (66% vs 21%) and thus achieved a higher rate of 3-month CMR (70% vs 52%; p=0.04). CNS relapses were identified in 11 pts overall (7%, 4 treated with imatinib and 7 with dasatinib) and all of them received 8 or less prophylactic ITs (IT ≤8, 10% vs IT >8, 0%; p=0.023). The median follow-up of the entire population was 81 months, and 97 and 43 months for pts who received ≤8 and >8 ITs, respectively. The 3 and 6-year CNS RFS was 89% and 88% in pts with ≤8 ITs and 100% in pts with >8 Its, respectively (overall P=0.041; 3-yr CNS RFS P=0.049; 6-yr CNS RFS P=0.045) (Figure B). The outcomes remained statistically significant even after censoring for ASCT (P=0.048) (Figure C). In a multivariate analysis and after adjusting for the follow-up time, a median of 12 prophylactic IT chemotherapies was a prognostic factor significantly associated with a decrease rate of CNS relapses (P=0.03; HR=0.64 95%, CI: 0.43-0.96) (Figure D). Conclusion: In pts with newly diagnosed Ph-positive ALL, incorporation of 12 prophylactic IT chemotherapy in addition to systemic therapy is a very effective strategy to reduce the long-term incidence of CNS relapses. Figure Disclosures Paul: Pfizer: Consultancy; Agios: Consultancy. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Kadia:BMS: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Kantarjian:BMS: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding.

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Melphalan/Prednisone/Lenalidomide (MPR) Versus High-Dose Melphalan and Autologous Transplantation (MEL200) in Newly Diagnosed Multiple Myeloma (MM) Patients <65 Years: Results of a Randomized Phase III Study

Blood ◽

10.1182/blood.v118.21.3069.3069 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3069-3069 ◽

Cited By ~ 7

Author(s):

Antonio Palumbo ◽

Federica Cavallo ◽

Izhar Hardan ◽

Barbara Lupo ◽

Valter Redoglia ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Risk Patients ◽

High Dose Melphalan

Abstract Abstract 3069FN2 Background: High-dose chemotherapy with haemopoietic stem-cell improves outcome in multiple myeloma (MM). The introduction of novel agents questions the role of autologous stem-cell transplantation (ASCT) in MM patients. Aims: In this prospective randomized study, we compared conventional melphalan-prednisone-lenalidomide (MPR) with tandem high-dose melphalan (MEL200) in newly diagnosed MM patients younger than 65 years. Methods: All patients (N=402) received four 28-day cycles of lenalidomide (25 mg, d1-21) and low-dose dexamethasone (40 mg, d1, 8, 15, 22) (Rd) as induction. As consolidation, patients were randomized to MPR (N=202) consisting of six 28-day cycles of melphalan (0.18 mg/kg d1-4), prednisone (2 mg/kg d1-4) and lenalidomide (10 mg d1-21); or tandem melphalan 200 mg/m2 MEL200 (N=200) with stem-cell support. All patients enrolled were stratified according to International Staging System (stages 1 and 2 vs. stage 3) and age (<60 vs. ≥60 years). Progression-free survival (PFS) was the primary end point. Data were analyzed in intention-to-treat. Results: Response rates were similar: at least very good partial response (≥VGPR) rate was 60% with MPR vs. 58% with MEL200 (p=.24); the complete response (CR) rate was 20% with MPR vs. 25% with MEL200 (p=.49). After a median follow-up of 26 months, the 2-year PFS was 54% in MPR and 73% in MEL200 (HR=0.51, p<.001). The 2-year overall survival (OS) was similar in the two groups: 87% with MPR and 90% with MEL200 (HR 0.68, p=.19). In a subgroup analysis, MEL200 significantly prolonged PFS in both standard-risk patients without t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 46% in the MPR group vs. 78% in the MEL200 group, HR=0.57, p=.007) and high-risk patients with t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 27% for MPR vs. 71% for MEL200, HR=0.32, p=.004). In patients who achieved CR, the 2-year PFS was 66% for MPR vs. 87% for MEL200 (HR 0.26; p<.001); in those who achieved a partial response (PR), the 2-year PFS was 56% for MPR vs. 77% for MEL200 (HR 0.45; p<.001). In the MPR and MEL200 groups, G3-4 neutropenia was 55% vs. 89% (p<.001); G3-4 infections were 0% vs. 17% (p<.001); G3-4 gastrointestinal toxicity was 0% vs. 21% (p<.001); the incidence of second tumors was 0.5% in MPR patients and 1.5% in MEL200 patients (p=.12). Deep vein thrombosis rate was 2.44% with MPR vs. 1.13% with MEL200 (p=.43). Conclusions: PFS was significantly prolonged in the MEL200 group compared to MPR. This benefit was maintained in the subgroup of patients with standard- or high-risk cytogenetic features. Toxicities were significantly higher in the MEL200 group. This is the first report showing a PFS advantage for ASCT in comparison with conventional therapies including novel agents. These data will be updated at the meeting. Disclosures: Palumbo: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria; Janssen-Cilag: Honoraria. Cavo:celgene: Honoraria. Ria:celgene: Consultancy. Caravita Di Toritto:Celgene: Honoraria, Research Funding. Di Raimondo:celgene: Honoraria. Boccadoro:celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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The Genomic and Transcriptomic Landscape of Double-Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2019-122197 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3056-3056 ◽

Cited By ~ 1

Author(s):

Bachisio Ziccheddu ◽

Giulia Biancon ◽

Chiara De Philippis ◽

Filippo Bagnoli ◽

Francesco Maura ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Alkylating Agents ◽

High Dose ◽

Advisory Committees ◽

Tp53 Mutations ◽

Travel Costs ◽

Oncology Research

In Multiple myeloma (MM) no treatment has a curative potential and even complete response to novel agents such as proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) are followed by relapse over time. Next generation sequencing (NGS) has showed how MM at diagnosis is defined by several somatic mutations, but only few drivers, even fewer "druggable" mutations, and many found at a subclonal level. At relapse, targeted studies have shown occasional mutations in drug target genes but the genomic and transcriptomic determinants of chemoresistance in MM remains elusive. We selected 42 MM patients refractory to both lenalidomide and PIs. Whole exome sequencing was performed in 40 of them, and RNAseq in 27. Clinical annotation was available for all patients. Standard analysis pipelines where applied to analyze mutations, copy number alterations (CNAs), mutational signatures, gene expression and expressed mutations. Patients received a median of 3 lines of treatment, with median overall survival of 14.6 months from sampling. We found a median of 77.5 mutations per patient, which is more than what reported at diagnosis (Bolli et al, Nature Communications 2014;5:2997). 100% of samples showed evidence of subclonality, and 37% of them exhibited a higher number of subclonal than clonal variants. Therefore, even at this advanced stage the MM genome is evolving and is composed of different subclones that may display different chemosensitivity. The mutational landscape was also different. TP53 mutations were the second most common after KRAS (20% and 17.5%, respectively). Interestingly TP53 mutations all clustered in patients receiving bortezomib as the last line of treatment. Only 2 patients showed a CRBN mutation, both subclonal. Combining mutations and CNA analysis, the TP53 pathway was the most frequently inactivated (45% of patients). Altogether, mutations or deletions of genes in the CRBN E3 ubiquitin ligase complex were found in 32.5% of patients, while proteasomal subunit genes were infrequently hit. Refractory cases were also uniquely characterized by a novel signature linked to exposure to alkylating agents, whose activity was more pronounced after high-dose melphalan suggesting a mutagenic effect of the drug on residual cells at the time of transplant. Whether this has any pathogenetic role on the disease course remains to be elucidated. RNAseq analysis did not show any influence of treatment or mutational data on the clustering of samples, which was mainly influenced by karyotypic events. The main cluster was composed by non-hyperdiploid patients with both amp(1q) and del(13): these showed CCND2 and MCL1 upregulation, the latter representing a marker of venetoclax resistance and novel target of experimental treatments. Only 26.3% of mutations were expressed, and this correlated with the clonality level of the mutation. However, most mutations in driver genes were expressed, with the notable exception of those causing nonsense mediated decay. Overall, classical high-risk features or CRBN pathway mutations were found in 65% of the cohort. However, only amp(1q) predicted survival in our cohort. The lack of prognostic value of high-risk lesions is likely explained by a higher prevalence of such features in double-refractory stages. Our data suggest that gene mutation is not a preferred mode of evolution of drug resistance in MM. Chemoresistance of the bulk tumor population is likely attained though differential, yet converging evolution of different subclones that are overall highly variable from patient to patient and within the same patient. Disclosures Kastritis: Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding. Cavo:bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Corradini:Janssen: Honoraria, Other: Travel Costs; Takeda: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Gilead: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Celgene: Honoraria, Other: Travel Costs; Amgen: Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Kite: Honoraria; BMS: Other: Travel Costs; Sanofi: Honoraria; Servier: Honoraria; Roche: Honoraria; Novartis: Honoraria, Other: Travel Costs. Bolli:Celgene: Honoraria; Novartis: Honoraria; Gilead: Other: travel expenses.

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Phase 2 Trial of Daratumumab, Ixazomib, Lenalidomide and Modified Dose Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-131476 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 864-864 ◽

Cited By ~ 5

Author(s):

Prashant Kapoor ◽

Morie A. Gertz ◽

Betsy Laplant ◽

Gabriella C Malave ◽

Eric Wolfe ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees ◽

Increased Risk

Background: The current commonly used regimens in newly diagnosed multiple myeloma (NDMM) utilize steroids (dexamethasone or prednisone) in various combinations: bortezomib, lenalidomide and dexamethasone (VRd), bortezomib, thalidomide and dexamethasone (VTd), daratumumab, lenalidomide and dexamethasone (DRd) and daratumumab, bortezomib, melphalan and prednisone (DVMP). However, steroid therapy may be associated with various adverse effects, including, but not limited to mood changes, insomnia, hypertension, hyperglycemia, osteoporosis, adrenal suppression, muscle weakness, and increased risk of opportunistic infections. A recent trial demonstrated improved tolerability of a regimen (Rd-R) involving an abbreviated course of dexamethasone, without compromising the efficacy in patients with intermediate-fit NDMM (Lorocca A., et al., ASH 2018). We designed a phase 2 clinical trial to examine the safety and efficacy of daratumumab, an anti-CD38 monoclonal antibody in combination with an all-oral regimen of ixazomib, a proteasome inhibitor, lenalidomide, an immunomodulatory drug, and modified dose dexamethasone (IRd). Patients and Methods: NDMM patients with measurable disease and adequate organ function were enrolled, irrespective of their transplant eligibility. The primary objective was to determine the rate of complete response (CR) to daratumumab-IRd. Treatment consisted of daratumumab, 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks, ixazomib, 4 mg days 1, 8, 15, lenalidomide, 25 mg days 1-21, and dexamethasone upto 40 mg intravenously weekly for no more than two cycles, followed by use only as a prophylactic premedication for daratumumab-associated infusion reactions. Myeloma risk stratification was assessed by cytoplasmic immunoglobulin fluorescence in-situ hybridization (cIg FISH) analysis. Results: Overall, 40 patients were accrued, with data available on all patients for analysis at the cutoff date of July 19, 2019. The median age at enrollment was 64.5 (33-81) years; 37.5% were female. Eight (20%) patients were high risk by FISH. The median number of cycles was 6 (2-11) and the median follow up was 6.1 (2-11.7) months. Among 40 patients who had received at least 2 cycles of therapy, responses were attained rapidly; at the end of cycle 2, 88% patients achieved at least a partial response and 33% at least a very good partial response (VGPR) that improved to 52% at the end of 4 cycles among 29 patients who had completed at least 4 cycles. The overall best confirmed response rate among all 40 patients (Figure 1) was 95%, including 10% stringent CR, 5% CR and 23% near CR (13% VGPR excluding nCR). Stem cell collection was completed in 17 patients so far, all of whom required filgrastim and plerixafor. The median CD34+ cell count was 7.7 (range 2.9-11.6) million/kg . All patients were alive and 39 (97.5%) patients were progression-free at last follow up. Four (10%) patients proceeded to autologous stem cell transplantation off study, per patient and/or investigator discretion (1 in CR, 2 in PR, 1 with progressive disease). Overall, 224 cycles have been administered across the study, with dose reduction/ hold required in a subset of patients; ixazomib (10%), lenalidomide (20%), daratumumab (0%) and dexamethasone (13%); the most frequent reasons for dose adjustment were skin rash and hematologic toxicities. A grade 3 or higher adverse event, at least possibly attributed to the study drugs, was observed in 40% of patients; hematologic in 30% (lymphopenia 25%, neutropenia 15%, thrombocytopenia 5% and anemia 2.5%) and non-hematologic in 18% of patients (hyperglycemia 8%, diarrhea 5%, infections 5%, ileus 2.5%, maculopapular rash 2.5%, and fatigue 2.5%). Updated results with additional 6 months of follow up and minimal residual disease assessment related data will be presented at the meeting. Conclusion: Our early results suggest that the combination of daratumumab, ixazomib, lenalidomide and modified dose dexamethasone is well-tolerated, with excellent activity, and does not adversely impact stem-cell mobilization in patients with NDMM. Disclosures Kapoor: Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Janssen: Research Funding; Glaxo Smith Kline: Research Funding; Cellectar: Consultancy. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Dispenzieri:Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. OffLabel Disclosure: Daratumumab in combination with Ixazomib, lenalidomide and dexamethasone for the management of newly diagnosed multiple myeloma

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Bortezomib Consolidation Following Autologous Transplant Equalizes the Outcome for Older Patients with Less Intensive Pretreatment Compared to Younger Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.516.516 ◽

2016 ◽

Vol 128 (22) ◽

pp. 516-516 ◽

Cited By ~ 3

Author(s):

Christian Straka ◽

Stefan Knop ◽

Martin Vogel ◽

Jurgen Müller ◽

Martin Kropff ◽

...

Keyword(s):

Multiple Myeloma ◽

Treatment Group ◽

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

High Dose ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Advisory Committees ◽

Younger Patients

Abstract Background High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the established standard-of-care for patients with newly diagnosed multiple myeloma (NDMM) who are young and/or fit. The number of older patients receiving HDT-ASCT is increasing, although they often receive lower-intensity treatment. Novel agent-based consolidation therapy can be used to improve responses following ASCT and prolong progression-free survival (PFS). The proteasome inhibitor bortezomib, given as post-ASCT consolidation therapy, resulted in an improved PFS compared with observation alone (median 33.6 vs 27.8 months, adjusted hazard ratio [HR] 0.70, p=0.0058) in a combined analysis of two phase 3 trials (MMY3012 [DSMM XIb; NCT00416273] and MMY3013 [DSMM X; NCT00416208]; JCO 2015;33:8511). These studies enrolled 222 patients aged ≤60 years and 158 aged >60 years. In this post-hoc analysis we investigated the effect of age and related treatment factors on PFS in more detail. Methods In both trials, 371 patients were randomized 1:1 following ASCT to receive four 35-day cycles of bortezomib consolidation (n=186; bortezomib 1.6 mg/m2 IV administered on days 1, 8, 15, and 22) or observation (n=185; no treatment). The primary endpoint was PFS from the start of induction chemotherapy. Response and progression were assessed at the start of each bortezomib cycle and at the end-of-treatment/observation visit (week 25), as well as during the follow-up period of 30-60 months. Patient characteristics and treatments were compared between trials; PFS following randomization was assessed separately for each study. Univariate, bivariate, and multivariate Cox regressions were conducted to evaluate the impact of treatment group, age (≤60 vs >60 years), single vs tandem ASCT, melphalan conditioning dose (MEL <200 vs 200 mg/m2), bortezomib exposure during induction (exposed vs naïve), post-ASCT response (partial response vs ≥very good partial response [VGPR]), and cytogenetics on PFS. Results A number of relevant factors were different between age groups (median age in ≤60 group 53 years vs 66 years in >60 group), including the HDT regimen received (MEL100 7% vs 10%; MEL140 3% vs 59%; MEL200 88% vs 31%). The rate of double transplantation was similar for the younger and older cohorts (55% vs 59%), likely due to the older patients receiving age-adjusted high-dose melphalan with a lower toxicity, allowing a similar rate of double transplantation as younger patients receiving MEL200. Among the 357 patients included in these analyses, median PFS from start of induction was 33.6 vs 27.8 months with bortezomib consolidation vs observation (log-rank p=0.0243). Median PFS for bortezomib vs observation was 33.6 vs 29.0 months (HR 0.86; p=0.3599) in the younger cohort and 33.4 vs 26.4 months (HR 0.60; p=0.0073) in the older cohort. PFS for older patients who received bortezomib consolidation was very similar to PFS in younger patients (p=0.861); survival curves were superimposable despite the older patients having received less intensive pretreatment. Univariate analysis demonstrated that treatment group (bortezomib vs observation) had an effect on PFS (HR 0.75; exploratory p-value <0.05), as did age (>60 vs ≤60 years; HR 1.30), melphalan dose (200 vs <200 mg/m2; HR 0.74), single vs tandem ASCT (HR 1.35), and cytogenetics (high-risk vs no change; HR 2.62). On bivariate analysis of treatment group plus other covariates, the PFS benefit of bortezomib consolidation vs observation remained consistent (HR 0.71-0.76) across analyses with other covariates. On multivariate Cox regression analysis (Table), bortezomib consolidation (HR 0.72), prior bortezomib during induction (HR 0.69), ≥VGPR post-ASCT (HR 0.76), high-risk cytogenetics (HR 2.58), and single vs tandem ASCT (HR 1.54) were independent prognostic factors for PFS. Conclusions For patients with NDMM, bortezomib consolidation post-ASCT appeared to equalize the outcome for older patients who had received less intensive pretreatment than younger patients prior to randomization. A consistent PFS benefit was demonstrated with bortezomib consolidation vs observation in the context of other prognostic factors. In a multivariate analysis, the use of tandem transplantation retained independent prognostic relevance, whereas MEL200 as first HDT did not. Table. Table. Disclosures Straka: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel/Accommodation/Expenses, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel/Accommodation/Expenses; Chugai: Research Funding. Knop:Takeda: Consultancy. Vogel:Janssen-Cilag GmbH: Employment. Kropff:Celgene: Consultancy, Other: Travel/Accommodation/Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodation/Expenses, Speakers Bureau; Onyx: Consultancy, Speakers Bureau. Metzner:Amgen: Consultancy; Sanofi: Consultancy; Celgene: Other: Travel/Accommodation/Expenses; Takeda: Other: Travel/Accommodation/Expenses. Langer:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Sayer:Riemser Pharma: Consultancy. Bassermann:Celgene: Other: Travel/Accommodation/Expenses. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Rösler:Janssen: Consultancy, Other: Travel/Accommodation/Expenses. Engelhardt:MSD: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel/Accommodation/Expenses , Research Funding. Fischer:Novartis: Consultancy, Honoraria. Einsele:Celgene: Consultancy, Honoraria, Other: Travel/Accommodation/Expenses , Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel/Accommodation/Expenses , Research Funding, Speakers Bureau; Novartis: Consultancy, Other: Travel/Accommodation/Expenses , Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

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Metaphase Cytogenetics for Risk Stratification in Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-122291 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4396-4396

Author(s):

Patrick Mellors ◽

Moritz Binder ◽

Rhett P. Ketterling ◽

Patricia Griepp ◽

Linda B Baughn ◽

...

Keyword(s):

Multiple Myeloma ◽

Risk Stratification ◽

Board Of Directors ◽

Research Funding ◽

Multivariable Analysis ◽

Risk Modeling ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cytogenetic Abnormalities ◽

Improve Risk Stratification

Introduction: Abnormal metaphase cytogenetics are associated with inferior survival in newly diagnosed multiple myeloma (MM). These abnormalities are only detected in one third of cases due to the low proliferative rate of plasma cells. It is unknown if metaphase cytogenetics improve risk stratification when using contemporary prognostic models such as the revised international staging system (R-ISS), which incorporates interphase fluorescence in situ hybridization (FISH). Aims: The aims of this study were to 1) characterize the association between abnormalities on metaphase cytogenetics and overall survival (OS) in newly diagnosed MM treated with novel agents and 2) evaluate whether the addition of metaphase cytogenetics to R-ISS, age, and plasma cell labeling index (PCLI) improves model discrimination with respect to OS. Methods: We analyzed a retrospective cohort of 483 newly diagnosed MM patients treated with proteasome inhibitors (PI) and/or immunomodulators (IMID) who had metaphase cytogenetics performed prior to initiation of therapy. Abnormal metaphase cytogenetics were defined as MM specific abnormalities, while normal metaphase cytogenetics included constitutional cytogenetic variants, age-related Y chromosome loss, and normal metaphase karyotypes. Multivariable adjusted proportional hazards regression models were fit for the association between known prognostic factors and OS. Covariates associated with inferior OS on multivariable analysis included R-ISS stage, age ≥ 70, PCLI ≥ 2, and abnormal metaphase cytogenetics. We devised a risk scoring system weighted by their respective hazard ratios (R-ISS II +1, R-ISS III + 2, age ≥ 70 +2, PCLI ≥ 2 +1, metaphase cytogenetic abnormalities + 1). Low (LR), intermediate (IR), and high risk (HR) groups were established based on risk scores of 0-1, 2-3, and 4-5 in modeling without metaphase cytogenetics, and scores of 0-1, 2-3, and 4-6 in modeling incorporating metaphase cytogenetics, respectively. Survival estimates were calculated using the Kaplan-Meier method. Survival analysis was stratified by LR, IR, and HR groups in models 1) excluding metaphase cytogenetics 2) including metaphase cytogenetics and 3) including metaphase cytogenetics, with IR stratified by presence and absence of metaphase cytogenetic abnormalities. Survival estimates were compared between groups using the log-rank test. Harrell's C was used to compare the predictive power of risk modeling with and without metaphase cytogenetics. Results: Median age at diagnosis was 66 (31-95), 281 patients (58%) were men, median follow up was 5.5 years (0.04-14.4), and median OS was 6.4 years (95% CI 5.7-6.8). Ninety-seven patients (20%) were R-ISS stage I, 318 (66%) stage II, and 68 (14%) stage III. One-hundred and fourteen patients (24%) had high-risk abnormalities by FISH, and 115 (24%) had abnormal metaphase cytogenetics. Three-hundred and thirteen patients (65%) received an IMID, 119 (25%) a PI, 51 (10%) received IMID and PI, and 137 (28%) underwent upfront autologous hematopoietic stem cell transplantation (ASCT). On multivariable analysis, R-ISS (HR 1.59, 95% CI 1.29-1.97, p < 0.001), age ≥ 70 (HR 2.32, 95% CI 1.83-2.93, p < 0.001), PCLI ≥ 2, (HR 1.52, 95% CI 1.16-2.00, p=0.002) and abnormalities on metaphase cytogenetics (HR 1.35, 95% CI 1.05-1.75, p=0.019) were associated with inferior OS. IR and HR groups experienced significantly worse survival compared to LR groups in models excluding (Figure 1A) and including (Figure 1B) the effect of metaphase cytogenetics (p < 0.001 for all comparisons). However, the inclusion of metaphase cytogenetics did not improve discrimination. Likewise, subgroup analysis of IR patients by the presence or absence of metaphase cytogenetic abnormalities did not improve risk stratification (Figure 1C) (p < 0.001). The addition of metaphase cytogenetics to risk modeling with R-ISS stage, age ≥ 70, and PCLI ≥ 2 did not improve prognostic performance when evaluated by Harrell's C (c=0.636 without cytogenetics, c=0.642 with cytogenetics, absolute difference 0.005, 95% CI 0.002-0.012, p=0.142). Conclusions: Abnormalities on metaphase cytogenetics at diagnosis are associated with inferior OS in MM when accounting for the effects of R-ISS, age, and PCLI. However, the addition of metaphase cytogenetics to prognostic modeling incorporating these covariates did not significantly improve risk stratification. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding. Kapoor:Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

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Superiority of Lenalidomide-Dexamethasone Versus Thalidomide-Dexamethasone as Initial Therapy for Newly Diagnosed Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.3884.3884 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3884-3884

Author(s):

Francesca Gay ◽

Suzanne Hayman ◽

Martha Q. Lacy ◽

Francis Buadi ◽

Morie A Gertz ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Initial Therapy ◽

High Dose ◽

Toxicity Profile ◽

Newly Diagnosed ◽

Advisory Committees ◽

Intention To Treat ◽

High Dose Dexamethasone ◽

Grade 3

Abstract Abstract 3884 Poster Board III-820 Background and Objective Thalidomide/dexamethasone (thal/dex) combination has shown high activity in newly diagnosed multiple myeloma (MM) (Rajkumar SV. at al, J Clin Oncol 2006;24:431-436). In newly diagnosed patients, lenalidomide/dexamethasone (len/dex) has demonstrated superiority compared with high-dose dexamethasone alone (Zonder JA et al, Blood 2007;110:77). Although both thal/dex and len/dex are active in newly diagnosed MM, no randomized trial has been reported comparing these two regimens, and unfortunately none are ongoing or planned. We compared the efficacy and the toxicity of thal/dex and len/dex as primary therapy in 411 newly diagnosed MM patients treated at the Mayo Clinic. Patients and methods 411 consecutive patients seen at Mayo Clinic between 2001 and 2008, who received induction with thal/dex (n=183) or len/dex (n=288) were retrospectively studied. Thalidomide was given at a dose ranging from 100 mg/day to 400 mg/day continuously; the lenalidomide dose was 25 mg/day, days 1-21 on a 28-day cycle. All patients received dexamethasone, either at high-dose (40 mg orally on days 1-4, 9-12, and 17-20) or at low-dose (40 mg orally day 1, 8, 15, 22); each cycle was repeated every 4 weeks. In addition, a case-matched subgroup analysis that adjusted for age, gender and transplantation status was performed among patients who received high-dose dexamethasone comparing the thal/dex (n=72) and len/dex (n=72) groups. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and all comparisons were determined by the log-rank test and by the Cox proportional hazards model. Results On intention-to-treat analysis, of 411 patients, 80.3% versus 61.2% patients, respectively in the len/dex group and in the thal/dex group (p < 0.001), achieved at least a partial response. A significant difference between the 2 groups was found in terms of both very good partial response or better (34.2% vs 12.0%, p < 0.001) and complete response rate (13.6% vs 3.3%, p < 0.001). Duration of therapy was significantly longer in len/dex patients as compared to thal/dex patients: 36.7% vs 12.6% of patients who did not stop treatment to receive SCT were still receiving therapy at 1 year (p < 0.001).Time-to-progression was significantly better in the len/dex group than in patients receiving thal/dex (median 27.4 vs 17.2 months, HR 0.64; 95% CI 0.44-0.93; p = 0.019). Similarly, progression-free-survival was significantly higher in len/dex patients (median 26.7 vs 17.1 months, HR 0.69; 95% CI 0.48-0.98; p = 0.036). This translated into an increase in overall survival (OS) (median not reached for len/dex group compared to 57.2 months in thal/dex patients, HR 0.60; 95% CI 0.40-0.92; p = 0.018). Survival advantages were evident in patients presenting with International Staging System Stage (ISS) I/II (HR 0.57; 95% CI 0.32-1.00; p = 0.052) at diagnosis but not in patients with ISS stage III in subgroup analysis. There was a trend toward better OS in len/dex group compared to thal/dex group both for patients who underwent transplant and for patients who did not. A similar rate of patients experienced at least one grade 3 or higher adverse event (57.5% vs 54.6% in len/dex and thal/dex groups, respectively, p = 0.568). However, the toxicity profile was different in the two groups: major grade 3-4 toxicities of len/dex were hematological, in particular neutropenia (14% with len/dex vs 0.6% with thal/dex, p<0.001) while the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, p = 0.058) and peripheral neuropathy (10.4% vs 0.9%, p < 0.001). The data on efficacy and safety shown above were also confirmed in the subgroup case-matched analysis which included only high-dose dexamethasone patients. Conclusions This cohort study shows the superiority of len/dex in terms of response rates and survival, compared to thal/dex. The toxicity profile of the 2 regimens is different and len/dex treatment, although more active, was not associated with increased toxicity (grade 3-4 AEs). These data need to be carefully evaluated and randomized prospective phase III studies are necessary to confirm these results and determine the optimal initial therapy for MM. Disclosures: Off Label Use: research drugs in combination to standard care. Lacy:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Bergsagel:amgen: Membership on an entity's Board of Directors or advisory committees; genetech: Membership on an entity's Board of Directors or advisory committees; merck: Research Funding; celgene: Membership on an entity's Board of Directors or advisory committees. Witzig:celgene: Research Funding. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Greipp:celgene: Research Funding.

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Lenalidomide Plus Dexamethasone Versus Lenalidomide Plus Melphalan and Prednisone: A Case-Control Study in Newly Diagnosed Elderly Myeloma Patients.

Blood ◽

10.1182/blood.v114.22.2877.2877 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2877-2877

Author(s):

Francesca Gay ◽

S. Vincent Rajkumar ◽

Patrizia Falco ◽

Shaji Kumar ◽

Angela Dispenzieri ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Case Control Study ◽

Case Control ◽

High Dose ◽

Primary Therapy ◽

Newly Diagnosed ◽

Advisory Committees ◽

Control Study

Abstract Abstract 2877 Poster Board II-853 Background and Objective: In newly diagnosed multiple myeloma (MM) patients, treatment with lenalidomide plus high-dose dexamethasone (RD) was superior to high-dose dexamethasone in terms of both response rates and 1-year progression-free survival (PFS) (Zonder JA et al, Blood 2007;110:77). Preliminary results suggest that the combination lenalidomide plus low-dose dexamethasone (Rd) compared to the RD regimen yields significantly better 2-year overall survival (OS) (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The combination of melphalan, prednisone, and lenalidomide (MPR) has been investigated in a phase I/II study showing promising results (Palumbo A et al, J Clin Oncol 2007; 25:4459-4465). The goal of this case –control study was to compare the efficacy and the toxicity of the lenalidomide/dexamethasone (len/dex) combination vs MPR as primary therapy for newly diagnosed elderly MM patients, to determine the additive value of melphalan compared to a regimen of lenalidomide plus corticosteroid. Patients and methods: Data from 51 newly diagnosed MM patients enrolled in Italy in a phase I/II dose-escalating trial, from January to October 2005, with MPR, were analyzed. For comparison of their outcome, 37 patients were identified among newly diagnosed patients seen at the Mayo Clinic from March 2005 to December 2008 who received len/dex as primary therapy and were enrolled in phase II or III trials. Patients treated with MPR received 9 monthly cycles of oral melphalan (doses ranging from 0.18 to 0.25 mg/kg on days 1-4), prednisone (2 mg/kg on days 1-4) and lenalidomide (doses ranging from 5 to 10 mg/day on days 1-21). After 9 cycles, patients started maintenance with lenalidomide alone (10 mg, days 1-21) until relapse or progression. Patients treated with len/dex received oral lenalidomide (25 mg/day, days 1-21) plus dexamethasone, either at low-dose (n=17) (40 mg orally days 1, 8, 15, 22) or at high-dose (n=21) (40 mg orally on days 1-4, 9-12, and 17-20). Treatment was continued until progression, relapse or unacceptable toxicity, or could be stopped at the physician's discretion. Patients (n=13) were allowed to receive transplant if they wished and were deemed eligible. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: On intention-to-treat analysis, 15.7% versus 23.7% patients, respectively in the MPR and in the len/dex group, (p=0.342) achieved a complete response, and 43.2% vs 47.4%, (p=0.691) achieved at least a very good partial response. Time-to-progression (TTP) (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.04; 95% CI 0.55-1.98; p=0.903), PFS (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.03; 95% CI 0.55-1.92; p=0.926) and OS (2-year OS: 86.2% in MPR group vs 89.1% in len/dex, HR 0.86; 95% CI 0.38-1.98; p=0.730) were not significantly different between the 2 groups. No significant differences in TTP, PFS and OS were reported when MPR patients were compared with the subgroup of patients treated with low-dose dexamethasone plus lenalidomide. Similar results were found when the analysis was restricted to MPR patients and len/dex pair mates receiving lenalidomide plus low/dose dexamethasone, matched according to age and sex, and who did not received transplant. The toxicity profile was different in the two groups. Hematologic grade 3-4 toxicities were more common with MPR compared with len/dex, in particular neutropenia (66.7% vs 21.1%, p < 0.001) and thrombocytopenia (31.4% vs 2.6%, p < 0.001), respectively. Grade 3-4 gastrointestinal events (13.2% vs 2.0%, p= 0.080), thrombotic events (13.2 vs 5.9, p= 0.279) and fatigue (10.5% vs 3.9%, p= 0.395) were more common with len/dex compared with MPR. Conclusion: Results of this case-control study show that both MPR and Rd are efficacious regimens for elderly MM patients. Data need however to be carefully evaluated and randomized control trials are needed to confirm these results. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Lacy:celgene: Research Funding. Musto:celgene: Honoraria. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Petrucci:celgene: Honoraria; Janssen Cilag: Honoraria. Greipp:celgene: Research Funding. Boccadoro:jansen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; pharmion: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria.

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A Comparison of Chemotherapy + G-CSF Versus Plerixafor (Mozobil®) + G-CSF for Stem Cell Mobilization In Patients with Multiple Myeloma Treated with Lenalidomide

Blood ◽

10.1182/blood.v116.21.2258.2258 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2258-2258

Author(s):

Tomer M Mark ◽

Adriana C Rossi ◽

Roger N Pearse ◽

Morton Coleman ◽

David Bernstein ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Yield ◽

High Dose ◽

Advisory Committees ◽

Cd34 Cells ◽

Stem Cell Collection

Abstract Abstract 2258 Background: Prior use of lenalidomide beyond 6 cycles of therapy in the treatment of multiple myeloma (MM) has been shown to negatively impact stem cell yield, but this phenomenon can be overcome with the addition of high-dose cyclophosphamide to standard G-CSF mobilization. We hypothesized that the use of plerixafor (Mozobil®) would compare similarly to chemotherapy in rescuing the ability to collect stem cells in lenalidomide-treated myeloma. Methods: We performed a retrospective study comparing the efficacy of plerixafor + G-CSF mobilization (PG) to chemotherapy + G-CSF (CG) (either high-dose cyclophosphamide at 3g/m2 or DCEP [4-day infusional dexamethasone/ cyclophosphamide/ etoposide/cisplatin]) in 49 consecutive stem cell collection attempts in patients with MM exposed to prior lenalidomide. The primary endpoint was the ability to collect sufficient stem cells for at least two transplants (minimum 5×106 CD34+ cells/kg), comparing results in terms of total exposure to lenalidomide and time elapsed from lenalidomide exposure until the mobilization attempt. The secondary endpoint was number of apheresis days required to meet collection goal. Resilts: Twenty-four patients underwent PG mobilization and twenty-five with CG (21 with G-CSF + cyclophosphamide, 4 with G-CSF+DCEP). The two groups did not differ in terms of total amount of lenalidomide exposure: median number of lenalidomide cycles for patients mobilized with PG was 6.5 (range 1.2–86.6), vs. 6 (range 2–21.6), for patients mobilized with CG (P = 0.663). The median time between mobilization and last lenalidomide dose was also similar between the two groups: 57.5 (range 12–462) days for PG vs. 154 (range 27–805) days for CG (P = 0.101). There was an equivalent rate of successful collection of 100% for PG and 96% for CG, P = 0.322. One patient failed collection in the CG group due to emergent hospitalization for septic shock during a period of neutropenia; no patient collected with PG had a serious adverse event that interrupted the collection process. Stem cell yield did not differ between the two arms (13.9 vs. 18.8 × 106 million CD34+ cells/kg for PG vs. CG respectively, P = 0.083). Average time to collection goal was also equal, with a median of time of 1 day required in both groups, (range 1–2 days for PG, 1–5 days for CG, P = 0.073). There was no relationship between amount of lenalidomide exposure and stem cell yield with either PG (P = 0.243) or CG (P = 0.867). Conclusion: A plerixafor + G-CSF mobilization schedule is equivalent in efficacy to chemotherapy + G-CSF in obtaining adequate numbers of stem cells for two autologous stem cell transplants in patients with MM exposed to lenalidomide; however, PG may be a less toxic approach than chemomobilization. Number of lenalidomide cycles has no impact on chances of stem cell collection success using either method. Disclosures: Mark: Celgene Corp: Speakers Bureau; Millenium Corp: Speakers Bureau. Zafar: Celgene Corp: Speakers Bureau. Niesvizky: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding.

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New US Myeloma Registry (Connect MM® – The Multiple Myeloma Disease Registry): Features of Newly Diagnosed Patients In 2010

Blood ◽

10.1182/blood.v116.21.5032.5032 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5032-5032

Author(s):

Brian G. M. Durie ◽

Jatin J. Shah ◽

Rafat Abonour ◽

Cristina Gasperetto ◽

Jayesh Mehta ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Staging System ◽

Bone Lesions ◽

Case Report Form ◽

Newly Diagnosed ◽

Community Based ◽

Advisory Committees ◽

Prior Therapy

Abstract Abstract 5032 Background: In the past decade, with the availability of novel therapies, the paradigm for myeloma management has changed. In 2010 it is especially important to understand baseline features and initial treatment decisions. The goal of the Connect MM® registry is to characterize patients with newly diagnosed active myeloma from 200 US sites. Approximately 80% of the patient population will be enrolled from community-based practices and 20% from academic centers. An electronic case report form was developed to collect clinical data, physician choices, patient health-related quality of life (HRQoL) and response, as well as data on survival end points. This is a prospective, observational, longitudinal study with a target accrual of 1,500 patients in 3 years, with a 5 year follow-up from the time of informed consent. There are no mandated treatments or clinical assessments. However, there are data collection requirements for diagnosis and disease monitoring. Results: Since late 2009, 340 patients from 135 sites have been accrued and were included in this interim analysis. Current study demographics include: 60% male, 83% white, and 14% black, with a median age of 67 years. Thus far, 97% have been enrolled from community-based practices. All patients met study enrollment criteria and had active myeloma at entry; prior monoclonal gammopathy of unknown significance (MGUS) was reported in 13% and smoldering MM in 8%. International Staging System (ISS) staging for evaluable patients were 26.3%, 36.4%, 37.3% for stages I, II, and III, respectively. Durie-Salmon Stage (A or B) were 13%, 35%, 52% for stages I, II, and III, respectively. Staging procedures included 82% skeletal survey; 44% computed tomography (CT); 40% magnetic resonance imaging (MRI); 7% positron emission tomography (PET); 2% PET/CT; and 4% had no imaging. International Myeloma Working Group (IMWG) CRAB criteria were assessed in all enrolled patients; 9% had hypercalcemia, 18% renal insufficiency, 36% anemia, and 66% had bone lesions. Median values were: calcium 9.5 mg/dL; serum creatinine 1.1 mg/dL; hemoglobin 10.9 gm/dL. Only 9% of patients had 3 or 4 CRAB features, while 49% had only 1 feature and 26% were asymptomatic (ECOG=0). The incidence of baseline peripheral neuropathy was 6%. Initial pain led to radiation therapy for 10% of patients, with 16% having vertebroplasty or kyphoplasty. Cytogenetic studies were performed at baseline in 64% of patients and fluorescence in situ hybridization (FISH) studies in 54%. Cytogenetics and FISH were normal in 27% of patients, while in 20% both were abnormal in patients who had both performed. FISH was abnormal with normal cytogenetics in 41% and only 2% had normal FISH but abnormal cytogenetics. The most common FISH abnormalities were: 13 q- (31%), 17 p- (28%), t(4; 14) (16%). Freelite® testing was performed in 56% of patients with an abnormal ratio in 94% [rFLC]. Of evaluable patients receiving frontline therapy 98% of patients received a novel agent and only 3 patients (1.4% of treated patients) received melphalan/prednisone. Two drug combinations were used in 53%, 3 drugs in 26%, 4 drugs in 1.3%, and single agents were used in 21% of the patients. The most common regimens were: bortezomib+dexamethasone (28%), lenalidomide+dexamethasone (20%), and bortezomib+lenalidomide+ dexamethasone (15%). Conclusion: These baseline features and treatment choices characterize myeloma patients primarily in community-based practices in the US in 2010. As academic centers enroll more patients, we will be able to further characterize that population. Of particular note, 26% of patients were asymptomatic at baseline but had biochemical evidence of myeloma and met enrollment criteria; conversely 95% had an abnormal rFLC and 73% had abnormal chromosome results. The Connect MM® registry will provide data regarding patient features as they pertain to patterns in testing and treatment in the clinical practice setting, as well as response and survival outcomes. Disclosures: Durie: Celgene & Millennium: Consultancy. Off Label Use: Revlimid (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Research Funding; Novartis: Research Funding. Abonour:Celgene & Millennium: Honoraria. Gasperetto:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Mehta:Celgene: Consultancy, Speakers Bureau; Takeda/Millennium: Speakers Bureau; Onyx: Research Funding. Pashos:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Toomey:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Swern:Celgene: Employment. Street:Celgene: Employment. Sullivan:Celgene: Employment, Equity Ownership. Rifkin:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau.

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