Treatment Regimens for Patients with Newly Diagnosed Multiple Myeloma Who Are Ineligible for Stem Cell Transplantation: A Systematic Literature Review and Network Meta-Analysis

Abstract Background: In patients with newly diagnosed multiple myeloma (ndMM) who are ineligible for autologous stem cell transplantation (ASCT), bortezomib, melphalan, and prednisone regimen (VMP) is standard of care as a first-line treatment in most regions of the world. Daratumumab is a new monoclonal antibody aimed to improve outcomes in ndMM. The ongoing ALCYONE study demonstrated significant improvement in progression-free survival (PFS) and overall response rate (ORR) for the combination of daratumumab plus VMP (D-VMP) compared to VMP in transplant-ineligible ndMM patients (Mateos, 2018). While direct head-to-head randomized controlled trials (RCTs) are lacking, it is important to assess how D-VMP compares with other treatment regimens used in clinical practice for ndMM patients who are ineligible for ASCT. Aims: The aim of this study is to investigate the comparative effectiveness (PFS, ORR) of D-VMP with other relevant treatment regimens used in patients with ndMM who are ineligible for ASCT. Methods: We conducted a Bayesian network meta-analysis (NMA) based on RCTs identified through a systematic literature review (SLR). Both fixed effects and random effects models were tested. The results are depicted in a network of evidence, forest plots, ranking histograms and probabilities of D-VMP being better than the comparator treatment regimens. Results: The SLR revealed 25 RCTs conducted in patients with ndMM who are ineligible for ASCT. For PFS, the NMA included 20 RCTs covering 20 treatments and for ORR, the NMA included 20 RCTs covering 21 treatments. Random-effects model is preferred for PFS as well as for ORR as this model showed lower deviance information criterion (DIC), and as the homogeneity assumption was violated for PFS. The results for both PFS and ORR are summarized in Table 1. For PFS and ORR, D-VMP ranked first in the evidence of network. For PFS, D-VMP was statistically significantly more effective compared to 10 out of the 19 treatment regimens. For ORR, D-VMP was significantly more effective as compared to 12 out of the 20 treatment regimens. Conclusion: In the absence of head-to-head RCTs, NMAs allow delineation of the comparative effectiveness of different treatments. This NMA suggests that D-VMP has a higher potential of being effective in improving ORR and PFS in patients with ndMM who are ineligible for transplant compared to other available treatment options. Updated results based on a 1-year update of ALCYONE will be presented at the meeting. References: Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528 Disclosures San-Miguel: Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Roche: Honoraria. Facon:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dimopoulos:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria. Mateos:Janssen: 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heeg:Ingress-health Nederland BV: Employment, Equity Ownership, Research Funding. van Beekhuizen:Ingress Health: Consultancy. Pisini:Janssen Research & Development, LLC: Employment. Nair:Janssen Research & Development, LLC: Employment. Lam:Janssen Global Services, LLC: Employment. Slavcev:Janssen Global Services, LLC: Employment.

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Final Results of a Frontline Phase 1/2 Study of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone (CRd) in Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v118.21.631.631 ◽

2011 ◽

Vol 118 (21) ◽

pp. 631-631 ◽

Cited By ~ 1

Author(s):

Andrzej J Jakubowiak ◽

Dominik Dytfeld ◽

Sundar Jagannath ◽

David H. Vesole ◽

Tara B. Anderson ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Growth Factors ◽

Partial Response ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Abstract 631 Introduction: In relapsed and/or refractory MM, the combination of carfilzomib (CFZ) with lenalidomide (Len), and low-dose dexamethasone (Dex) (CRd) has shown very promising efficacy (78% ≥partial response [PR], 40% ≥very good partial response [VGPR], and 24% CR/nCR) and good tolerability including a low rate of peripheral neuropathy (Wang et al, ASCO, 2011). In a Phase I/II study of newly diagnosed MM, the regimen was well tolerated in the Phase I portion of the study up to a maximum dose of CFZ 36 mg/m2, Len 25 mg, and Dex 40 mg, and very active with 96% ≥PR, 70% ≥VGPR, and 55% CR/nCR (Jakubowiak et al, ASH 2010). The lack of overlapping toxicities has allowed these agents to be used at full doses and for extended periods. Here we report the results for all patients (pts) enrolled in both phases of this first prospective trial of CFZ combination in new MM. Methods: In the initial eight 28-day cycles, pts were treated with CFZ at 20 mg/m2, 27 mg/m2 (Phase I), and 36 mg/m2 (Phase I and II), given IV on days 1, 2, 8, 9, 15 and 16, Len at 25 mg PO (days 1–21), and Dex at 40/20 mg PO weekly (cycles 1–4/5–8). Pts achieving ≥PR could proceed to stem cell collection (SCC) using growth factors alone (protocol recommendation) and autologous stem cell transplant (ASCT) after 4 cycles. Per protocol, ASCT candidates were offered the option to continue CRd treatment after SCC. After 8 cycles, pts received 28-day maintenance cycles of CFZ (days 1, 2, 15, 16), Len days 1–21, and Dex weekly at the doses tolerated at the end of 8 cycles. Responses were assessed by IMWG criteria with the addition of nCR. Results: Enrollment was completed (53 pts): 4 pts at CFZ 20 mg/m2, 13 at CFZ 27 mg/m2 and 36 at CFZ 36 mg/m2 (18 in Phase I and 18 in Phase II). Median age was 59 years (range 35–81; 23 pts ≥65), 60% had ISS stage II/III, and 33% (of 49 with available data) had unfavorable cytogenetics: del 13 or hypodiploidy by metaphase, or t(4;14), t (14;16), del 17p by FISH. As of June 30, 2011, toxicity data (cycles 1–8) were available for 51 pts. Hematologic toxicities were reversible and included Grade (G) 3/4: anemia (18%), neutropenia (12%), and thrombocytopenia (10%). The most common non-hematologic toxicities (all G) were hyperglycemia (76%), hypophosphatemia (61%), and infection (53%). G3/4 non-hematologic AEs included hyperglycemia (24%), DVT/PE while on ASA prophylaxis (10%), infection (6%), and mood alteration (2%). PN was limited to G1/2 sensory (24%). Forty-five pts continue treatment with 22 pts in the maintenance phase. Six pts discontinued treatment: 2 proceeded to ASCT, 1 due to toxicity, and 3 due to events unrelated to treatment or per pt wish. The majority of pts did not require dose modifications, either in the initial (31%) or in the maintenance (25%) phase. After a median of 8 cycles (range 1–20), the best responses per IMWG criteria for 49 response-evaluable pts (all pts who completed 1+ cycle) are shown in the Table. Responses were rapid with 46/49 pts achieving at least PR after 1 cycle, and improved with the duration of treatment reaching 100% ≥PR after 4 cycles and 100% ≥VGPR, 79% CR/nCR after 12 cycles. Responses were deep even at the 2 lower dose levels with the majority of pts at 36 mg/m2 still early in treatment. Responses in pts with unfavorable cytogenetics were similar to response rates in all remaining pts and included a 100% ≥PR in 6 pts with del 17p. Twenty-four pts proceeded to SCC after a median of 5 cycles of CRd (range 4–9); using growth factors only in 23 pts and cyclophosphamide and growth factors in 1 pt, with a median 6.55 × 106 CD34+ cells/kg collected (range 3.75–9.6); all resumed CRd treatment. After a median of 9.5 months of follow-up, only 1 pt has progressed, and all are alive Conclusions: CRd is highly active and well-tolerated allowing the use of full doses for an extended time in newly-diagnosed MM pts with limited need for dose modification. Responses are rapid and improve over time reaching 100% ≥VGPR and early time-to-event data are very encouraging. These results compare favorably to the best frontline regimens in MM. Disclosures: Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria. Off Label Use: Use of the investigational agent carfilzomib, proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; OrthoBiotec.Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Hussein:Celgene Corporation: Employment. Leveque:Onyx Pharmaceuticals: Employment. Vij:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau.

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Response To First-Line Treatment In Stem Cell Transplant (SCT) and Non-SCT Patients With Newly Diagnosed Multiple Myeloma Who Are Enrolled In The Connect MM Registry

Blood ◽

10.1182/blood.v122.21.3207.3207 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3207-3207

Author(s):

Rafat Abonour ◽

Jatin J. Shah ◽

Brian Durie ◽

Howard Terebelo ◽

Cristina J Gasparetto ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Initial Therapy ◽

Newly Diagnosed ◽

Advisory Committees ◽

Off Label ◽

Trial Setting

Abstract Introduction The advent of new therapies for the treatment of multiple myeloma (MM) has resulted in improved clinical outcomes and patient (pt) survival. However, the best combination of agents from different drug classes and subsequent therapeutic strategies for pts with newly diagnosed MM (NDMM), while investigated, has not yet been established. The goal of the Connect(R) MM registry is to provide insight into the disease and explore the management and outcomes of pts with NDMM who are treated at community and academic sites in the United States. This analysis aims to describe the combinations used in NDMM outside the interventional clinical trial setting and the activity and outcome response to different regimens by class of therapeutic agents in clinical practice. Methods Connect MM is an ongoing prospective, longitudinal, observational registry of NDMM pts. This multicenter US pt registry was initiated in 2009. Pts who were newly diagnosed with symptomatic MM within 2 months of enrollment were eligible to participate. Data were collected at baseline and every 3 months. Pts who had response data 12 months after enrollment, met CRAB criteria, and received treatment were eligible for this analysis. Treated pts were stratified according to SCT status. Data on baseline demographic and clinical characteristics, and initial therapies (proteasome inhibitors [PI], IMiD(R) immunomodulating agents, alkylating agents [AA], corticosteroids, and combinations) were collected. The overall response rate (ORR), as assessed by the site investigator, was defined as the best response during the course of initial therapy and is presented as cumulative ORR over 3, 6, and 12 months. Results As of the data cutoff (April 15, 2013), 1494 pts were enrolled in the registry; 1312 pts met CRAB criteria and received treatment. Of these, 439 received SCT or were anticipated to receive (had undergone a stem cell harvest) SCT and 873 would not receive SCT (non-SCT). Mean (SD) age for SCT and non-SCT pts was 58.9 years (8.7) and 69.8 years (10.7), respectively. Majority of pts in both groups were male (62.0% vs 56.5%) and Caucasian (85.4% vs 81.4%). Among SCT pts, ISS stages were: I/II (55.1%), III (25.3%), and unknown (19.6%) and ECOG performance status (PS) was 0/1 (63.1.%), 2/3 (7.1%), and unknown (29.8%). Among non-SCT pts, ISS stages were: I/II (42.0.%), III (32.2%), and unknown (25.8%) and ECOG PS was 0/1 (56.6%), 2/3/4 (14.7%), and unknown (28.8%). ORR to initial therapy and 1-year survival for the 5 most commonly used regimens are presented in the Table. A triplet regimen is 2 times more likely to be selected for SCT pts than for non-SCT pts, suggesting investigator bias in selecting more aggressive therapy for younger pts. For the 5 most commonly used regimens, 1-year survival was 97.9% for SCT pts and 83.3% for non-SCT pts. Conclusion Outside an interventional clinical trial setting, the most commonly used initial treatment regimens for NDMM were IMiD + PI + steroid for SCT pts and PI + steroid for non-SCT pts. Response rates were higher among SCT pts regardless of regimen. The investigator-assessed response rates were similar across the various combinations including 2 vs 3 drug combinations in SCT pts. Disclosures: Abonour: Celgene: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding. Off Label Use: This abstract will report on an observational study. There is no pre-specified use of drugs; treating physicians determined what drugs to use and some could be off-label. Shah:Millenium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Durie:Celgene: Consultancy; Millennium: Consultancy; Onyx: Consultancy. Terebelo:Amgen: Honoraria; Millennium: Honoraria. Gasparetto:Celgene ( 2012): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium (2012): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Narang:Celgene: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene: Consultancy. Sullivan:Celgene: Employment. Srinivasan:Celgene: Employment. Nagarwala:Celgene: Employment. Rifkin:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

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Incidence and Clinical Features of Extramedullary Multiple Myeloma in Patients Who Underwent Stem Cell Transplantation

Blood ◽

10.1182/blood.v124.21.5746.5746 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5746-5746

Author(s):

Matthew Weinstock ◽

Yosra Aljawai ◽

Irene M. Ghobrial ◽

Elizabeth A. Morgan ◽

Jacob P. Laubach ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Medical Center ◽

Academic Medical Center ◽

Advisory Committees ◽

Treatment Regimens

Abstract Background: Extramedullary disease (EMD), strictly defined as an infiltrate of clonal plasma cells at an anatomic site distant from the bone marrow or adjacent soft tissue in a patient with underlying multiple myeloma, is an uncommon manifestation of multiple myeloma. Comparatively little is known about this disease entity, with no large case series published in the last decade. Patients and Methods: 663 consecutive patients with multiple myeloma who underwent autologous or allogeneic stem cell transplantation at a single, large, academic medical center in the United States from January 2005 to December 2011 were assessed for the presence or absence of EMD, as well as baseline demographic and biochemical characteristics, treatment regimens, and response to therapy. Results: A cohort of 55 patients with biopsy-proven EMD was identified, comprising 8.3% of the total study population. Among the patients with EMD, 13 (23.6%) were found to have EMD at the time of initial presentation, while the remainder developed EMD during the course of their illness. Patients with EMD received a median of 5 different treatment regimens during the course of their illness, most commonly with combinations of dexamethasone, thalidomide, lenalidomide, and bortezomib, as well as autologous hemotopoietic stem cell transplantation. Patients had received a median of 3 lines of therapy prior to experiencing an extramedullary relapse. Patients with EMD had markedly elevated maximum serum LDH levels (median 613.5 units/L) and low minimum hemoglobin levels (median 7.8 g/dL). Common cytogenetic abnormalities included deletion 13q, deletion 11q, t(11;14), and deletion 17p. Available immunohistochemical data suggest that EMD specimens had frequent expression of CXCR4, CD44, and CD56. The median overall survival data of these patients was 3.2 years (range, 0.9-9.5) and the median time from diagnosis of EMD to death was 0.5 years (range, 0.002-3.2). Conclusions: This report describes a large series of multiple myeloma patients with EMD who were treated in the era of stem cell transplant at a single academic medical center. Further studies to examine the molecular characteristics of extramedullary multiple myeloma are necessary to better define this entity and characterize therapeutic options that can prolong survival in this otherwise very vulnerable population. Disclosures Ghobrial: Millennium/Takeda: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Laubach:Novartis: Research Funding; Onyx Pharmaceuticals: Research Funding. Schlossman:Millennium: Consultancy. Mitsiades:Millennium Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Research Funding; Johnson & Johnson: Research Funding; DFCI: patent submission on stromal co-culture technologies Patents & Royalties.

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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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Effect of Autologous Transplantation on PFS2 in Myeloma Patients Receiving Front-Line Bird (clarithromycin, lenalidomide, dexamethasone)

Blood ◽

10.1182/blood.v124.21.5778.5778 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5778-5778

Author(s):

Ekta Aneja ◽

Adriana C Rossi ◽

Tomer M Mark ◽

David Jayabalan ◽

Roger Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Second Line ◽

Newly Diagnosed ◽

Advisory Committees ◽

Line Therapy ◽

Progression Of Disease

Abstract Background: BiRd (clarithromycin, lenalidomide, dexamethasone) combination therapy yields >90% overall response rates in newly diagnosed patients with symptomatic multiple myeloma (MM). Long term follow up of the phase II BiRd study revealed 49% of patients went on to receive autologous hematopoietic stem cell transplants (ASCT), either as consolidation or salvage. Here we evaluate progression free survival 2 (PFS2) and overall survival (OS) in our cohort of patients, and assess the impact of ASCT. Methods: Seventy-two patients with newly diagnosed MM were enrolled on the BiRd trial between Dec 2004 and Nov 2006. BiRd is lenalidomide 25mg PO daily (d1-21), clarithromycin 500mg PO BID, dexamethasone 40mg PO weekly, for 28 day cycle. Patients remained on BiRd until progression of disease, consolidation with autologous stem cell transplant (ASCT), or unacceptable toxicity, and all continued to be monitored through subsequent lines of therapy. We performed a retrospective chart review of all patients enrolled in the BiRd trial. PFS2 was defined as the time elapsed from start of BiRd until progression of disease on 2nd line therapy. Results: With over 8 years of follow up, 6 patients remain on continuous BiRd, 28 received ASCT consolidation, and another 6 received ASCT as salvage. Nine patients died on induction therapy and the remaining patients received second line chemotherapy. Patients were stratified by no ASCT, consolidation ASCT and salvage ASCT. Median PFS2 was 98 months, 94 months, and 53 months, respectively (p<0.22). Twenty-three patients died during second line therapy. Median OS was not reached, 102 months, and 55 months respectively (p<0.92). Discussion: Advances in the treatment of patients with multiple myeloma over the past decade have introduced increasing numbers of therapeutic options, improving survival considerably. While multiple myeloma is still considered an incurable disease, patients today will likely receive several lines of therapy. The contribution and timing of each option must be considered. In our cohort of patients, receiving ASCT in the salvage setting trended toward shorter PFS, however failed to reach statistical significance. Consolidation with ASCT in our patient cohort did not translate into survival advantage. The optimal timing and utility of ASCT in the era of novel agents and increasing treatment options warrants further review, and is an area of active investigation. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Rossi: celgene: Speakers Bureau; millenium: Speakers Bureau. Mark:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Speakers Bureau. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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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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A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma

Blood ◽

10.1182/blood-2021-146284 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 5043-5043

Author(s):

Elizabeth K. O'Donnell ◽

Clifton C. Mo ◽

Andrew J. Yee ◽

Omar Nadeem ◽

Andrew R. Branagan ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Newly Diagnosed ◽

Advisory Committees ◽

Stem Cell Collection ◽

Minimal Residual

Abstract Background: Clinical data support the combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). Recently, the GRIFFIN study evaluated the addition of the CD38 antibody, daratumumab to lenalidomide, bortezomib, and dexamethasone in transplant-eligible NDMM and demonstrated improved efficacy with an acceptable safety profile. Isatuximab is a newer CD38 monoclonal antibody that binds to a specific epitope of the CD38 receptor. In addition to antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity, isatuximab eliminates MM cells via direct apoptosis without the need for crosslinking. Isatuximab enhances immune function by boosting the activation and cytotoxic activity of natural killer cells and by depleting CD38+ immune suppressor cells such as regulatory T cells and inducing clonal expansion of T cells. Isatuximab is approved in combination with carfilzomib and dexamethasone for relapsed, refractory MM based on the results of the IKEMA study. The MANHATTAN study evaluated the 4-drug combination of daratumumab, lenalidomide, carfilzomib, and dexamethasone. The primary end point, minimal residual disease negativity was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%). Building upon these data, our study evaluates the addition of isatuximab to weekly carfilzomib, lenalidomide, and dexamethasone. Study Design and Methods: A phase II, open-label clinical trial is being conducted to evaluate the efficacy of once weekly carfilzomib, lenalidomide, dexamethasone, and isatuximab (Isa-KRd) in 50 patients with newly diagnosed, transplant-eligible MM (NCT04430894). Eligible patients will have NDMM, age ≥18 years, ECOG PS of 0-2, and are deemed eligible for stem cell transplantation (SCT). All patients will receive 4 cycles of induction therapy with Isa-KRd followed by stem cell collection with the option to either proceed to upfront SCT versus deferred SCT. Patients undergoing upfront SCT will receive 4 cycles of therapy followed by stem cell collection, high-dose chemotherapy, and autologous SCT followed by 2 additional cycles of therapy then maintenance. Patients deferring SCT following collection will receive 4 cycles of therapy followed by stem cell collection followed by 4 additional cycles of therapy then maintenance. Each 28-day cycle will consist of isatuximab 10 mg/kg IV Q1 week for 8 weeks, then Q2 weeks for 16 weeks, thereafter Q4 weeks; carfilzomib (20 mg/m 2 Day 1 only) 56 mg/m 2 IV on Days 1, 8, 15; lenalidomide 25 mg po on Days 1-21; and dexamethasone 20 mg po day of and day after all doses of carfilzomib (Days 1, 2, 8, 9, 15, and 16) and isatuximab (Cycles 1 and 2 Days 22 and 23). For maintenance, patients will be stratified based on cytogenetics (high-risk cytogenetics include deletion (del) 17p, translocation t(4:14), t(14;16), t(14;20)). Patients with standard-risk cytogenetics will receive lenalidomide 10 mg po Days 1-21. Patients with high-risk cytogenetics will receive carfilzomib 56 mg/m 2 Days 1, 15; lenalidomide 10 mg po Days 1-21; and isatuximab 10 mg/kg IV Day 1. Dexamethasone, 20 mg orally or IV will be administered to patients as a pre-infusion medication prior to isatuximab dosing. Main Outcomes and Measures: The primary end point is complete response (CR + stringent CR) rate after 4 cycles of Isa-KRd as assessed by the International Myeloma Working Group (IMWG) Uniform Response Criteria. Secondary endpoints include determining safety and tolerability of Isa-KRd, minimal residual disease (MRD) after 4 cycles, at completion of consolidation (post-transplant) or induction (transplant-deferred), and sustained MRD at 24 months, progression-free survival, overall survival rates, and quality of life. Efficacy analysis will be performed both in the intent-to-treat (ITT) population and efficacy evaluable (EE) population. The ITT population will include all treated patients, and the EE population will include all patients who receive at least 1 cycle of study drug. The primary analysis will be based on the EE population, and will use the investigator-assessed response data evaluated according to consensus recommendations based on the IMWG criteria. CR (CR+sCR) rate after 4 cycles of Isa-KRd will be reported with 90% confidence interval. Support: Amgen and Sanofi Figure 1 Figure 1. Disclosures O'Donnell: Oncopeptide: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Bristol Myer Squibb: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy. Mo: Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee: Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Oncopeptides: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Nadeem: GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Bristol Myer Squibb: Consultancy. Branagan: Sanofi-Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive: Consultancy; CSL Behring: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rosenblatt: Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Attivare: Consultancy; Wolters Kluwer Health Inc: Consultancy, Patents & Royalties. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Richardson: AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.

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Evaluation of Efficacy and Safety of Front-Line Regimens for the Treatment of Transplant Ineligible Patients with Multiple Myeloma: A Network Meta-Analysis of Phase 2/3 Randomized Controlled Trials

Blood ◽

10.1182/blood-2019-130389 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2188-2188

Author(s):

Smith Giri ◽

Madan R Aryal ◽

Han Yu ◽

Alyssa Grimshaw ◽

Ranjan Pathak ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Meta Analysis ◽

Risk Of Bias ◽

Line Treatment ◽

Efficacy And Safety ◽

Front Line ◽

Advisory Committees ◽

Treatment Regimens

Background: Several options exist for front-line treatment of previously untreated patients with Multiple Myeloma (MM) ineligible for hematopoietic cell transplant (HCT). Many of these have not been evaluated in head to head clinical trials. Since these patients are often old and frail, treatment regimens should have dual goals: a) maximize clinical efficacy b) minimize therapy related toxicity. However, published network meta-analysis (NMA) till date have ignored the equally important safety outcome. In this systematic review, we provide an updated comparative efficacy and safety data of various front-line treatment regimens for HCT ineligible MM patients, using a Bayesian framework. Methods: We searched Medline, Embase, Web of Science Core Collection and the Cochrane library for published phase II/phase III RCTs from inception to October 2018 comparing at least two frontline regimens for the treatment of HCT ineligible MM patients. The primary efficacy outcome was progression free survival (PFS) whereas secondary outcomes included overall response rate (ORR) and overall Survival (OS). We defined safety as rate of all-cause and common grade 3 or higher adverse events (AE) in each arm. Risk of bias was assessed using Cochrane Risk of Bias Assessment Tool. Using aggregate data, a Bayesian random-effect hierarchical model was fit with non-informative priors and adjusting for correlation between effects in multi-arm trials. Assessment of inconsistency was performed by node-splitting approach. For toxicity, a multivariate Bayesian probit-normal regression model was fitted to the observed number of adverse events for each toxicity in an arm based meta-analytic approach. The relative ranking of agents was assessed using surface under the cumulative ranking (SUCRA) probabilities. (PROSPERO # CRD42018115364) Results: After screening 5587 publications, we selected 27 clinical trials involving 12,194 patients comparing 25 different regimens for final analysis (table 1). 26 of these studies were incorporated into one network geometry. The median age of study participants ranged from 63 to 79 years and 47% were females (table 1). Our NMA showed that for PFS, the three most effective regimens were: Daratumumab, Bortezomib, Melphalan and Prednisone (Dara-VMP, SUCRA 0.960) followed by Daratumumab, lenalidomide and dexamethasone (Dara-RD, SUCRA 0.847) and Bortezomib, melphalan, prednisone, thalidomide followed by maintenance with bortezomib-thalidomide (VMPT-VT, SUCRA 0.834), with results consistent for ORR and OS (table 2). For safety, we extracted data on 33 different grade ¾ AEs, 7 of which were reported by >50% of studies (anemia, neutropenia, thrombocytopenia, infections, neuropathy, thrombosis and gastrointestinal AEs) and used for further analyses. Among the three most efficacious regimens, the toxicity profile was most favorable for Dara-RD (median additional AEs per patient vs dexamethasone=0.74; 95% CrI 0.51-1.17; SUCRA 0.430) followed by Dara-VMP (median additional AE 0.91; 95% CrI 0.65-1.34; SUCRA 0.279) and VMPT-VT (median additional AE 0.98; 95% CrI 0.79-1.24; SUCRA 0.224) (figure 3). Conclusion: We provide direct/indirect comparison of efficacy and safety of various frontline regimens for HCT ineligible MM patients. While Dara-VMP was most likely to be the most efficacious regimen, Dara-RD provided the best balance between efficacy and safety. The results of our analysis should provide guidance to clinicians and patients in choosing the right regimen tailored to individual patient needs. Disclosures Huntington: Celgene: Consultancy, Research Funding; Genentech: Consultancy; Bayer: Consultancy, Honoraria; DTRM Biopharm: Research Funding; Pharmacyclics: Honoraria; AbbVie: Consultancy. Dhakal:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

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Efficacy and Safety of Carfilzomib at 56mg/m2 with Cyclophosphamide and Dexamethasone (K56Cd) in Newly Diagnosed Multiple Myeloma Patients Followed By ASCT or K56Cd Consolidation: Initial Results of the Phase 2 Cardamon Study

Blood ◽

10.1182/blood-2019-127992 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 861-861 ◽

Cited By ~ 3

Author(s):

Kwee Yong ◽

Rakesh Popat ◽

William Wilson ◽

Gavin Pang ◽

Richard Jenner ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Cell Transplant ◽

Newly Diagnosed ◽

Advisory Committees ◽

Risk Patients ◽

Standard Risk

Introduction: Carfilzomib (20/36mg/m2) triplets with Lenalidomide-Dexamethasone (KRd), or Cyclophosphamide-Dexamethasone (KCd) are safe and effective in patients with newly diagnosed multiple myeloma(NDMM). The higher dose of 56mg/m2 is effective as a doublet with Dexamethasone in the relapsed setting, but there is limited data on this dose in triplet combinations in the frontline setting. Aim: The CARDAMON study evaluated KCd with bi-weekly carfilzomib (56mg/m2) as induction in NDMM patients, and the benefit of ASCT versus K56Cd consolidation followed by carfilzomib maintenance. Co-primary endpoints were major response (≥VGPR rate) to 4 induction cycles of K56Cd, and 2-year PFS for ASCT versus K56Cd consolidation. Here we report interim analysis of the first primary endpoint of ≥VGPR rate to K56Cd induction. Methods: Transplant eligible ND patients received 4 x 28d cycles of K56Cd (carfilzomib:20/56mg/m2, IV d1, 2, 8, 9, 15, 16, cyclophosphamide 500mg orally d1, 8, 15 and dexamethasone 20mg d1, 2, 8, 9, 15, 16). Responding patients with a successful stem cell harvest (PBSCH) were randomised to autologous stem cell transplant (ASCT) or 4 more cycles of K56Cd as consolidation, followed by 18 months carfilzomib maintenance (K56 days 1, 8, 15) for both arms. Trial recruitment completed in July 2019. Response was assessed by IMWG criteria; all patients had MRD testing by multi-parameter flow cytometry (10-5) after PBSCH. Adverse risk genetics was any one of t(4;14), t(14;16), t(14,20) or del(17p). Results: 281 pts were registered between 06/2015 and 07/2019; we report outcomes for 252 patients who either completed induction or came off study before end of induction. Median age was 58yrs(33-74), 91% ECOG 0-1, 45.2% ISS I, 24.7% adverse risk (48.5% when including 1p/1q+). Best response at end of induction or after PBSCH (n=250) was: ≥VGPR 59.2%, ORR 87.6%. ≥VGPR rate in adverse risk patients was 53.4% vs 61.9% in standard risk(SR), (p=0.25), ORR was similar: adverse risk, 87.9% vs standard risk, 88.1%. Post-PBSCH, 24.1% of patients were MRD-negative (patients who were withdrawn due to insufficient induction response or toxicity and those with an inconclusive result were grouped with the MRD-positive). Of 19 patients in sCR/CR, 9 were MRD-negative(47.4%) while 40/110 (36.4%) of VGPR patients were MRD-negative. MRD-negative rates in adverse and standard risk patients were 22.8% and 24.7% respectively. 10 patients progressed during or at end of induction, and 12 were withdrawn for toxicity. There were 4 deaths during induction, one from myocardial infarction, the other 3 from cardiac arrest, associated with bronchopneumonia and sepsis. During induction, 114 serious adverse events (SAEs) were reported in 72/252 patients, notable ones were thrombotic microangiopathy (2), grade 3 cardiac ischaemia (4), infection (16.3%, mainly lung), renal impairment (6), G3 hypertension (3), thromboembolism(2). Specific guidance for hypertension management was incorporated. 25% of patients are currently reported to have received a dose modification during induction. Full details of adverse events and dose intensity will be presented at the meeting. Conclusion: K56Cd is an effective induction regimen in NDMM patients, and has equivalent MRD negative rates in adverse and standard risk disease. The SAE profile is in keeping with published safety data with carfilzomib. Disclosures Yong: Sanofi: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Autolus: Consultancy; Janssen: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Popat:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria; Takeda: Honoraria, Other: travel, accommodations, expenses. Ramasamy:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NAPP Pharmaceuticals Ltd.: Research Funding; Janssen-Cilag Ltd.: Research Funding; Oncopeptides and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chapman:Takeda: Honoraria. Benjamin:Allogene: Research Funding; Gilead: Honoraria; Novartis: Honoraria; Pfizer: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Servier: Research Funding; Eusapharm: Consultancy. Owen:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel/ meeting support. OffLabel Disclosure: Carfilzomib is used with cyclophosphamide as 1st line treatment for myeloma

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Cybord-Dara Is a Highly Effective Upfront Treatment for Newly Diagnosed Multiple Myeloma. Initial Efficacy Results of the 16-Bcni-001/Ctrial-IE (ICORG) 16-02 Study

Blood ◽

10.1182/blood-2018-99-112375 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3242-3242

Author(s):

Robert Henderson ◽

Mary R Cahill ◽

Philip Murphy ◽

Vitaliy Mykytiv ◽

John Quinn ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Liver Toxicity ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Introduction : Daratumumab (DARA), a human IgG1k monoclonal antibody with single activity in multiple myeloma (MM) shows strong synergy in combination with other anti-MM agents, including immunomodulatory drug (IMiDs) and proteasome inhibitors (PI). This has led to the exploration of DARA in combination with front line regimens. Triplets including a PI and an IMiD are considered an ideal backbone with which to combine DARA prior to Autologous Stem Cell Transplantation (ASCT). However, based on the ability of Cyclophosphamide (Cy) to enhance DARA mediated antibody dependent cellular phagocytosis, we hypothesized that CyBorD may provide an alternative option (Naicker, ASH 2017). We are currently exploring the preliminary safety and efficacy of CyBorD and DARA as part of an ongoing phase 1b study in newly diagnosed MM (NDMM) pts eligible for ASCT. Last year we reported on the safety of this combination with an absence of dose limiting toxicity (DLT) with weekly subcutaneous (SQ) Bortezomib (Bor) 1.5mg/m2, Cy 300mg/m2 and DARA 16mg/kg (McEllistrim, ASH 2017). We now report on the efficacy of this regimen as pre-transplant induction, including the rate of CR post ASCT. Methods : Pts received 4 cycles of induction therapy with weekly CyBorD and DARA 16mg/kg weekly for cycles 1 and 2 and every 2 weeks for cycles 3 and 4. Following induction therapy, pts proceeded to stem cell mobilization and ASCT followed by 2 cycles of consolidation therapy with weekly CyBorD plus DARA 16mg/kg on days 1 and 15. Following completion of consolidation therapy, all pts receive DARA maintenance every 28-days for 2 yrs or until progression, unacceptable toxicity or withdrawal of consent. Pts with high-risk features receive Bor on days 1 and 15 during maintenance phase. The primary endpoints were the incidence of DLT within the first cycle of combination at each dose level and CR rate post ASCT. Secondary endpoints included: safety, CR rate at the end of induction, consolidation and maintenance, best overall response, minimal residual disease (MRD) negative rate, progression-free survival, clinical benefit rate and overall survival. Responses were investigator-assessed as per IMWG criteria. This trial is registered at www.clinicaltrials.gov as NCT02955810. Results : Eighteen pts were enrolled between Nov 2016 and Dec 2017 and received at least 1 dose of treatment. Baseline characteristics were: median age = 56 y (range 32-66); M (61%), F (39%), ISS stage I, II, III in 78%, 17% and 6% of pts, respectively. 28% patients were identified with high risk genetic features [17p deletion and/or t(4;14) by FISH and/or SKY92 (SkylineDx)]. Three patients discontinued therapy early (primary refractory, persistent liver toxicity, death, respectively). Overall, treatment was well tolerated. The most common grade (gr) 3/4 hematologic treatment emergent adverse events (TEAE) were lymphopenia (44%), neutropenia (11%) and anemia (11%). The most common gr 3/4 non-hematologic TEAE were diarrhea (11%) and infection (61%). One patient died from gr 5 diffuse alveolar damage 7 weeks post ASCT. A single patient developed gr 3 liver toxicity. DARA-associated infusion reactions were ≤ gr 2 (11%). On an intent to treat (ITT) basis 94% achieved ≥ very good partial response (VGPR) with ≥ complete response (CR) in 44% pts (Figure). Among the sixteen patients completing 4 cycles of induction ORR was 100%, ≥ VGPR (69%), ≥ CR (13%). Informative NGS data (Adaptive Biotech) are available on 11/16 patients post induction, of whom 100% are MRD negative post induction at a level of ≥ 10e4. Following the induction phase 15/16 patients readily mobilized sufficient CD34 positive progenitors and proceeded to ASCT, one patient failed repeated mobilization. One patient died prior to post ASCT response assessment and data on the last patient is pending. Thus 13/15 patients are currently evaluable for response post ASCT. Responses deepened post ASCT with 100% achieving ≥ VGPR and 62% achieving ≥ CR. Based on EBMT criteria the CR/nCR rate post ASCT was 92%. Post ASCT PET-CT scans were consistent with complete metabolic response in all 13 patients. Updated results, including MRD status post ASCT will be presented at the meeting. Conclusions: CyBorD-DARA is a highly active, well tolerated induction therapy for NDMM patients undergoing ASCT. These data support the further development of this combination as a convenient, cost effective alternative to PI-IMiD-DARA based combinations. Disclosures Quinn: Janssen: Honoraria. O'Dwyer:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Glycomimetics: Research Funding; Onkimmune: Equity Ownership, 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; BMS: Research Funding.

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