Response Adaptive Salvage Treatment with Carfilzomib-Thalidomide-Dexamethasone for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients Failing Front-Line Bortezomib-Based Induction Therapy - Final Analysis from the Australasian Leukemia and Lymphoma Group (ALLG) MM17 Trial

Abstract BACKGROUND Survival rates in multiple myeloma (MM) have significantly improved in recent decades with the advent of high-dose chemotherapy conditioned autologous stem cell transplantation (ASCT) and the availability of novel agents for induction therapy (Kumar SK et al. Blood 2008). Failure to respond to front-line bortezomib-based induction therapy remains a significant clinical challenge in transplant eligible (TE) newly diagnosed multiple myeloma (NDMM), and is associated with poor outcomes with shortened progression free survival (PFS) and overall survival (OS) (Lee SE et al. Ann Hematol. 2014). In combination with immunomodulatory agents (IMiDs), carfilzomib, a second generation proteosome inhibitor, has been shown to be highly effective in the context of MM induction with high rates of negativity for minimal residual disease (MRD) and few dose limiting toxicities (Langren O et al. Leukemia 2019). The ALLG MM17 trial is a multicentre single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in TE NDMM patients refractory or with suboptimal response to bortezomib-based induction therapy, designed to evaluate the efficacy of early response adaption with a switch to an intensive salvage strategy. METHOD Eligible patients included those with TE NDMM, aged 18 years and older, demonstrating sub-optimal response to bortezomib-based induction therapy (failure to achieve a minimal response after 2 cycles, partial response [PR] after 4 cycles, or disease progression within 60 days of completing induction). Salvage therapy consisted of 100mg daily oral thalidomide, with 20 mg of oral dexamethasone and 20mg/56mg of IV carfilzomib on days 1, 2, 8, 9, 15, and 16, with of each 28-day cycle. Following 4 cycles, patients in stringent complete response (sCR) proceeded to melphalan conditioned ASCT whereas those in less than sCR received a further 2 cycles of KTd prior to ASCT. Consolidation therapy consisted of a further 2 cycles of KTd, followed by maintenance 100mg daily thalidomide and 40mg weekly dexamethasone (Td) continuing until progressive disease, unacceptable toxicity, or 12 months of therapy. Primary objectives were to determine the overall response rate (ORR) and safety profile of treatment with KTd salvage therapy, with secondary objectives to determine the maximal depth of response, progression free survival (PFS), and overall survival (OS) achieved with sequential treatment with KTd salvage, ASCT, post-ASCT consolidation, and maintenance Td therapy. Efficacy assessments were performed via serum protein electrophoresis, serum free light chain and bone marrow evaluation. Next generation flow (NGF) cytometry MRD evaluation of bone marrow aspirate was undertaken pre-ASCT, at day 100 post-ASCT, after 2 cycles of consolidation KTd, and following completion of Td using standardized 8-colour EuroFlow platform. RESULTS 50 patients were recruited across 6 Australian sites between September 2016 and April 2018. Overall response rate to KTd salvage was 78% (Credible Interval 95%: 64.4-87.1%), with dual proof of concept criteria met (observed ORR ≥ 50% and posterior probability that the true ORR exceeds 30% is ≥ 0.90). Response rates included 12% sCR, 6% CR, 38% VGPR, and 22% PR. Sixteen patients discontinued treatment (32%) including 10 cases (20%) of progressive disease, and 2 patient deaths without progression. NGF MRD negativity was found to be 32%, 36% and 55% at the pre-ASCT, post-ASCT and post-consolidation time-points. At the cut-off date, estimated median follow-up for disease status was 38.6 months and median PFS and OS had not been reached. At 36 months PFS and OS were 63.9% (95%CI: 49.0 - 75.5%) and 79.9% (95%CI: 65.8 - 88.6%) respectively (Figure 1). KTd was found to be well tolerated with 44% of patients experiencing a grade 3 of higher adverse event (AE). Most common AEs included upper respiratory infection (48%), peripheral neuropathy (36%), musculoskeletal pain (32%), dyspnoea (28%), fatigue or lethargy (28%), and constipation (28%). Significant cardiac toxicity was not observed at this higher dose level of carfilzomib. CONCLUSION Results demonstrate that response-adaptive utilisation of KTd salvage, ASCT, and consolidation therapy induces high response rates, improving depth of response with high levels of sequential MRD negativity, and durable responses with an acceptable toxicity profile in TE NDMM patients failing bortezomib-based induction therapy. Figure 1 Figure 1. Disclosures Quach: Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kalff: Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Roche: Honoraria; CSL: Honoraria; Sandoz: Honoraria. Bergin: Amgen: Other: Travel to workshop; Celgene: Consultancy. Reynolds: Novartis AG: Current equity holder in publicly-traded company; Alcon: Current equity holder in publicly-traded company; Abbvie: Research Funding. Spencer: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria.

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Phase I/Ib Trial of the Efficacy and Safety of Combination Therapy with Lenalidomide/Bortezomib/Dexamethasone (RVD) and Panobinostat in Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.33.33 ◽

2014 ◽

Vol 124 (21) ◽

pp. 33-33 ◽

Cited By ~ 1

Author(s):

Jatin J. Shah ◽

Lei Feng ◽

Elisabet E. Manasanch ◽

Donna M. Weber ◽

Sheeba K. Thomas ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Progression Free Survival ◽

Newly Diagnosed ◽

Advisory Committees ◽

Free Survival ◽

Depth Of Response

Abstract Background: Induction therapy prior to consolidation with autologous stem cell transplantation (ASCT) continues to improve with the use of proteasome inhibitors and imids and combination regimens such as RVD. Bortezomib-based induction therapy has improved overall response rates (ORR) prior to transplant, which has translated to improvements in ORR and progression free survival post ASCT. However, complete remission (CR) rates with RVD remain low (10-15%) after 4 cycles of induction therapy. Panobinostat, a histone deacetylase inhibitor, in combination with bortezomib/dexamethasone, has demonstrated a significant improvement in depth of response and progression free survival in patients (pts) with relapsed myeloma as seen in PANORMA I. Preclinical data demonstrate synergy between the combination of bortezomib and panobinostat. We undertook a phase I/Ib trial in pts with newly diagnosed myeloma (NDMM) of RVD + Panobinostat to establish the safety of the combination and goal of improving the depth of response with induction therapy prior to ASCT. Methods: The primary objective was to determine the maximum tolerated dose (MTD) and safety/tolerability of RVD + panobinostat in NDMM. Secondary objectives were to determine efficacy as measured by the CR/nCR rate after 4 cycles, ORR, tolerability/toxicity, and progression free survival. Pts had to have NDMM with indication for therapy, candidates for ASCT with and had adequate organ function. Panobinostat was administered on days 1, 3, 5, 8, 10, 12; bortezomib 1.3 mg/m2 was administered subcutaneously on days 1, 4, 8, 11; lenalidomide 25 mg on days 1-14; dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 on a 21 day cycle. Dose-escalation of panobinostat used a standard 3+3 schema with dose-limiting toxicities (DLTs) assessed during cycle 1. Three dose levels were studied with Panobinostat escalated from 10 to 20 mg. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results: 22 pts were enrolled; 12 pts in the completed phase 1 dose escalation portion of the study and 10/20 in the ongoing dose expansion. The median age was 61 (range 53-79); ISS stage I 12; stage II 7/20; stage III in 3/20 pts. No DLTs were observed in 3 pts dosed in cohort 1, with Panobinostat at 10 mg. In cohort 2, panobinostat was dosed at 15 mg, 2/6 pts encountered a DLT. One patient experienced Grade 4 (G4) thrombocytopenia, and the second patient had G3 diarrhea without supportive measures, for <12 hours and resolved with supportive measures. In cohort 1, 3 additional patients were enrolled and no DLTs were encountered in the remaining 3 pts. The final recommended dose was Panobinostat 10 mg in combination with RVD in NDMM. Treatment emergent SAEs related to therapy observed in 5 pts with 2 incidences of G3 diarrhea; 2 pts with atrial fibrillation; and other events included G4 thrombocytopenia; G3 bacteremia, G3 cellulitis, G3 myocardial infarction (MI), G3 pulmonary emboli; G3 pneumonia. Hematologic adverse events G3/4 included anemia 3/22; neutropenia 4/22; thrombocytopenia 7/22. G3/4 nonhematologic toxicities included ALT elevation (n=2); AST elevation (n=1); constipation (n=2); diarrhea (n=2); fatigue/muscle weakness (n=2); MI (n=1); pneumonia (n=3). Among 18/22 pts who have completed 4 cycles of therapy and are evaluable for efficacy, the ORR (≥PR) was 100%: including nCR/CR in 5/18 (28%), VGPR in 5/18 (28%), PR in 8/18 (44%). Conclusions: MTD has been established at level 1, with panobinostat 10 mg and full dose RVD in NDMM. The DLTs were diarrhea (irrespective of supportive care) and thrombocytopenia. This is the first experience with panobinostat and subcutaneous bortezomib and first experience in combination with RVD. The combination is well tolerated with limited toxicity and side effects can be managed with supportive care. The preliminary activity after 4 cycles of therapy demonstrated a high ORR of 100% and a promising depth of response with a nCR/CR of 27%. Enrollment in a dose expansion cohort is near completion and full data will be presented at ASH. Disclosures Shah: Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array: Consultancy, Research Funding. Off Label Use: Carfilzomib for use in front-line tx of multiple myeloma . Weber:OncPep: Research Funding. Thomas:Novartis, Celgene, Millenium, Idera Pharmaceuticals: Consultancy, Research Funding. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Characteristics Of Multiple Myeloma Patients With 6-Year Or Longer Progression-Free Survival After a Single Autologous Transplant

Blood ◽

10.1182/blood.v122.21.3366.3366 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3366-3366 ◽

Cited By ~ 2

Author(s):

Kehinde U.A. Adekola ◽

Qaiser Bashir ◽

Nina Shah ◽

Sai Ravi Pingali ◽

Simrit Parmar ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Induction Therapy ◽

Progression Free Survival ◽

High Dose ◽

Cell Transplant ◽

Advisory Committees ◽

Free Survival ◽

Autologous Transplant ◽

Preparative Regimen

Background High dose chemotherapy followed by an autologous stem cell transplant (auto-HCT) is considered standard of care in patients with newly diagnosed multiple myeloma (MM). In a recent randomized trial, median progression free survival (PFS) after auto-HCT, with or without maintenance therapy was 46 and 27 months, respectively (McCarthy P et al. NEJM 2012). However, about 15% of patients are reported to have much longer PFS (Pineda-Roman M et al. Cancer 2008). Here we tried to identify the factors that may predict a long PFS after auto-HCT. Methods We performed a retrospective chart review of patients who received an auto-HCT for MM between January 2000 and March 2007. A total of 1135 patients underwent an auto-HCT during this period, and 194 patients (17%) had a minimum PFS of 72 months or longer after a single auto-HCT. The primary objective was to determine the variables associated with a long PFS and overall survival (OS). Results Patient characteristics and outcomes are shown in the attached Table. The median age at auto-HCT was 56 years, and the median time from diagnosis to auto-HCT was 7.5 months. Twenty-three (13%) patients had ≥ 10% plasma cells in the bone marrow at auto-HCT and only 9 patients (4.8%) had high-risk cytogenetic abnormalities. One-hundred and fifty (77%) patients received induction therapy containing either an immunomodulatory (IMiD) agent or a proteasome inhibitor (PI). At the time of the auto-HSCT, only 13 (6.7%) patients were in CR and 38 (19.6%) were CR or VGPR after induction therapy (Table). One-hundred and sixty three (84%) patients received mephalan alone as conditioning regimen. Eighty-one (42%) patients received post auto-HCT maintenance. Eighty (41%) patients achieved a CR, while 104 (54%) achieved CR + VGPR after auto-HCT. Six patients (3.1%) developed a second primary malignancy post- autologous transplant. After a median follow-up of 95.4 months, median PFS was 97.3 months and median OS has not been reached. The 10-year PFS and OS were 41% and 73% respectively. Use of melphalan alone as preparative regimen was associated with a longer PFS and OS (p=0.004 and 0.004, respectively). Achievement of CR after auto-HCT was associated with a longer PFS only (p=0.001), and the use of IMiD or a PI as induction was associated with a longer OS (p=0.01). Conclusion Approximately 17% patients achieved a median PFS of 6 years or longer after a single auto-HCT. The long PFS in this cohort may be associated with younger age, low incidence of HR cytogenetics, use of an IMiD or PI as induction therapy, relatively low disease burden at auto-HCT, transplant from the year 2000 onwards, achievement of CR in >40% and the use of melphalan alone as preparative regimen. Disclosures: Shah: Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Qazilbash:Celgene: Membership on an entity’s Board of Directors or advisory committees.

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Efficacy of Daratumumab, Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma Among Patients with 1 to 3 Prior Lines of Therapy Based on Previous Treatment Exposure: Updated Analysis of Pollux

Blood ◽

10.1182/blood.v128.22.489.489 ◽

2016 ◽

Vol 128 (22) ◽

pp. 489-489 ◽

Cited By ~ 13

Author(s):

Philippe Moreau ◽

Jonathan L. Kaufman ◽

Heather J. Sutherland ◽

Marc Lalancette ◽

Hila Magen ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Statistical Significance ◽

Previous Treatment ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Refractory Multiple Myeloma

Abstract Introduction: Daratumumab is an anti-CD38 IgGκ monoclonal antibody that has been combined successfully with lenalidomide and dexamethasone. The combination of daratumumab with lenalidomide and dexamethasone (DRd) has been compared with lenalidomide and dexamethasone alone (Rd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM) in a randomized phase 3 study (Dimopoulos MA, et al. N Engl J Med 2016; in press). In a pre-specified interim analysis, the DRd combination demonstrated significantly longer progression-free survival (PFS) in addition to deep and durable responses compared with the Rd arm. We performed subgroup analyses to further examine these efficacy data according to prior treatment exposure. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to Rd (lenalidomide: 25 mg PO on Days 1-21 of each 28-day cycle; dexamethasone: 40 mg PO weekly) with or without daratumumab (16 mg/kg IV qw for 8 weeks, q2w for 16 weeks, then q4w until progression). The primary endpoint was PFS. Pts who were refractory to lenalidomide were not eligible. All analyses were performed in pts who received 1 to 3 prior lines of therapy. Results: Median follow-up was 13.5 months. Pts who were lenalidomide-naive prior to the start of study treatment (DRd, n=226; Rd, n=219) demonstrated significantly longer PFS with DRd vs Rd (median: not reached [NR] vs 18.4 months; HR, 0.36; 95% CI, 0.25-0.52; P<0.0001), with estimated 12-month PFS rates of 83.0% vs 59.9%, respectively. ORR was significantly higher with DRd vs Rd (96% vs 79%), with ≥VGPR rates of 76% vs 47% and ≥CR rates of 44% vs 21%, respectively (P<0.0001 for all). In the lenalidomide-exposed subgroup (DRd, n=46; Rd, n=45), median PFS was NR in both treatment groups (HR, 0.49; 95% CI, 0.22-1.12; P=0.0826); estimated 12-month PFS rates were 84.1% vs 63.1%, respectively. ORR was higher with DRd vs Rd but did not reach statistical significance (87% vs 71%; P=0.0729); however, rates of ≥VGPR (78% vs 38%; P=0.0001) and ≥CR (44% vs 12%; P=0.0011) were significantly improved with DRd vs Rd, respectively. For bortezomib-naive pts (DRd, n=44; Rd, n=45), PFS was significantly longer with DRd vs Rd (median: NR vs 15.8 months; HR, 0.34; 95% CI, 0.13-0.86; P=0.0170), with estimated 12-month PFS rates of 85.4% vs 69.2%, respectively. ORR was significantly higher with DRd vs Rd (98% vs 82%; P=0.0158), with trends toward increased rates of ≥VGPR (74% vs 55%; P=0.0544) and ≥CR (42% vs 23%; P=0.0576). In the bortezomib-exposed pts (DRd, n=228; Rd, n=219), median PFS was NR in DRd vs 18.4 months in Rd (HR, 0.35; 95% CI, 0.24-0.50 P<0.0001); estimated 12-month PFS rates were 82.8% vs 58.7%, respectively. Significant differences in ORR (93% vs 77%), rate of ≥VGPR (77% vs 43%) and rate of ≥CR (44% vs 19%) were observed with DRd vs Rd, respectively (P<0.0001 for all). Among bortezomib-refractory patients (DRd, n=54; Rd, n=49), the PFS benefit of DRd compared with Rd was maintained (median: NR vs 10.3 mo, respectively; HR, 0.46; 95% CI, 0.25-0.85; P=0.0117; Figure). The estimated 12-month PFS rates were 70.8% vs 44.4%, respectively. Similar to bortezomib-exposed pts, ORR (92% vs 68%; P=0.0024), rate of ≥VGPR (75% vs 36%; P=0.0001), and rate of ≥CR (46% vs 13%; P=0.0003) were all significantly higher with DRd vs Rd for bortezomib-refractory pts. Updated data will be presented at the meeting. Conclusions: Among pts who received 1 to 3 prior lines of therapy, significantly longer PFS and higher ORR were observed with DRd vs Rd among pts who previously received bortezomib or were refractory to bortezomib or were lenalidomide-naive. Higher rates of deeper responses were observed in pts who previously received lenalidomide or bortezomib. Follow-up is ongoing to assess PFS in pts who received 1 to 3 prior lines of therapy and previously received lenalidomide. These results further strengthen the significant benefit of combining daratumumab with Rd for RRMM. Figure Progression-free Survival in Bortezomib-refractory Patients who Received 1 to 3 Prior Lines of Therapy Figure. Progression-free Survival in Bortezomib-refractory Patients who Received 1 to 3 Prior Lines of Therapy Disclosures Moreau: Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Kaufman:Pharmacyclics: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Sutherland:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Lalancette:Celgene: Honoraria; BMS: Honoraria. Iida:Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding. Prince:Janssen: Honoraria; Celgene: Honoraria. Cochrane:BMS: Other: Received sponsorship to attend international meetings; Novartis: Other: Received sponsorship to attend international meetings; Celgene: Other: Received sponsorship to attend international meetings; Takeda: Other: Received sponsorship to attend international meetings. Khokhar:Janssen: Employment. Guckert:Johnson & Johnson: Equity Ownership; Janssen: Employment. Qin:Janssen: Employment. Oriol:Janssen: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.74.74 ◽

2012 ◽

Vol 120 (21) ◽

pp. 74-74 ◽

Cited By ~ 8

Author(s):

Jatin J. Shah ◽

Edward A. Stadtmauer ◽

Rafat Abonour ◽

Adam D Cohen ◽

William I. Bensinger ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Grade 3

Abstract Abstract 74 Background: Carfilzomib, a novel proteasome inhibitor (PI), and pomalidomide, an immunomodulatory agent (IMiD), have both demonstrated promising activity as single agents or in combination with dexamethasone in relapsed/refractory multiple myeloma. IMiD+PI combinations including lenalidomide, bortezomib, dexamethasone and lenalidomide, carfilzomib, dexamethasone have had high response rates and good tolerability. We aimed to combine carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) for the first time and hypothesized that this regimen would be highly active in patients with relapsed/refractory multiple myeloma. Here, we report the first findings from the Phase I dose-escalation and expansion portions of the first phase I/II trial of Car-Pom-d in patients with relapsed/refractory multiple myeloma (NCT01464034). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of Car-Pom-d. Secondary objectives included determination of overall response rate, time to progression, progression free survival, and time to next therapy. All patients had to be refractory to prior lenalidomide, and must have been relapsed/refractory to their most recent therapy. Treatment consisted of 28-day cycles of oral pomalidomide once daily on days 1–21, intravenous (IV) carfilzomib over 30 minutes on days 1, 2, 8, 9, 15, and 16, and oral or IV dexamethasone 40 mg on days 1, 8, 15, and 22. Dose-escalation of carfilzomib started with 27mg/m2 carfilzomib/4mg pomalidomide/40 mg dexamethasone using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Carfilzomib was initiated at 20 mg/m2for Cycle 1, days 1–2 at all dose levels. Investigators were permitted to adjust the dose of dexamethasone at any point based on their discretion. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results: In the Phase I dose-escalation portion of the trial, a total of 12 patients were enrolled from 6 centers. The median age was 61 years (range 44–78), 67% were male. The median number of prior regimens was 6 (range 2–15), and median time from diagnosis was 5.1 years. Four (33%) patients had prior stem cell transplant, 11 (92%) had prior bortezomib, and all were lenalidomide-refractory. Cytogenetic abnormalities included 5 patients with del(17p), 2 patients with t(4;14), and 1 patient each with del(13), t(11;14), and t(14;16). In these first 12 patients, drug-related AEs occurring in >20% of patients included fatigue (42%), anemia (33%), pneumonia (33%), dyspnea (25%), and thrombocytopenia (25%). Six (50%) patients experienced grade ≥3 AEs including 2 incidence each of neutropenia and febrile neutropenia. The MTD was established as the starting dose level (carfilzomib 20/27 mg/m2, pomalidomide 4mg, dexamethasone 40 mg). At this dose, 1 of 6 patients experienced a protocol-defined DLT of febrile neutropenia. At dose level 2 (carfilzomib 20/36 mg/m2, pomalidomide 4 mg, dexamethasone 40 mg), 2 of 6 patients experienced DLTs, consisting of grade 4 thrombocytopenia and grade 3 rash. All 12 patients were response evaluable with 2 very good partial response (VGPR), 4 partial response (PR), 2 minor response (MR), 2 stable disease (SD), and 2 progressive disease (PD) for a ≥ MR rate of 67%. The 6 month progression free survival was 70% (95% CI: 37 to 90%). Of the 5 patients with del(17p), 1 achieved VGPR, 2 achieved PR, 1 achieved SD. We then enrolled an expansion cohort of 20 patients from 8 centers resulting in a total study population of 32 patients, with 25 still receiving treatment. Three patients have died, all from progressive multiple myeloma. Early response assessments in 27 out of 32 patients show 2 VGPR, 7 PR, 6 MR, 8 SD, and 4 PD for a ≥MR rate of 56%. Conclusions: The Car-Pom-d regimen is well tolerated and achieves a high response rate in a heavily pre-treated, lenalidomide-refractory population with prior bortezomib exposure. Importantly, we have seen responses in patients with poor risk cytogenetics, specifically del (17p). We are beginning enrollment in a larger phase 2 cohort, and updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Array: Consultancy. Stadtmauer:Celgene: Consultancy, Speakers Bureau; Millennium: Consultancy, Speakers Bureau. Abonour:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau. Cohen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:Onyx: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau. Gasparetto: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. Kaufman:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Lentzsch:Celgene: Consultancy, Research Funding. Vogl:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Research Funding; Otsuka: Consultancy; Acetylon: Research Funding. Orlowski:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Durie:Onyx: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Amgen: Consultancy.

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Progression-Free Survival Outcomes By Response Status for Bortezomib, Melphalan, and Prednisone with or without Daratumumab in Newly Diagnosed Multiple Myeloma: Pooled Subgroup Analysis of Octans and Alcyone

Blood ◽

10.1182/blood-2021-148937 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1648-1648

Author(s):

Jianxiang Wang ◽

Weijun Fu ◽

Soo-Mee Bang ◽

Honghui Huang ◽

Kihyun Kim ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Publicly Traded ◽

Primary Analysis ◽

Advisory Committees ◽

Once Daily ◽

Free Survival ◽

Asian Patients

Abstract Introduction: Daratumumab is a human IgGκ monoclonal antibody that targets CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the primary analysis (median follow-up, 16.5 months) of the global phase 3 ALCYONE trial, daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) significantly improved progression-free survival (PFS) versus VMP alone in patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for transplant (median PFS, not reached vs 18.1 months; hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.38-0.65; P<0.001). In the primary analysis (median follow-up, 12.3 months) of the phase 3 OCTANS trial, D-VMP significantly prolonged PFS versus VMP in transplant-ineligible Asian patients with NDMM (median PFS, not reached vs 18.2 months; HR, 0.43; 95% CI, 0.24-0.77; P=0.0033). Here, we present a pooled subgroup analysis of PFS stratified by best response in Asian and global patients from the OCTANS and ALCYONE studies, respectively. Methods: Eligible patients in OCTANS and ALCYONE were ≥18 years of age, were diagnosed with NDMM, and were not eligible for autologous stem cell transplant due to age (≥65 years) or comorbidities. All patients received up to 9 cycles (42-days) of bortezomib (1.3 mg/m 2; subcutaneous) twice weekly on Weeks 1, 2, 4, and 5 of Cycle 1 and once weekly on Weeks 1, 2, 4, and 5 of Cycles 2 to 9; melphalan (9 mg/m 2; oral) once daily on Days 1 to 4 of each cycle; prednisone (60 mg/m 2; oral) once daily on Days 1 to 4 of each cycle. For patients in the D-VMP group, daratumumab (16 mg/kg, intravenous) was administered once weekly in Cycle 1, once every 3 weeks in Cycles 2 to 9, and once every 4 weeks thereafter until disease progression or unacceptable toxicity. Response over time (at 6, 12, 18, 24, 54 weeks) and disease progression were assessed by a validated computer algorithm in accordance with the IMWG criteria. Minimal residual disease (MRD) negativity (10 -5) was assessed by multi-parameter flow cytometry in OCTANS and by next-generation sequencing in ALCYONE. Results: In the OCTANS study, 220 Asian patients were randomized (D-VMP, n=146; VMP, n=74); in the ALCYONE study, 706 global patients were randomized (D-VMP, n=350; VMP, n=356). Median age in OCTANS was 69 (range, 57-84) years and 71 (range 40-93) years in ALCYONE. Patients were pooled from both studies (D-VMP, n=496; VMP, n=430). D-VMP increased the rate of complete response or better (≥CR; 10.2% vs 5.6%) and the rate of very good partial response or better (≥VGPR; 58.5% vs 38.1%) versus VMP after 18 weeks of treatment (Figure A). Responses deepened over time among patients in both the D-VMP and VMP groups, as shown by the ≥CR rate (D-VMP, 38.8%; VMP, 21.6%) and the ≥VGPR rate (D-VMP, 74.0%; VMP, 50.7%) at 54 weeks. At a median follow-up of 12.3 months for OCTANS and 16.5 months for ALCYONE, among patients who achieved a VGPR (D-VMP: n=145 [29.2%]; VMP: n=109 [25.3%]), the median PFS was not reached in the D-VMP group versus 19.9 months in the VMP group (HR, 0.61; 95% CI, 0.36-1.00; P=0.0499; Figure B). All patients who achieved ≥CR with or without MRD negativity (10 -5) demonstrated prolonged PFS, regardless of treatment (≥CR: HR, 1.54; 95% CI, 0.65-3.65; P=0.3210; ≥CR+MRD negativity: HR, 0.67; 95% CI, 0.13-3.40; P=0.6225; Figure B); however, more patients treated with D-VMP achieved this level of response (≥CR: D-VMP , n=212 [42.7%]; VMP, n=100 [23.3%]; ≥CR+MRD negativity: D-VMP, n=116 [23.4%]; VMP, n=27 [6.3%]; Figure B). Conclusion: In a pooled analysis of OCTANS and ALCYONE, more patients with transplant-ineligible NDMM achieved deeper responses with D-VMP versus VMP. More patients treated with D-VMP achieved ≥CR with or without MRD negativity compared with those treated with VMP alone, leading to prolonged PFS regardless of treatment. These results support the use of daratumumab in addition to VMP in transplant-ineligible Asian patients with NDMM. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Kim: BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Li: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Chim: Janssen, Takeda & Amgen: Other: received sponsorship for overseas meetings. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria; Clínica Universidad de Navarra: Current Employment. Liberati: abbvie, amgen, archigen, beigene, BMS, celgene, DR REDDY'S LABORATORIES SPA, fibrogen, glaxo, Janssen, Karyopharm, Morphosys, Novartis, Onconova, Oncopeptides ab, Roche, Sanophi, Secura Bio, Takeda, Verastem,: Research Funding. Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; SRL: Consultancy; Adaptive Biotechnologies, Eisai: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Dimopoulos: BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Wroblewski: Janssen: Current Employment, Current equity holder in publicly-traded company. Carson: Janssen: Current Employment. Qi: Janssen: Current Employment, Current equity holder in publicly-traded company. Wang: Janssen: Current Employment. Song: Janssen: Current Employment. Jia: Janssen: Current Employment. Yang: Janssen: Current Employment, Current equity holder in publicly-traded company. Liu: Janssen: Ended employment in the past 24 months. Li: Janssen: Current Employment. Zhang: Janssen: Current Employment.

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Phase II Trial of Combination of Elotuzumab, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽

10.1182/blood-2018-154 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 154-154 ◽

Cited By ~ 10

Author(s):

Chia-jen Liu ◽

Irene M. Ghobrial ◽

Mark Bustoros ◽

Kaitlen Reyes ◽

Kalvis Hornburg ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Therapeutic Intervention ◽

Research Funding ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Genomic Studies ◽

Equity Ownership

Abstract Background This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, Lenalidomide, and Dexamethasone in patients with high-risk smoldering multiple myeloma (SMM). ClinicalTrials.gov Identifier: NCT02279394. Aims The overarching objective of this trial is to determine progression free survival to symptomatic multiple myeloma (MM). Furthermore, the study examined whether genomic studies can help in determining patients who would benefit the most from this early therapeutic intervention. Methods Patients enrolled in this study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al, Blood 2014. Patients were administered weekly elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1-21. For cycles 3-8, patients were administered elotuzumab infusions on days 1, 8, and 15. dexamethasone (40mg) was given on days 1, 8 and 15 to 40 of the 50 enrolled patients. After 8 cycles or best response, patients were given the option to mobilize with either cyclophosphamide or plerixafor and collect stem cells for future transplant. Patients were then allowed to continue on maintenance therapy where they were administered elotuzumab (20 mg/kg) on day 1, in combination with lenalidomide days 1-21 of a 28-day cycle. Bone marrow (BM) samples of 32 patients were obtained before starting therapy for baseline assessment and whole exome sequencing (WES) of plasma cells. Results In total, 50 patients were enrolled on this study from January 2015 and completed accrual in December 2016, with the participation of eight sites. The median age of enrolled patients was 62 years (range, 29-79) with 18 males (36%) and 32 females (64%). Interphase fluorescence in situ hybridization (iFISH) detected high-risk cytogenetics (defined by the presence of 17p deletion, t(4;14), and 1q gain) in 20 patients. The median time to response was 2.8 months (range, 1.8-4.6). The most common toxicities were fatigue (92%), followed by diarrhea (72%), and hyperglycemia (62%). The most common grade 3 or more adverse events were hypophosphatemia (34%), neutropenia (26%), and lymphocyte count decreased (22%). Three patients (6%) had grade 4 hypophosphatemia during treatment. Additionally, grade 4 cholecystitis, cataract, lymphocyte count increase, hyperglycemia, neutropenia, and thrombocytopenia occurred in one patient (2%). Diabetic Ketoacidosis and sepsis led to death in a patient (2%). Stem cell collection was successful in all mobilized patients to date. As of this abstract date, the overall response rate is 84% (41/49). There were 3 complete responses (6%), 18 very good partial responses (37%), 20 partial responses (41%), 5 minimal responses (10%), 3 stable disease (6%), and 2 unevaluable patients. All the study participants except for three have finished treatment and are currently under follow up. None of the patients showed progression to overt MM to date. We continue to collect data for progression free survival. WES was performed on 32 samples at the time of initiation of therapy. Recurrent mutations in the MAPK pathway (KRAS, NRAS) and tumor suppressor gene, TP53, were detected in 40% of the cases (16% and 24%, respectively), while mutations in the NF-KB and plasma cell differentiation pathways were present in 13% of patients. Somatic copy number alterations (SCNAs) were called based on WES: 1q duplication, 13q, 17p, and 1p deletions were identified in 25, 31, 12, and 7% of cases, respectively. Interestingly, in 6 patients, high-risk SCNAs (1q gain and 17p deletion) were not reported in iFISH but were detected by WES. The analysis of these 32 samples showed that patients who are harboring mutations in the DNA repair pathway genes, had modest response to treatment. Finally, we are analyzing the transcriptomic profile of CD138 negative cells, which represent the BM microenvironment cells (immune and stromal cells) to characterize the BM microenvironment at baseline and end of treatment, and thus, elucidate the role of these cells in the differential response to therapy. Conclusion The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rate with no progression to overt MM to date. Correlation with genomic studies can help define patients who benefit the most from this early therapeutic intervention. Disclosures Ghobrial: Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy. Bustoros:Dava Oncology: Honoraria. Badros:GSK: Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Rosenblatt:Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Karyopharm: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Zonder:Celgene: Consultancy, Honoraria; Pharmacyclics: Other: DSMC; Janssen: Honoraria; Takeda: Honoraria; Alnylam: Honoraria; Coelum: Honoraria; BMS: Research Funding. Munshi:OncoPep: Other: Board of director. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; OncoPep: Equity Ownership, Other: Scientific founder; Millennium Takeda: Consultancy; Celgene: Consultancy. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Outcomes of Myeloma Patients with Deletion 1p Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Therapy

Blood ◽

10.1182/blood-2018-99-114368 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1884-1884 ◽

Cited By ~ 1

Author(s):

Levani Odikadze ◽

Nisha Joseph ◽

Timothy M. Schmidt ◽

Leonard Heffner ◽

Craig C Hofmeister ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Progression Free Survival ◽

Control Group ◽

Advisory Committees ◽

Best Response ◽

Significant Difference ◽

1P Deletion

Abstract Introduction: Previous studies indicated that 1p deletion (del 1p) in multiple myeloma patients has a negative effect on overall survival (OS) and progression free survival (PFS). However, majority of studies were conducted before the introduction of current first line therapy of Lenalidomide, Bortezomib and Dexamethasone (RVD). Our study investigated the association between del 1p and clinical outcomes in patients with MM treated with RVD. Methods: Single-center, retrospective analysis of an IRB approved myeloma database of 1000 newly diagnosed multiple myeloma patients treated with RVD induction therapy per Richardson et al (Blood 2010), planned stem cell transplant and risk adapted maintenance (Nooka et al, Leukemia, 2014). 1p deletion status was determined by FISH. The primary outcomes were response to RVD, response to ASCT, progression free survival (PFS), and overall survival (OS). Treatment responses were evaluated as per IMWG Uniform Response Criteria. Results: We identified 1000 multiple myeloma patients who started RVD treatment from July 2005 to August 2016. Among these, 83 patients (8.3 %) were found to have 1p deletion on FISH. The remaining 917 patients formed the control group. Median age at diagnosis, sex and race were similar between groups. Patients with del 1p were more likely to have IgA isotype compared to controls (28.1% vs 19.7%, P=0.054). There was no significant difference between groups in baseline hemoglobin, calcium, platelet count, creatinine and albumin levels. Baseline LDH levels were more likely to be high in the del 1p group (P=0.009). 49.6% of del 1p patients had high risk status (t(4:14), t(14:16), 17p deletion) vs 26.6% in the control group (p<0.0001). There was no significant difference in the best response to induction therapy between groups, with an achievement of a VGPR or better in 62.8% vs 69.3% in the del 1p and control groups respectively (p=0.148). However, the del 1p group had lower best response after transplant, with a VGPR or better in 67.1% vs 89.2% respectively (P<0.001). Univariate regression analysis also showed a significant association of del 1p with decreased PFS (HR 1.782, P=0.002), which stayed significant after adjusting for disease stage, high risk FISH and maintenance (HR 2.265, p<0.001). There was no statistical decrease in OS in the del 1p population. Conclusion: This analysis demonstrated that the del 1p continues to be associated with adverse outcomes in the era of uniform induction therapy with RVD, transplant and risk-adapted maintenance. There was no significant difference in response to induction treatment, however, del 1p was a significant independent adverse prognostic factor for best response and PFS after ASCT. The lack of decrease in OS may be due to the routine use of risk adapted maintenance. Disclosures Heffner: Genentech: Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Research Funding; ADC Therapeutics: Research Funding. Hofmeister:Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Lonial:Amgen: Research Funding. Nooka:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Roche: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; BMS: Consultancy.

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Bone Marrow CD4+ and CD8+ Lymphocyte Infiltration Patterns Define Overall- and Progression Free Survival in Multiple Myeloma and May Predict IMiD Response: an Analysis from the Austrian Myeloma Registry

Blood ◽

10.1182/blood.v128.22.5659.5659 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5659-5659

Author(s):

Ella Willenbacher ◽

Andrea Brunner-Veber ◽

Roman Weger ◽

Wolfgang Willenbacher

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Immune Dysregulation ◽

Phase Iii ◽

Lymphocyte Infiltration ◽

Advisory Committees ◽

Free Survival

Abstract Introduction: In Multiple Myeloma immune dysregulation with quantitative and qualitative changes in T-cell subpopulations is thought to result in a reduced anti-tumour immune response promoting disease progression. Methods: A retrospective cohort of 45 myeloma patients was analyzed for the extent of tumor infiltrating CD4+ and CD8+ lymphocytes by means of immunohistochemistry using sophisticated automated evaluation software. Results: Here, for the first time we analyzed trephine biopsies of myeloma patients and we report a significant association of different patterns of immune cell infiltrations with OS and PFS suggesting that these patients might particularly benefit from immune modulating therapeutic strategies: CD4+ T-cells below a cutoff of 0.28% lymphocytes/total nucleated cells were associated with a significantly longer overall survival, while CD8+ T-cells above the cutoff of 6.51% predicted a longer progression free survival. Treatment with immunomodulatory drugs resulted in a significantly better overall- and progression free survival for patients with adverse local immunological features compared to those treated with proteasome inhibitors or non-novel agents. We suggest that immune dysregulation in myeloma significantly influences overall- and progression free survival. We will now validate this immuno algorithm of lymphocyte infiltration patterns as a predictive biomarker of IMiD responsiveness in the framework of a large randomized phase III trial. If confirmed they might be used as a putative biomarker to guide rational therapy allocation in the future. Disclosures Willenbacher: Celgene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Willenbacher:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commision: Research Funding.

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Evomela® Significantly Increases the Risk of Engraftment Syndrome in Patients with Multiple Myeloma Treated with Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-132114 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3316-3316 ◽

Cited By ~ 1

Author(s):

Marshall McKenna ◽

Phyllis McKiernan ◽

David S. Siegel ◽

Scott D. Rowley ◽

Noa Biran ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Engraftment Syndrome ◽

Equity Ownership

Background: Evomela, a Melphalan bioequivalent, was approved by the FDA in 2016 for high-dose conditioning treatment prior to hematopoietic stem cell transplantation for multiple myeloma (MM). Evomela has increased solubility and stability compared to traditional Melphalan which requires propylene glycol, a stabilizing agent. A retrospective review (Miller et al. 2019) showed that there was no difference in outcomes or short term morbidity in autologous stem cell transplant (ASCT) recipients conditioned with either Melphalan or Evomela. There was, however, an increased incidence of C. difficile-negative diarrhea in the Evomela group. Engraftment syndrome (ES) is a well characterized, although poorly understood, conglomerate of symptoms occurring in the autologous peri-engraftment period. We have previously demonstrated (McKiernan et al. 2017) that patients with ES have an adverse overall outcome. This study aims to evaluate the effect of Evomela conditioning on patients with MM receiving ASCT. Methods: Our study cohort included 644 patients with MM who received ASCT between January 2008 and December 2018. Evomela conditioning was administered to all patients treated on or after September 4, 2016, defining the Melphalan and Evomela cohorts. ES was defined as diarrhea, rash, non-infectious fever, hepatic dysfunction, pulmonary infiltrates, or encephalopathy not attributed to other causes from 3 days prior to 15 days post engraftment. High-risk disease (HRD) was defined as del 17p, 1q gain, t(4;14), t(14;16), t(14;20) by FISH, monosomy 13, del 13q or hypodiploidy by standard cytogenetics, or high-risk gene expression profiling. Response criteria from the International Myeloma Working Group was used to determine response. Progression free survival (PFS) and overall survival (OS) probabilities were estimated using log rank or Wilcoxon tests. Cox hazard regression model was examined for factors influencing ES. Results: Of the 644 patients, 78 were conditioned with Evomela and 554 were conditioned with Melphalan. Thirty five percent of the total patient population had HRD, 234 (36%) were age 65 or older, and 369 (57%) were males. A total of 197 (30%) patients developed ES with 171 (87%) receiving treatment with corticosteroids. Conditioning with Evomela was associated with a significantly higher incidence of ES 15 days post ASCT compared to Melphalan (40.3% vs 24.8%, p=0.0006). Multivariate analysis showed that patients conditioned with Evomela were 60% more likely (HR-1.597, 95% CI, 1.116-2.285, p=0.0105) to develop ES than traditional Melphalan. Across both cohorts, higher median CD34+ stem cell doses (5.22 vs 5.85 x 10e6/kg, p=0.0026) were protective against ES. Age greater than 65 was associated with increased 15 day post ASCT incidence of ES (HR-1.903, 95% CI, 1.435-2.523, p=<0.0001). There was no PFS (p=0.2996) or OS (p=0.2778) difference between the Evomela group and the Melphalan group. There was a trend towards decreased OS (p=0.0914) among patients with ES, but it was not statistically significant. There was no statistically significant progression difference between ES and non-ES groups (p=0.9739). Conclusion: Patients conditioned with Evomela are significantly more likely to develop ES than patients conditioned with traditional Melphalan. We were not able to show any survival or progression-free survival advantage for patients treated with Evomela. We would caution the use of Evomela in patients with other risk factors for ES. More studies are needed to further understand the differences between Melphalan and Evomela. Disclosures Siegel: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Merck: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Goldberg:Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership. Goy:Hackensack University Medical Center, RCCA: Employment; Takeda: Other: Grants outside of the submitted work; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding.

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Patients with Relapsed/Refractory Marginal Zone Lymphoma in the MAGNIFY Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance

Blood ◽

10.1182/blood-2020-134363 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-25

Author(s):

Morton Coleman ◽

David Jacob Andorsky ◽

Abdulraheem Yacoub ◽

Jason M. Melear ◽

Suzanne R. Fanning ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Complete Response ◽

Publicly Traded ◽

Advisory Committees ◽

Free Survival ◽

The Past ◽

Genetics Research ◽

Phase Iiib

Background: Relapse is expected when treating patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL), with a shortened response associated with each relapse. Lenalidomide combined with rituximab (R2) has shown enhanced activity, with a recently reported median progression free-survival (PFS) of 39.4 months in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma, including those with FL and MZL (AUGMENT; J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase IIIb trial in patients with R/R FL grades 1-3b, transformed FL (tFL), MZL, or mantle cell lymphoma (MCL; NCT01996865) in which optimal lenalidomide duration is being explored. Patients received 12 cycles of R2 (lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m2 weekly in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11) followed by 1:1 randomization in patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R2 versus rituximab maintenance for 18 months. Data presented here focus on induction R2 in efficacy-evaluable MZL patients compared with the overall population of FL grades 1-3a+MZL (not including FL grade 3b, tFL, or MCL) receiving ≥ 1 treatment with baseline/post-baseline assessments. The primary end point is progression-free survival (PFS) by 1999 International Working Group criteria. Results: As of November 30, 2019, 393 patients with FL grades 1-3a and MZL enrolled; 76 (19%) had MZL. The median age of MZL patients was 68 years (range, 46-90), 68 (89%) had stage III/IV disease, and 72 (95%) had prior rituximab-containing therapy. Overall response rate was 68% with 39% CR/CRu, and median duration of response was 38.6 months (95% CI, 29.4-not reached [NR]). The median PFS was 41.2 months (95% CI, 38.4-NR). Efficacy results for MZL subtypes and the overall population (FL grades 1-3a + MZL) are shown in the table. Forty-two patients (55%) have completed 12 cycles of R2, and 41 (54%) have been randomized and entered maintenance. Twenty-eight patients (37%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs; n = 11; 14%) and progressive disease (n = 6; 8%). The most common (≥ 20%) all-grade AEs were neutropenia (49%), diarrhea (37%), anemia (25%), thrombocytopenia (24%), and constipation (24%). Most common (≥ 10%) grade 3/4 AEs were neutropenia (41%; 1 patient [1%] had febrile neutropenia), thrombocytopenia (13%), and leukopenia (11%). Conclusions: R2 is active with a tolerable safety profile in patients with R/R MZL. The efficacy and safety profile of R2 in MZL patients were similar to results observed in the overall MAGNIFY population. Disclosures Coleman: Seattle Genetics: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Innocare: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; BMS (Celgene Corporation): Research Funding; Eli Lilly and Company: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Ipsen Group: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Novartis Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Boston BIoMedical, Inc.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding. Andorsky:CTI: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Dynavax: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau. Melear:Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Fanning:Takeda: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; TG Therapeautics: Consultancy; Abbvie: Consultancy; Prisma Health: Current Employment; Sanofi Aventis: Speakers Bureau. Kolibaba:Atara Biotech: Consultancy; Compass Oncology: Ended employment in the past 24 months; Verastem: Honoraria; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Novartix: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lansigan:BMS: Consultancy; Seattle Genetics: Consultancy; BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding. Reynolds:IHA Hematology/Oncology Consultants: Current Employment. Nowakowski:Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Curis: Consultancy; Kite: Consultancy; MorphoSys: Consultancy, Research Funding; Denovo: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; Celgene/BMS: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Gharibo:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Bayer: Ended employment in the past 24 months. Ahn:BMS: Current Employment, Current equity holder in publicly-traded company. Li:BMS: Current Employment, Current equity holder in publicly-traded company. Rummel:Roche: Honoraria; Amgen GmbH: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Novartis Pharma GmbH: Honoraria. Sharman:BeiGene: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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