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

Ella Willenbacher; Andrea Brunner-Veber; Roman Weger; Wolfgang Willenbacher

doi:10.1182/blood.v128.22.5659.5659

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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Improved Progression-Free Survival (PFS) of Alemtuzumab (Campath®, MabCampath®) Plus Fludarabine (Fludara®) Versus Fludarabine Alone as Second-Line Treatment of Patients with B-Cell Chronic Lymphocytic Leukemia: Preliminary Results From a Phase III Randomized Trial.

Blood ◽

10.1182/blood.v114.22.537.537 ◽

2009 ◽

Vol 114 (22) ◽

pp. 537-537 ◽

Cited By ~ 2

Author(s):

Andreas Engert ◽

Liana Gercheva ◽

Tadeusz Robak ◽

Pilipenko Galina ◽

Jingyang Wu ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Second Line ◽

Second Line Therapy ◽

Advisory Committees ◽

Free Survival ◽

Line Therapy

Abstract Abstract 537 Introduction: Single-arm pilot and Phase II trial data suggested that the combination of fludarabine and alemtuzumab (FluCam) may improve outcome for patients (pts) with relapsed or refractory chronic lymphocytic leukemia (CLL). To validate these observations, a Phase III, multicenter, open-label, randomized study was conducted to compare the efficacy and safety of FluCam vs. fludarabine (Flu) alone as second-line therapy for pts with relapsed or refractory CLL. Methods: Patients with Rai Stages I-IV were randomized to FluCam or Flu using the minimization method to ensure a balance between treatment arms by study center, Rai stage, disease status, age, sex, prior Flu therapy, and maximum lymph node (LN) size. FluCam was administered in Phases A and B. Patients received escalating doses of intravenous (IV) alemtuzumab alone (Phase A). Once alemtuzumab 30 mg IV was tolerated, pts received FluCam as Flu 30 mg/m2 IV followed immediately by alemtuzumab 30 mg IV on days 1-3 of a 28 day cycle (Phase B). In the Flu arm, pts received 25 mg/m2IV on days 1-5 of a 28 day cycle. For both arms, all pts could receive up to six cycles depending on response and toxicity. All pts received prophylaxis with trimethoprim/sulfamethoxazole DS and famciclovir until CD4+ counts were ≥200 cells/μL. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response (OR), complete response (CR), overall and 3 year survival, and safety. The primary analysis was based on the independent response review panel's (IRRP) assessment of response and date of progression for each patient. Two interim analyses were prospectively planned and conducted by the data and safety monitoring board (DSMB) with the final analysis planned after a total of 190 events. The 2nd interim analysis included 139 PFS events and met the pre-specified criteria; the DSMB recommended early study termination. Results: 335 pts were randomized (FluCam n=168 and Flu n=167); Rai Stage III-IV: 37%; median age: 60 years; prior Flu therapy: 20% and maximum LN size ≥5 cm: 14%. The median treatment cycles received were 6 for both arms. 60% of FluCam and 64% of Flu pts received 6 cycles of treatment. The median IRRP determined PFS for FluCam was significantly prolonged compared to Flu (29.6 months vs. 20.7 months, respectively; p=0.005; HR 1.63 [95% CI: 1.16, 2.28]; Figure 1). Median PFS by Rai Stage was: Stage I-II - 27.4 months for FluCam (n = 105) vs. 21.3 months for Flu (n = 103), p=0.215; Stage III-IV - 26.1 months for FluCam (n = 61) vs. 12.1 months for Flu (n = 62), p=0.003. Per investigator response assessment, FluCam resulted in significantly higher OR and CR rates (OR: FluCam 84.8% vs. Flu 67.9%, p<0.001; and CR: FluCam 30.4% vs. Flu 16.4%, p=0.002). The IRRP assessment of response was not completed for all pts and is not availabel for the 2nd interim analysis. No differences in survival have been observed (FluCam 37 deaths and Flu 41 deaths) with a median follow up of 17 months. Adverse events (AEs) occurring in >10% of the pts included pyrexia, neutropenia, leukopenia, thrombocytopenia, anemia, chills, lymphopenia, rash, infusion related reactions, nausea and urticaria in the FluCam arm; and, neutropenia, thrombocytopenia, anemia and leukopenia in the Flu arm. Treatment-emergent grade 3/4 thrombocytopenia (18% vs. 22%), neutropenia (60% vs. 66%) and anemia (13% vs. 22%) were comparable in FluCam vs. Flu arms. Overall, 33% (n=54) of pts in the FluCam arm experienced a SAE vs. 26% (n=42) in the Flu arm. Reported SAEs for neutropenia were 4.9% in the FluCam arm and 1.8% in the Flu arm; however, febrile neutropenia was similarly reported in the two arms 3.7% vs 3.6% of pts, respectively. Infections including CMV occurred in 47% and 35% of the FluCam and Flu pts, respectively. Symptomatic CMV infection occurred only in the FluCam arm in 8% of pts, of which 1% were SAEs and 0% classified as grade 4 or higher. Deaths occurring on therapy or within 30 days after last dose were 2% on the FluCam arm vs. 5% on the Flu arm. Conclusions: The 2ndinterim analysis indicates that the combination of FluCam is superior to Flu as second-line therapy for pts with relapsed or refractory CLL, including those with advanced disease stage. With significantly longer PFS, higher OR and CR rates, an acceptable safety profile and a convenient administration regimen, FluCam may be an additional second-line treatment option for pts with relapsed or refractory CLL. Disclosures: Engert: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Alemtuzumab (Campath, MabCampath) is indicated for the treatment of CLL. This trial examined the use of alemtuzumab in combination with fludarabine monophospate.. Gercheva:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Robak:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Galina:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wu:Genzyme Corporation: Employment. Sirard:Genzyme Corporation: Employment. Elter:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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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

Blood ◽

10.1182/blood-2021-152034 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1663-1663

Author(s):

Rose Turner ◽

Hang Quach ◽

Noemi Horvath ◽

Ian H Kerridge ◽

Flora Yuen ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Progressive Disease ◽

Progression Free Survival ◽

Publicly Traded ◽

Advisory Committees ◽

Free Survival ◽

Depth Of Response

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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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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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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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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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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Daratumumab, Bortezomib and Dexamethasone Versus Bortezomib and Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma Based on Prior Treatment Exposure: Updated Efficacy Analysis of Castor

Blood ◽

10.1182/blood.v128.22.3313.3313 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3313-3313 ◽

Cited By ~ 5

Author(s):

Asher A. Chanan-Khan ◽

Suzanne Lentzsch ◽

Hang Quach ◽

Noemi Horvath ◽

Marcelo Capra ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Employment Equity ◽

Advisory Committees ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Equity Ownership ◽

Line Of Therapy

Abstract Introduction: Daratumumab is a human CD38 IgGκ monoclonal antibody that demonstrated significant activity and a manageable safety profile in combination with bortezomib and dexamethasone. In a randomized phase 3 study, daratumumab in combination with bortezomib and dexamethasone (DVd) significantly prolonged progression-free survival (PFS) versus bortezomib and dexamethasone alone (Vd) in a pre-specified interim analysis of patients (pts) with relapsed or refractory multiple myeloma (RRMM; Palumbo A. N Engl J Med 2016; in press). Herein, we examine subgroups from this study to compare the efficacy of DVd vs Vd in bortezomib-naive and bortezomib-experienced pt populations. In addition, the efficacy of DVd vs Vd in pts who were refractory to lenalidomide at last prior line of therapy was also evaluated. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to 8 cycles (q3w) of Vd (bortezomib: 1.3 mg/m2 SC on Days 1, 4, 8, 11; dexamethasone: 20 mg PO on Days 1, 2, 4, 5, 8, 9, 11, 12) with or without daratumumab (16 mg/kg IV qw in Cycles 1-3, Day 1 of Cycles 4-8, then q4w until progression). Pts who were refractory to bortezomib were not eligible. The primary endpoint was PFS. Bone marrow aspirate samples that had been prepared with Ficoll were evaluated for minimal residual disease (MRD) using three different thresholds (10-4, 10-5, and 10-6) based on the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA, USA). Results: Median follow-up was 7.4 months. Among bortezomib-naive pts (DVd, n=89; Vd, n=83), PFS was significantly improved with DVd vs Vd (median: not reached [NR] vs 7.5 months; HR, 0.25; 95% CI, 0.13-0.47; P<0.0001); estimated 12-month PFS rates were 72% vs 28%, respectively. ORR was 88% with DVd vs 70% with Vd (P=0.0040), with ≥very good partial response (VGPR) rates of 72% vs 42% (P<0.0001), and ≥complete response (CR) rates of 30% vs 20% (P=0.1199), respectively. For pts who previously received a bortezomib-containing regimen (DVd, n=162; Vd, n=164), PFS was also significantly longer with DVd vs Vd (median: 12.3 vs 6.7 months; HR, 0.46; 95% CI, 0.32-0.66; P<0.0001). Estimated 12-month PFS rates were 55% vs 27%, respectively. ORR was significantly higher with DVd vs Vd (80% vs 60%; P=0.0001), along with significantly higher rates of ≥VGPR (52% vs 22%; P<0.0001) and ≥CR (13% vs 3%; P=0.0019). Among pts who were refractory to lenalidomide at the last prior line of therapy (DVd, n=45; Vd, n=60), PFS was significantly longer in DVd vs Vd (median: 10.3 vs 4.4 mo; HR, 0.37; 95% CI, 0.21-0.65; P=0.0004; Figure). Within this subgroup, ORR was significantly higher for DVd vs Vd (81% vs 50%; P=0.0021), and the same trends were observed for rates of ≥VGPR (54% vs 12%; P<0.0001) and ≥CR (20% vs 5%; P=0.0261). Updated efficacy and safety data, including MRD analyses across different sensitivity thresholds (10-4, 10-5, and 10-6), will be presented at the meeting. Conclusions: These analyses confirm that addition of daratumumab to Vd significantly improves outcomes for RRMM pts regardless of prior treatment with bortezomib. Importantly, this treatment benefit of DVd vs Vd was maintained in pts who were refractory to lenalidomide at the last prior line of therapy. These data lend further support to adding daratumumab to a standard-of-care regimen in RRMM. Figure Progression-free Survival in Patients Refractory to Lenalidomide at the Last Prior Line of Therapy Figure. Progression-free Survival in Patients Refractory to Lenalidomide at the Last Prior Line of Therapy Disclosures Lentzsch: BMS: Consultancy; Foundation One: Consultancy; Celgene: Consultancy, Honoraria. Quach:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Ovilla:Janssen: Consultancy. Qi:Janssen: Employment. Deraedt:Janssen: Employment, Equity Ownership. Schecter:Janssen: Employment, Equity Ownership. Amin:Janssen: Employment. Qin:Janssen: Employment. Casneuf:Johnson & Johnson: Equity Ownership; Janssen R&D, Beerse, Belgium: Employment. Chiu:Janssen: Employment. Sasser:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals R&D: Employment. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.

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Long-Term Efficacy and Safety (27 months) of the Biosimilar CT-P10 in Patients with Low Tumor Burden Follicular Lymphoma

Blood ◽

10.1182/blood-2020-135999 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-28

Author(s):

Larry W Kwak ◽

Juan Manuel Sancho ◽

Seok-Goo Cho ◽

Hideyuki Nakazawa ◽

Junji Suzumiya ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Time To Progression ◽

Advisory Committees ◽

Free Survival ◽

Travel Costs ◽

Single Transition ◽

Second Year

We assessed long-term safety and efficacy of CT-P10 and rituximab in patients with newly diagnosed low-tumour-burden follicular lymphoma (LTBFL), and following a single transition from rituximab to CT-P10. This double-blind, parallel-group, active-controlled phase 3 trial randomized patients with CD20+ LTBFL to receive CT-P10 or US-sourced rituximab (375 mg/m2 intravenous). Induction therapy (weekly for 4 cycles) was followed by a 2-year maintenance period for patients achieving disease control (CR, CRu, PR and SD). During the maintenance, CT-P10 or rituximab were administered every 8 weeks (6 cycles) in the first year and additional CT-P10 was administered every 8 weeks (6 cycles) in the second year. Secondary endpoints (reported here) were overall response rate during the study period, progression-free survival, time-to-progression, and overall survival. Safety and immunogenicity were also evaluated over the study period. Between Nov 9, 2015 and Jan 4, 2018, 258 patients were randomised (130 CT-P10; 128 rituximab). Over the study period, 115 (88%; CT-P10) and 111 (87%; rituximab) patients achieved overall response. At a median follow-up of 29·2 months (IQR: 26·1-33·7), median progression-free survival, time-to-progression, and overall survival were not estimable. The KM estimates (95% CI) for OS at 36 months were 98% (93-99) and 97% (89-99) in the CT-P10 and rituximab groups, respectively. Corresponding values for PFS were 80% (70-87) and 68% (54-79), while results for TTP were 82% (72-88) and 68% (54-79) in the CT-P10 and rituximab groups, respectively. (Figure A. OS; Figure B. PFS and Figure C. TTP) Over the study period, 114 (88%) and 104 (81%) patients in the CT-P10 and rituximab groups, respectively, experienced at least one treatment-emergent adverse event (TEAE) and 14 (11%) patients in each group experienced TE-serious adverse events (TESAEs). There were no unexpected safety findings observed during the second year of the maintenance period after single transition from rituximab to CT-P10. Figure 1 Disclosures Kwak: Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Xeme Biopharma/Theratest: Other: equity; CJ Healthcare: Consultancy; Sellas Life Sciences Grp: Consultancy; Enzychem Life Sciences: Membership on an entity's Board of Directors or advisory committees; Antigenics: Other: equity; InnoLifes, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pepromene Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Consultancy. Sancho:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gelgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Menne:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Speakers Bureau; Novartis: Honoraria, Other: Travel costs, Speakers Bureau; Pfizer: Honoraria, Other: Travel costs, Speakers Bureau; Celgene: Honoraria, Other: Travel grants; Roche: Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Astra Zeneca: Research Funding; Takeda: Honoraria, Speakers Bureau. Jurczak:Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Acerta: Research Funding; Bayer: Research Funding; Janssen: Research Funding; MeiPharma: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Trneny:Gilead: Consultancy, Honoraria, Other: Travel Expenses; Janssen: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb Company: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel Expenses. Ogura:Cellgene: Honoraria; Chugai: Honoraria; Denovo Biopharma: Membership on an entity's Board of Directors or advisory committees; MejiSeika Pharma: Membership on an entity's Board of Directors or advisory committees; Mundi Pharma: Membership on an entity's Board of Directors or advisory committees; SymBio: Membership on an entity's Board of Directors or advisory committees; TevaTakeda: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Membership on an entity's Board of Directors or advisory committees. Kim:Pfizer: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; F. Hoffmann-La Roche: Research Funding; Kyowa Kirn: Research Funding; Celltrion: Research Funding; JJ: Research Funding. Lee:Celltrion, Inc.: Current Employment. Kim:Celltrion, Inc.: Current Employment. Ahn:Celltrion, Inc.: Current Employment. Buske:Roche, Janssen, Bayer, MSD: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen, AbbVie, Pfizer, Celltrion: Honoraria, Speakers Bureau. OffLabel Disclosure: Rituximab monotherapy to LTBFL patients

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Progressive but Previously Untreated CLL Patients with Greater Array CGH Complexity Exhibit A Less Durable Response to Chemoimmunotherapy

Blood ◽

10.1182/blood.v116.21.2406.2406 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2406-2406

Author(s):

Neil E. Kay ◽

Jeanette Eckel Passow ◽

Esteban Braggio ◽

Scott Van Wier ◽

Tait Shanafelt ◽

...

Keyword(s):

Clinical Outcome ◽

Board Of Directors ◽

Copy Number ◽

Research Funding ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Genomic Complexity ◽

Duration Of Response ◽

Gains And Losses

Abstract Abstract 2406 The outcome for a given CLL patient is difficult to predict. While there are promising models, they require collation of multiple clinical and laboratory parameters, and it remains to be seen whether they will apply to typical CLL patients in the community. To further dissect out explanations for this dramatic clinical heterogeneity, we sought to understand genomic complexity of clonal B-cells as a possible explanation of clinical variability with specific application to genomic complexity as a predictor of therapeutic response and clinical outcome in CLL. Thus we wished to identified global gains and losses of genetic material in order to define copy-number abnormalities (CNA) in 48 clinically progressive CLL patients who were about to be treated on a chemoimmunotherapy protocol. This protocol was previously reported by us (Blood. 109:2007) and had an induction phase with pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2) and rituximab (375 mg/m2) given every 3 weeks for 6 cycles and then responding patients were followed ever three months until relapse. In order to estimate CNA, we employed array-based comparative genomic hybridization (aCGH) using a one-million oligonucleotide probe array format on the leukemic B-cells from the 48 patients entering this trial. In those same patients, the aCGH data were compared to a) FISH detecxtable data using a panel for the common recurring genetic defects seen in CLL and b) to their clinical outcome on this trial. With aCGH we found that 288 CNA were identified (median of 4 per patient; range 0–32) of which 215 were deletions and 73 were gains. The aCGH method identified most of the FISH detected abnormalities with a complete concordance for 17p13.1- deletion (17p-) between aCGH and FISH. We also identified chromosomal gain or loss in ≥6% of the patients on chromosomes 3, 8, 9, 10, 11, 12, 13, 14 and 17. We found that CLL patients with ≥15 CNA had a significantly worse progression free survival (PFS) than patients with <15 CNA (p=0.004)(figure). Patients with ≥15 CNA also had a shorter duration of response than those with <15 CNA (p=0.0726). Of interest, more complex genomic features were found both in patients with a 17p13.1 deletion and in more favorable genetic subtypes such as 13q14.1. Thus, for 5 patients with >15 CNAs the following FISH patterns were seen: +12/13q14.1-x1/13q14.1 -x2, 13q14.1 ×1 (n=2), and 17p13.1 (n=2). In addition, a 17p- by FISH was positively associated with the number of CNA and total deletion size. The odds of having an overall response decreased by 28% (95% CI: 5–55%; p=0.015) with each additional CNA for the 17p13.1- patients. In addition to defining genomic complexity as the total number of CNA for each patient, we also defined complexity as the sum of the lengths of all interstitial chromosomal gains and losses. When defined as the total size of chromosomal gains or losses, genomic complexity was significantly associated with 17p13.1 and worse overall clinical response. In summary, this analysis utilized the global assessment of copy number abnormalities using a high-resolution aCGH platform for clinically progressive CLL patients prior to initiation of their treatment. One outcome was that we found higher genomic complexity was associated with shorter progression-free survival, reduced duration of response and predicted a poor response to treatment. In addition since we did find genomic complexity in more traditionally favorable FISH categories, such as 13q14.1 type defects, this may explain why some of the latter patients do not fare as well as might be expected even with aggressive chemoimmunotherapy approaches. This study adds information on the association between inferior trial response and increasing genetic complexity as CLL progresses. Disclosures: Off Label Use: Pentostatin. Kipps: GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding; Memgen: Research Funding; Igenica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Research Funding; Abbott Laboratories: Research Funding.

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