Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 1 results.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8003-8003 ◽  
Author(s):  
Philippe Moreau ◽  
Michel Attal ◽  
Cyrille Hulin ◽  
Marie-Christine Béné ◽  
Annemiek Broijl ◽  
...  
Keyword(s):  
Randomized Study ◽  
Final Analysis ◽  
Standard Of Care ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Depth Of Response ◽  
Risk Of Progression ◽  
Grade 3 ◽  
Clinical Trial Information

8003 Background: VTd is a standard of care (SoC) for TE NDMM. CD38 mAb DARA significantly reduced the risk of progression/death and improved CR and MRD-negative rates in relapsed refractory MM or transplant-ineligible NDMM in phase 3 studies. We report the primary and final analysis of Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts 18-65 y were randomized 1:1 to VTd (6 28-day cycles [C; 4 pre-ASCT induction, 2 post-ASCT consolidation] of V 1.3 mg/m2 SC BIW Week [W] 1-2; T 100 mg PO QD; d 40-80 mg/week PO or IV W 1-4 C 1-2, W 1-3 C 3-6) ± DARA (16 mg/kg IV QW C 1-2, Q2W C 3-6). Melphalan 200 mg/m2 was pre-ASCT HDT. The primary endpoint, post-consolidation sCR rate, was assessed at Day [D] 100 post-ASCT. Part 2 (maintenance) is ongoing. Results: A cohort of 1085 pts (D-VTd, 543; VTd, 542) was randomized. The D 100 post-ASCT sCR rate was significantly higher for D-VTd vs VTd (28.9% vs 20.3%; P = 0.0010; Table). At 18.8-mo median follow-up, PFS from first randomization favored D-VTd with HR 0.47 (95% CI, 0.33-0.67; P <0.0001). With median PFS NR in either arm, 18-mo PFS rates were 92.7% vs 84.6% for D-VTd vs VTd. Rates of ≥CR, ≥VGPR, and MRD negativity supported sCR results (Table). OS is immature with 46 deaths on study (D-VTd, 14; VTd, 32; HR, 0.43; 95% CI, 0.23-0.80). The most common (≥10%) grade 3/4 TEAEs (D-VTd/VTd) were neutropenia (27.6%/14.7%), lymphopenia (17.0%/9.7%), stomatitis (12.7%/16.4%), and thrombocytopenia (11.0%/7.4%). In the D-VTd arm, infusion-related reactions occurred in 35.4% of pts. Conclusions: D-VTd in induction prior to and consolidation after ASCT improved depth of response (sCR, ≥CR, and MRD negativity) and PFS with acceptable safety. The favorable benefit-risk profile supports the use of D-VTd in TE NDMM. CASSIOPEIA is the first study to demonstrate clinical benefit of DARA + SoC in TE NDMM. Clinical trial information: NCT02541383. [Table: see text]

Impact of age on efficacy and safety of daratumumab in combination with lenalidomide and dexamethasone (D-Rd) in patients (pts) with transplant-ineligible newly diagnosed multiple myeloma (NDMM): MAIA.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8035-8035
Author(s):  
Saad Zafar Usmani ◽  
Thierry Facon ◽  
Shaji Kumar ◽  
Torben Plesner ◽  
Philippe Moreau ◽  
...  
Keyword(s):  
Dose Intensity ◽  
Standard Of Care ◽  
Newly Diagnosed ◽  
Median Dose ◽  
Phase 3 ◽  
Risk Of Progression ◽  
Grade 3 ◽  
The Impact ◽  
Clinical Trial Information

8035 Background: D-Rd significantly reduced the risk of progression/death by 44% in transplant-ineligible NDMM pts vs Rd in the phase 3 MAIA study. To examine the impact of age on efficacy/safety of D-Rd vs Rd in this population, a subgroup analysis was conducted in pts <75 and ≥75 y of age. Methods: Transplant-ineligible NDMM pts were randomized 1:1 to Rd ± DARA; stratification was based on age (<75 vs ≥75 y), ISS (I, II, III), and region (North America vs Other). Pts received 28-day cycles of either R 25 or 10 mg (based on renal function) PO QD on Days 1-21 and either d 40 or 20 mg (based on age or BMI) PO/IV weekly until progression. In the D-Rd arm, pts received daratumumab 16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter until progression. PFS is the primary endpoint. Results: Among 737 randomized pts (D-Rd, n=368; Rd, n=369), 321 (44%) were ≥75 y of age. For D-Rd vs Rd, relative median dose intensity for R was 79% vs 93% for <75 y subgroup and 66% vs 89% for ≥75 y subgroup, respectively. After median follow-up of 28 mo, significant PFS benefit of D-Rd vs Rd was maintained in both <75 and ≥75 y subgroups (Table). Deeper responses and MRD-negative rate (10-5 threshold) remained higher with D-Rd vs Rd in both subgroups (Table). Most common (≥10%; D-Rd/Rd) grade 3/4 TEAEs in ≥75 y pts were neutropenia (60%/41%), lymphopenia (19%/12%), anemia (16%/22%), pneumonia (15%/10%), leukopenia (12%/6%), and thrombocytopenia (8%/11%). Fewer pts receiving D-Rd vs Rd discontinued treatment due to TEAEs (<75 y: 5% vs 12%; ≥75 y: 10% vs 21%). Conclusions: D-Rd pts received less R vs Rd group regardless of age. Efficacy of D-Rd in <75 and ≥75 y pts was consistent with the ITT population, and D-Rd demonstrated acceptable tolerability regardless of age. Together with the phase 3 ALCYONE study, these studies confirm clinical benefit of daratumumab plus standard-of-care in transplant-ineligible NDMM pts ≥75 y of age. Clinical trial information: NCT02252172. [Table: see text]

CTIM-25. A RANDOMIZED PHASE 3 STUDY OF NIVOLUMAB OR PLACEBO COMBINED WITH RADIOTHERAPY PLUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA WITH METHYLATED MGMT PROMOTER: CHECKMATE 548

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi55-vi56
Author(s):  
Michael Weller ◽  
Michael Lim ◽  
Ahmed Idbaih ◽  
Joachim Steinbach ◽  
Gaetano Finocchiaro ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Final Analysis ◽  
Standard Of Care ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma ◽  
Grade 3 ◽  
Patients Experience ◽  
Methylated Mgmt Promoter

Abstract BACKGROUND Novel therapies are needed in newly diagnosed glioblastoma as nearly all patients experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ), including patients with tumors with methylated MGMT promoter, a positive prognostic factor and predictor of benefit with TMZ. Here, we report the final analysis of progression-free survival (PFS), overall survival (OS), and safety from an international randomized, single-blind phase-3 study of nivolumab (NIVO)+RT+TMZ in patients with newly diagnosed glioblastoma with methylated/indeterminate MGMT promoter (CheckMate 548; NCT02667587). METHODS Patients (N=716) aged ≥ 18y were randomized 1:1 regardless of tumor PD-L1 expression to NIVO (240 mg Q2W×8, then 480 mg Q4W) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 QD during RT, then 4-week break, then 150–200 mg/m2 QD on days 1–5 of every 28-day cycle for 6 cycles) or placebo (PBO)+RT+TMZ. The dual-primary endpoints were PFS by blinded independent central review and OS, both overall and without baseline corticosteroids. RESULTS As of December 22, 2020, median PFS was 10.6 months (95% CI, 8.9–11.8) with NIVO+RT+TMZ and 10.3 months (95% CI, 9.7–12.5) with PBO+RT+TMZ (HR, 1.06 [95% CI, 0.90–1.25]). Median OS was 28.9 months (95% CI, 24.4–31.6) with NIVO+RT+TMZ and 32.1 months (95% CI, 29.4–33.8) with PBO+RT+TMZ (HR, 1.10 [95% CI, 0.91–1.33]). Among patients without baseline corticosteroids, median OS was 31.3 months (95% CI, 28.6–34.8) with NIVO+RT+TMZ and 33.0 months (95% CI, 31.0–35.1) with PBO+RT+TMZ (HR, 1.12 [95% CI, 0.87–1.43]). Grade 3–4 treatment-related adverse events were 52.4% and 33.6% with NIVO+RT+TMZ and PBO+RT+TMZ, respectively. CONCLUSIONS NIVO added to RT+TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated/indeterminate MGMT promoter. No new safety signals were observed with NIVO. The role of immunotherapy in this treatment landscape remains an area for further investigation.

scholarly journals Evidence-Based Minireview: Should all newly diagnosed MM patients receive CD38 antibody–based treatment?

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 259-263
Author(s):  
Charlotte L. B. M. Korst ◽  
Niels W. C. J. van de Donk
Keyword(s):  
Progression Free Survival ◽  
Standard Of Care ◽  
Standards Of Care ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Free Survival ◽  
Depth Of Response ◽  
Cytogenetic Aberrations ◽  
Number Of Patients ◽  
Pretreated Patients

Abstract CD38 antibodies were first evaluated in extensively pretreated patients with multiple myeloma (MM). Currently, there are 3 CD38 antibody–based regimens approved for the treatment of both transplant-eligible (daratumumab plus bortezomib-thalidomide-dexamethasone [D-VTd]) and transplant-ineligible (daratumumab plus lenalidomide-dexamethasone [D-Rd] or daratumumab plus bortezomib-melphalan-prednisone [D-VMP]) patients with newly diagnosed MM (NDMM). The phase 3 studies that evaluated these regimens uniformly showed that the addition of daratumumab to backbone regimens improved the depth of response, which translated into improved progression-free survival and also overall survival in 2 of the studies. Importantly, elderly patients age 75 years or older benefit from these regimens, indicating that these regimens have an acceptable safety profile. Although the number of patients with high-risk cytogenetics was relatively small, these patients also experienced benefit from the addition of daratumumab to standard-of-care regimens, but poor risk conferred by the cytogenetic aberrations is not completely abrogated. Altogether, daratumumab-based regimens have high anti-MM activity and a favorable toxicity profile and therefore represent new standards of care for patients with NDMM.

First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: Updated results of KEYNOTE-021 cohort G.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9094-9094 ◽  
Author(s):  
Vassiliki Papadimitrakopoulou ◽  
Shirish M. Gadgeel ◽  
Hossein Borghaei ◽  
Leena Gandhi ◽  
Amita Patnaik ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
First Line ◽  
End Point ◽  
Background Data ◽  
Risk Of Progression ◽  
Grade 3 ◽  
Clinical Trial Information ◽  
Nonsquamous Nsclc ◽  
Radiologic Progression

9094 Background: Data from the randomized, phase 2 cohort G of KEYNOTE-021 (NCT02039674) showed that adding pembro to first-line CP in patients (pts) with advanced nonsquamous NSCLC significantly improved the primary end point of ORR (55% vs 29%, P = 0.0016) and the key secondary end point of PFS (HR 0.53, P= 0.0102) compared with CP alone and had a manageable safety profile (grade 3-4 treatment-related AEs, 39% vs 26%; treatment-related AEs leading to discontinuation, 10% vs 13%). We present updated efficacy for cohort G based on 5 mo additional follow-up. Methods: 123 pts with stage IIIB/IV, chemotherapy-naive, nonsquamous NSCLC and no EGFR mutation or ALK translocation were randomized to 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m2 Q3W ± 24 mo of pembro 200 mg Q3W; maintenance pemetrexed was permitted in both arms. Eligible pts in the CP arm who had radiologic progression could crossover to pembro monotherapy. Response was assessed per RECIST v1.1 by blinded, independent central review. All Pvalues are nominal. Results: As of Dec 31, 2016, median follow-up was 14.5 mo (range, 0.8-24.0). 36 of 48 pts (75.0%) in the CP arm who discontinued CP received subsequent anti–PD-1 or PD-L1 therapy. There was 1 additional response in each arm, and ORR was 56.7% (95% CI 43.2%-69.4%) with pembro + CP vs 30.2% (95% CI 19.2%-43.0%) with CP ( P = 0.0016). Median DOR was not reached for pembro + CP (range, 1.4+ to 18.6+ mo) and was 16.2 mo (range, 2.8 to 20.7+) for CP alone. PFS remained longer with pembro + CP (HR 0.49, 95% CI 0.29-0.83, P = 0.0035; median [95% CI] NR [9.7 mo-NR] vs 8.9 mo [6.2-10.3]; 12-mo estimate, 56% vs 34%). With 16 deaths in the pembro + CP arm and 23 deaths in the CP arm, HR for OS was 0.69 (95% CI 0.36-1.31, P= 0.13). Median OS was not reached in either arm; at 12 mo, estimated OS was 76% in the pembro + CP arm and 69% in the CP alone arm. Conclusions: With 5 mo additional follow-up, first-line pembro + CP continues to provide a substantial, clinically relevant improvement in efficacy over CP alone in pts with advanced nonquamous NSCLC, including an almost doubled ORR, halved risk of progression or death, and a trend toward improved OS despite a 75.0% crossover rate in the CP arm. Clinical trial information: NCT02039674.

Daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (RRMM): Efficacy and safety update (CASTOR).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8036-8036 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Katja C. Weisel ◽  
Maria-Victoria Mateos ◽  
Vania Hungria ◽  
Markus Munder ◽  
...  
Keyword(s):  
Residual Disease ◽  
Randomized Study ◽  
Safety Data ◽  
Efficacy And Safety ◽  
Depth Of Response ◽  
Common Grade ◽  
Previously Treated ◽  
Grade 3 ◽  
Line Of Therapy

8036 Background: Daratumumab (D), a human, CD38-targeting mAb, is well tolerated and induces deep and durable responses in patients (pts) with RRMM. We provide an update of CASTOR (NCT02136134), a multicenter, phase 3, randomized study of DVd vs Vd in RRMM. Methods: All pts received ≥1 prior line of therapy (LOT) and were administered 8 cycles (Q3W) of Vd (1.3 mg/m2 SC bortezomib on days 1, 4, 8, and 11; 20 mg PO/IV dexamethasone on days 1-2, 4-5, 8-9, and 11-12) ± D (16 mg/kg IV once weekly in Cycles 1-3, every 3 weeks for Cycles 4-8, then every 4 weeks until progression). Bortezomib-refractory pts were ineligible. Minimal residual disease (MRD) was assessed upon suspected CR and at 6 and 12 months following the first dose at sensitivities of 10–4, 10–5, and 10–6using the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA). Results: Pts received a median (range) of 2 (1-10) prior LOTs. 66% were previously treated with bortezomib and 21% were refractory to lenalidomide in their last prior LOT. After a median follow-up of 13.0 months, PFS was significantly prolonged with DVd vs Vd (median: not reached vs 7.1 months; HR, 0.33; 95% CI, 0.26-0.43; P< 0.0001). This PFS benefit was seen regardless of number of prior LOTs received, with greatest benefit observed in 1 prior line pts (median: not reached vs 7.9 months; HR, 0.22; 95% CI, 0.14-0.34; P< 0.0001). ORR was also significantly higher for DVd vs Vd (84% vs 63%), along with ≥VGPR (62% vs 29%) and ≥CR (26% vs 10%; P< 0.0001 for all). MRD-negative rates were ≥4-fold higher at all three sensitivity thresholds with DVd vs Vd (10% vs 2% at 10–5 threshold). Pts who achieved MRD negativity demonstrated prolonged PFS compared with MRD-positive pts. 37 (15%) and 58 (24%) deaths were observed in DVd vs Vd, respectively, and follow up is ongoing. The most common grade 3/4 TEAE was thrombocytopenia (45% vs 33%). Updated efficacy and safety data will be presented. Conclusions: DVd provided significant benefits with respect to PFS, ORR, depth of response, and MRD-negative rate vs Vd. No new safety signals were reported. These data continue to support the use of DVd in RRMM pts and indicate that pts with 1 prior LOT will derive the most benefit. Clinical trial information: NCT02136134.

Randomized study evaluating trifluridine/tipiracil (TAS-102) versus + trifluridine/tipiracil + bevacizumab as last-line therapy in patients with chemorefractory unresectable metastatic colorectal cancer (mCRC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 637-637 ◽  
Author(s):  
Per Pfeiffer ◽  
Mette Yilmaz ◽  
Sören Möller ◽  
Line Maltha ◽  
Merete Krogh ◽  
...  
Keyword(s):  
Task Force ◽  
Day Treatment ◽  
Randomized Study ◽  
Progression Free Survival ◽  
Inclusion Criteria ◽  
Free Survival ◽  
Small Phase ◽  
Grade 3 ◽  
Clinical Trial Information

637 Background: Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) is approved for the use in patients with chemorefractory mCRC. Inspired by the encouraging results of a small phase I/II study, C-TASK FORCE, evaluating the combination of FTD/TPI and bevacizumab in chemorefractory mCRC patients (Kuboki et al, 2017), we designed the present randomized trial. Methods: This randomized study enrolled as planned 80 mCRC patients. The main inclusion criteria were: histologically confirmed and chemorefractory mCRC; PD during or after therapy with fluoropyrimidine, irinotecan, oxaliplatin, EGFR-inhibitor (RAS wildtype), and bevacizumab was optional; PS 0-1. In arm A, FTD/TPI was administered orally at the dose of 35 mg/m²/dose bid from day 1 to day 5 and from day 8 to day 12 and in arm B the same dose of FTD/TPI was combined with bevacizumab at a dose of 5 mg/kg on day 1 and on day 15 of a 28-day treatment cycle. The primary endpoint was to increase progression-free survival (PFS) from 1.8 months to 3.8 months. Secondary objectives included overall survival (OS) and safety. Results: Eighty patients with chemorefractory mCRC were randomized from September 2017 to August 2018. The median PFS was significantly improved from 2.6 months (arm A) to 5.9 months (arm B) with a hazard ratio (HR) 0.51 (95% CI, 0.28 to 0.92; P < 0.03) and median OS was significantly improved from 7.3 months (arm A) to 10.3 months (arm B) with HR 0.42 (95% CI, 0.18 to 0.99; P < 0.05). After median follow-up for OS of 5.6 months, 57 patients were alive at September 7th, 2018. Therapy was well tolerated with adverse events as expected, patients receiving FTD/TPI + bevacizumab had more grade 3-4 neutropenia (56% in arm B vs 30% in arm A, p = 0.03) and three patients in arm B (vs zero in arm A ) developed febrile neutropenia. SAEs were observed in 13 (arm A) and 11 patients (arm B), respectively. Conclusions: In patients with chemorefractory mCRC, FTD/TPI + bevacizumab, as compared with FTD/TPI monotherapy, was associated with a significant and clinical relevant improvement in PFS and OS with tolerable toxicity. Clinical trial information: 2016-005241-23.

SWOG S1216: A phase III randomized trial comparing androgen deprivation therapy (ADT) plus TAK-700 with ADT plus bicalutamide in patients (pts) with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) (NCT01809691).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5001-5001
Author(s):  
Neeraj Agarwal ◽  
Catherine Tangen ◽  
Maha H. A. Hussain ◽  
Shilpa Gupta ◽  
Melissa Plets ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Performance Status ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Meaningful Improvement ◽  
Intention To Treat ◽  
Grade 3

5001 Background: Tak is an oral selective nonsteroidal 17, 20-lyase inhibitor that blocks the synthesis of gonadal and adrenal androgens. We evaluated the clinical benefit of Tak with ADT in pts with newly diagnosed mHSPC. Methods: Pts with mHSPC with a Zubrod performance status (PS) of 0-2 and a PSA of ≥ 2 ng/ml were randomized 1:1 to ADT+Tak (300 mg twice daily) or ADT+Bic (50 mg daily). Stratification factors included PS (0-1 vs ≥2), extent of disease (minimal vs extensive), and receipt of ADT prior to registration (yes vs no). The primary endpoint was overall survival (OS). Secondary endpoints were progression free survival (PFS; based on PSA, imaging or clinical progression), PSA at 7 months (≤0.2 vs 0.2 < PSA; ≤-4 vs. > 4 ng/ml) and adverse event (AE) profile. With 2.75 yrs to accrue 1,186 eligible pts and 3 additional yrs of follow-up, we would have 90% power to determine a 33% improvement in OS from 54 to 72 mos (1-sided α = 0.025). A final analysis was pre-specified after 523 deaths using a 1-sided α = 0.022 to account for interim analyses. Results: Between 3/2013 and 7/2017, 1,313 pts were randomized and 1,279 were included in the intention-to-treat (ITT) analysis (32 pts were ineligible and 2 pts withdrew consent). Median age was 68 yrs and 10% of subjects were Black. Median PSA was 30 ng/mL (range 2-6710) and 49% of pts had extensive disease. After a median follow-up of 4.9 yrs, PFS and PSA response were significantly improved with Tak over Bic but no significant improvement in OS was observed (Table). More grade 3/4 AEs occurred in Tak vs. Bic arms (43% vs. 14%), and included hypertension (20% vs. 5%) and fatigue (5% vs. 2%). Five pts in Tak and 1 pt in the Bic arm had grade 5 AE. Conclusions: Despite clinically meaningful improvement in various outcome measures with Tak+ADT over Bic+ADT in this representative population of mHSPC, the improvement in OS did not meet the pre-specified criteria for statistical significance. The median OS of 70 mos in the control arm (standard ADT) was higher than that reported in contemporary phase 3 trials in this setting, and 16 mos higher than originally estimated. This trial sets a new landmark for survival estimates when pts with mHSPC have access to multiple approved subsequent life-prolonging therapies. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820; U10CA180821; and in part by Millennium Pharmaceuticals, Inc. (Takeda Pharmaceutical Company LTD) Clinical trial information: NCT01809691. [Table: see text]

Safety and efficacy of daratumumab-based regimens in elderly (≥75 y) patients (Pts) with relapsed or refractory multiple myeloma (RRMM): Subgroup analysis of POLLUX and CASTOR.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8033-8033 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Andrew Spencer ◽  
Ajay K. Nooka ◽  
Ludek Pour ◽  
Katja C. Weisel ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Phase 3 ◽  
Safety And Efficacy ◽  
Common Grade ◽  
Grade 3 ◽  
Line Of Therapy ◽  
Experienced Grade ◽  
Clinical Trial Information

8033 Background: Daratumumab (D) plus lenalidomide and dexamethasone (Rd; POLLUX) or with bortezomib and dexamethasone (Vd; CASTOR) demonstrated prolonged PFS and tolerability compared with Rd and Vd alone, respectively, in RRMM pts. We examined the safety and efficacy profiles of DRd and DVd in elderly (≥75 y) pts from these phase 3 studies. Methods: Pts with ≥1 prior line of therapy were enrolled. All pts in POLLUX were treated until progression; CASTOR pts received 8 cycles of Vd ± daratumumab. Different D (16 mg/kg) dosing schedules were used in POLLUX (qw for cycles 1-2, q2w for cycles 3-6, and q4w thereafter) and CASTOR (qw in Cycles 1-3, q3w for Cycles 4-8, and q4w thereafter). Elderly pts received a reduced dexamethasone dose (20 mg once weekly). Results: In POLLUX, 29/286 (DRd) and 35/283 (Rd) were ≥75 y, with 86% and 91% having ECOG status ≤1, respectively. With 17.3 months of median follow up, 10% in DRd and 11% in Rd discontinued due to treatment-emergent adverse events (TEAEs). Common (>10%) grade 3/4 TEAEs for DRd included neutropenia and hypokalemia (Table). Twelve (41%) DRd pts experienced infusion-related reactions (IRR) and 4 (14%) experienced grade 3/4 IRR; none discontinued due to IRR. Median PFS was not reached (NR) in DRd vs 11.4 months in Rd (HR 0.19; 95% CI, 0.06-0.55; P=0.0007), and ≥CR % was significantly higher with DRd vs Rd (52% vs 9%; P=0.0002). In CASTOR, 23/251 (DVd) and 35/247 (Vd) were ≥75 y, with 100% and 94% having ECOG status ≤1, respectively. With 13.0 months of median follow up, rates of discontinuation due to TEAEs were similar (15% vs 20%). Thrombocytopenia, fatigue, and pneumonia were common grade 3/4 TEAEs for DVd (Table). Thirteen (65%) pts reported IRR (10% grade 3/4) and no pts discontinued due to IRR. Median PFS was NR in DVd vs 8.1 months in Vd (HR 0.27; 95% CI, 0.12-0.61; P=0.0007), and significantly higher ≥CR % was observed in DVd vs Vd (25% vs 3%; P=0.0154). Conclusions: The safety and efficacy profiles in elderly pts were generally comparable with the overall population in each study. Clinical trial information: NCT02136134 and NCT02076009. [Table: see text]

Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients (pts) with newly diagnosed multiple myeloma (MMY1001): An open-label, phase 1b study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8000-8000 ◽  
Author(s):  
Andrzej J. Jakubowiak ◽  
Ajai Chari ◽  
Sagar Lonial ◽  
Brendan M. Weiss ◽  
Raymond L. Comenzo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Safety Profile ◽  
Standard Of Care ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Open Label ◽  
Frontline Treatment ◽  
Grade 3

8000 Background: DARA in combination with established standard of care regimens prolongs PFS, deepens responses, and demonstrates a favorable safety profile in relapsed or refractory multiple myeloma (MM). The tolerability and efficacy of DARA-KRd in newly diagnosed MM pts was examined. Methods: Newly diagnosed pts regardless of transplantation eligibility were enrolled. Pts received DARA 16 mg/kg QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter. All pts received the 1st dose of DARA split over 2 days. Carfilzomib (K) was administered on Days 1, 8 and 15 of each 28-day cycle (20 mg/m2 on C1D1, 36 or 70 mg/m2 subsequently based on tolerability of first dose) for ≤13 cycles or elective discontinuation for ASCT. Lenalidomide 25 mg was given on Days 1-21 and dexamethasone 20-40 mg per week. The primary endpoint was tolerability. Results: Twenty-two pts (median [range] age, 60 [34-74] y) were enrolled and received a median of 8 (1-10) treatment cycles. Nineteen pts escalated K dose to 70 mg/m2 by C1D15. Median (range) duration of follow-up was 7.4 (4.0-9.3) months. Six (27%) pts discontinued treatment (1 AE [pulmonary embolism]; 1 PD; 4 other [ASCT]). Serious AEs occurred in 46% of pts, and 14% were possibly related to DARA; 18 (82%) experienced a grade 3/4 TEAE. The most common grade 3/4 TEAEs (>10%) were lymphopenia (50%) and neutropenia (23%); 1 (5%) cardiac grade 3 TEAE was observed (congestive heart failure) which resolved; pt quickly resumed study treatment with reduced K dose. No grade 5 TEAE was reported. All DARA-associated infusion reactions (27% of pts) were grade ≤2. Treatment with DARA-KRd yielded an ORR (≥partial response) of 100% (5% complete response, 86% ≥very good partial response) in 21 response-evaluable pts. The 6-month PFS rate was 100%. Conclusions: The addition of DARA to KRd was well tolerated; the overall safety profile was consistent with that previously reported for KRd, with no additional toxicity observed with the addition of DARA. Deep and durable responses were observed. These data support further investigation of DARA-KRd as a frontline treatment regimen. Updated data will be presented based on longer follow up. Clinical trial information: NCT01998971.

scholarly journals Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial

Blood ◽  
2020 ◽  
Vol 136 (8) ◽  
pp. 936-945 ◽  
Author(s):  
Peter M. Voorhees ◽  
Jonathan L. Kaufman ◽  
Jacob Laubach ◽  
Douglas W. Sborov ◽  
Brandi Reeves ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Depth Of Response ◽  
Grade 3 ◽  
Intent To Treat

Abstract Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10−5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P &lt; .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.

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