scholarly journals Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Katja Weisel ◽  
Andrew Spencer ◽  
Suzanne Lentzsch ◽  
Hervé Avet-Loiseau ◽  
Tomer M. Mark ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Subgroup Analysis ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Sensitivity Threshold ◽  
Risk Patients ◽  
Poor Outcomes

Abstract Background Multiple myeloma (MM) patients with high cytogenetic risk have poor outcomes. In CASTOR, daratumumab plus bortezomib/dexamethasone (D-Vd) prolonged progression-free survival (PFS) versus bortezomib/dexamethasone (Vd) alone and exhibited tolerability in patients with relapsed or refractory MM (RRMM). Methods This subgroup analysis evaluated D-Vd versus Vd in CASTOR based on cytogenetic risk, determined using fluorescence in situ hybridization and/or karyotype testing performed locally. High-risk patients had t(4;14), t(14;16), and/or del17p abnormalities. Minimal residual disease (MRD; 10−5 sensitivity threshold) was assessed via the clonoSEQ® assay V2.0. Of the 498 patients randomized, 40 (16%) in the D-Vd group and 35 (14%) in the Vd group were categorized as high risk. Results After a median follow-up of 40.0 months, D-Vd prolonged median PFS versus Vd in patients with standard (16.6 vs 6.6 months; HR, 0.26; 95% CI, 0.19-0.37; P < 0.0001) and high (12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21–0.83; P = 0.0106) cytogenetic risk. D-Vd achieved deep responses, including higher rates of MRD negativity and sustained MRD negativity versus Vd, regardless of cytogenetic risk. The safety profile was consistent with the overall population of CASTOR. Conclusion These updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status. Trial registration ClinicalTrials.gov, NCT02136134. Registered 12 May 2014

scholarly journals Daratumumab, lenalidomide, and dexamethasone in relapsed/refractory myeloma: a cytogenetic subgroup analysis of POLLUX

2020 ◽  
Vol 10 (11) ◽  
Author(s):  
Jonathan L. Kaufman ◽  
Meletios A. Dimopoulos ◽  
Darrell White ◽  
Lotfi Benboubker ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Subgroup Analysis ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Free Survival ◽  
Poor Outcomes ◽  
Line Of Therapy

Abstract High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10–5) was assessed via the clonoSEQ® assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk.

Impact of proteasome inhibitor vs. IMiD maintenance therapy on outcomes of patients with high-risk multiple myeloma (HRMM).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20557-e20557
Author(s):  
Eric Leon Tam ◽  
David Joseph Iberri ◽  
Michaela Liedtke ◽  
Lori S. Muffly ◽  
Parveen Shiraz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Maintenance Therapy ◽  
Proteasome Inhibitor ◽  
Post Transplant ◽  
Risk Patients ◽  
To Receive ◽  
Standard Risk

e20557 Background: The ideal choice of maintenance therapy in patients with HRMM high-risk multiple myeloma remains unknown. We analyzed the outcomes of patients with HRMM undergoing transplant receiving different maintenance approaches. Methods: Patients with MM undergoing their first ASCT from 2012-19 within 1 year of diagnosis were identified from the prospectively maintained database of patients undergoing ASCT. HRMM was defined as having t(4;14), t(14;16), t(14;20), del17p13, or gain 1q detected on fluorescent in situ hybridization (FISH). Results: Of the 412 patients undergoing ASCT within 1 year of diagnosis, 333 had FISH data available and of these, 37% (124/333) patients had high-risk cytogenetics. Distribution of HR cytogenetics was as follows: deletion 17p: 37% (n = 46), t(4;14): 27% (n = 34), t(14;16) or t(14;20): 12% (n = 26), gain1q: 31% (n = 41). 9% (n = 12) had more than one HR abnormality. In patients with HRMM, median age at transplant was 59 years (range: 39 to 73), and 61% (n = 103) were males. 64% (n = 107) of high-risk patients received post-transplant maintenance therapy. Maintenance therapy in this group included a proteasome inhibitor (PI) in 34% (n = 29), immunomodulatory drug (IMiD) in 59% (n = 51), or both in 7% (n = 6). There was no difference in baseline characteristics of HRMM patients receiving PI vs. IMiD maintenance, except that patients with del17p were more likely to receive PI maintenance therapy (55% vs 28%, p = 0.01). (Table) After a median follow-up of 3.1 years from diagnosis, patients with HRMM had inferior PFS compared to patients with standard risk disease, with median PFS of 3 vs. 4.8 years, p < 0.001. Amongst the 86 HRMM patients receiving maintenance therapy, median PFS in patients receiving PI vs. IMiD vs. both PI + IMiD maintenance was 3 vs. 3.2 vs. 2.2 years, respectively, log-rank p = 0.7. In the sub-group of patients with 17p deletion, median PFS in the three groups was 3 vs. 2.9 vs. 2.2 years, respectively, log-rank p = 0.7. Conclusions: Patients with HRMM have inferior PFS compared to patients with standard risk disease. We observed similar outcomes in HRMM patients post-transplant regardless of the choice of maintenance therapy. [Table: see text]

Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high-risk cytogenetics: IKEMA subgroup analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8042-8042
Author(s):  
Ivan Spicka ◽  
Philippe Moreau ◽  
Thomas G. Martin ◽  
Thierry Facon ◽  
Gracia Martinez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Subgroup Analysis ◽  
Safety Profile ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Disease Response ◽  
Efficacy Analysis ◽  
New Treatment

8042 Background: A prespecified interim efficacy analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d) (Isa-Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (HR 0.531; 99% CI, 0.318–0.889; P= 0.0007), with a clinically meaningful increase in minimal residual disease negativity (MRD-) (29.6% vs 13.0%) and complete response (CR) (39.7% vs 27.6%) rates, and a manageable safety profile. This subgroup analysis of IKEMA examined efficacy and safety in pts with high-risk cytogenetics [t(4;14), del(17p), and t(14;16)] and/or gain(1q21). Methods: Pts with 1–3 prior lines of therapy were randomized 3:2 to receive Isa-Kd (n = 179) or Kd (n = 123). High-risk cytogenetics was assessed by central laboratory analysis and defined as ≥1 of the following: del(17p): 50% cutoff; t(4;14) or t(14;16): 30% cutoff. Assessment of gain(1q21) was prespecified as ≥3 copies: 30% cutoff. Results: Of the randomized pts, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk cytogenetic abnormality (CA); 26.3% (Isa-Kd) and 25.2% (Kd) had isolated gain(1q21). The addition of Isa to Kd improved PFS for pts with ≥1 high-risk CA and standard-risk pts (Table); pts with t(4;14) (HR 0.549; 95% CI, 0.232–1.301) had a more pronounced treatment effect than pts with del(17p) (HR 0.837; 95% CI, 0.281–2.496). A clear PFS benefit with Isa-Kd was also seen for pts with isolated gain(1q21) and gain(1q21) combined with other high-risk CA (Table). The trend toward improved CR, ≥very good partial response (VGPR), and MRD- rates with the addition of Isa was more pronounced in pts with gain(1q21) than in pts with high-risk CA alone. Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd vs Kd, but the incidence of serious and fatal TEAEs was similar with both arms for high-risk pts (Table). Conclusions: The addition of Isa to Kd improved PFS in pts with high-risk CA and disease response in pts with gain(1q21) isolated or combined with high-risk CA, with a manageable safety profile, consistent with the benefit observed in the overall IKEMA population. Isa-Kd is a potential new treatment option for the difficult-to-treat subgroup of pts with RMM and high-risk cytogenetics. Funding: Sanofi. Clinical trial information: NCT03275285. [Table: see text]

Efficacy and safety of daratumumab, lenalidomide, and dexamethasone (D-Rd) in relapsed or refractory multiple myeloma (RRMM): Updated subgroup analysis of POLLUX based on cytogenetic risk.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8038-8038 ◽  
Author(s):  
Jonathan L. Kaufman ◽  
Meletios A. Dimopoulos ◽  
Merav Leiba ◽  
James Morton ◽  
P. Joy Ho ◽  
...  
Keyword(s):  
High Risk ◽  
Subgroup Analysis ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Significant Efficacy ◽  
Poor Outcomes ◽  
Line Of Therapy ◽  
Next Generation Sequencing Ngs ◽  
Std Risk ◽  
High Median

8038 Background: High-risk cytogenetic abnormalities confer poor outcomes in MM patients (pts). In POLLUX, D-Rd demonstrated significant clinical benefit, including prolonged progression-free survival (PFS) vs lenalidomide and dexamethasone (Rd), and tolerability in RRMM pts. We present a subgroup analysis of POLLUX, based on cytogenetic risk. Methods: Pts had ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of fluorescence in situ hybridization/karyotype testing and next-generation sequencing (NGS). High-risk pts had t(4;14), t(14;16), or del17p abnormalities; standard (std)-risk pts did not meet high-risk criteria. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ® assay V2.0. Results: In POLLUX (D-Rd, n = 286; Rd, n = 283), 17.1% of pts in the D-Rd group and 20.1% of pts in the Rd group had high-risk abnormalities. After 44.3 months (mo) of median follow up, D-Rd prolonged PFS vs Rd in pts with high- (median 26.8 vs 8.8 mo; HR, 0.54 [95% CI, 0.32-0.91]; P = 0.0175) or std-risk (median not reached [NR] vs 19.9 mo; HR, 0.41 [95% CI, 0.31-0.55]; P <0.0001). Responses with D-Rd were deep, including higher rates of MRD negativity and sustained MRD negativity vs Rd (Table). D-Rd prolonged PFS in first relapse pts (high risk: median 46.0 vs 7.3 mo; HR, 0.26 [95% CI, 0.11-0.59]; P = 0.0005; std risk: median NR vs 20.6 mo; HR, 0.43 [95% CI, 0.28-0.66]; P <0.0001) and prolonged PFS2 vs Rd in high- (median 38.3 vs 22.1 mo; HR, 0.53 [95% CI, 0.30-0.93]; P = 0.0249) or std-risk (median NR vs 33.8 mo; HR, 0.53 [95% CI, 0.39-0.72]; P <0.0001) pts. Additional data will be presented. Conclusions: D-Rd demonstrates significant efficacy in high-risk RRMM. Among high-risk pts, MRD negativity was only achieved with D-Rd. Clinical trial information: NCT02076009. [Table: see text]

Efficacy and safety of daratumumab, bortezomib, and dexamethasone (D-Vd) in relapsed or refractory multiple myeloma (RRMM) based on cytogenetic risk: Updated subgroup analysis of CASTOR.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8040-8040 ◽  
Author(s):  
Katja Weisel ◽  
Andrew Spencer ◽  
Suzanne Lentzsch ◽  
Herve Avet-Loiseau ◽  
Tomer M. Mark ◽  
...  
Keyword(s):  
High Risk ◽  
Subgroup Analysis ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Significant Efficacy ◽  
First Relapse ◽  
Poor Outcomes ◽  
Line Of Therapy ◽  
Next Generation Sequencing Ngs ◽  
Std Risk

8040 Background: MM patients (pts) with high cytogenetic risk have poor outcomes. In CASTOR, D-Vd prolonged progression-free survival (PFS) vs bortezomib and dexamethasone (Vd) alone, and exhibited tolerability in RRMM pts. We conducted a subgroup analysis of D-Vd vs Vd in CASTOR, based on cytogenetic risk. Methods: Pts received ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of next-generation sequencing (NGS) and fluorescence in situ hybridization/karyotype testing. High-risk pts had t(4;14), t(14;16), or del17p abnormalities. Standard (std)-risk pts were confirmed negative for all 3 abnormalities. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ assay V2.0. Results: In CASTOR (D-Vd, n = 251; Vd, n = 247), high-risk was confirmed in 26.7% and 25.9% of pts in the D-Vd and Vd groups, respectively. At a median follow up of 40.0 months (mo), D-Vd prolonged PFS vs Vd in pts with high- (median 13.4 vs 7.2 mo; HR, 0.40 [95% CI, 0.24-0.65]; P = 0.0002) or std-risk (median 18.4 vs 6.8 mo; HR, 0.28 [95% CI, 0.20-0.37]; P < 0.0001). Higher rates of ORR, MRD negativity, and sustained MRD negativity were seen with D-Vd vs Vd (Table). D-Vd prolonged PFS in first relapse pts (high risk: median 20.1 vs 8.4 mo; HR, 0.30 [95% CI, 0.14-0.64]; P = 0.0012; std risk: median 32.6 vs 7.9 mo; HR, 0.18 [95% CI, 0.11-0.29]; P < 0.0001) and PFS2 vs Vd (high risk: median 27.9 vs 18.6 mo; HR, 0.59 [95% CI, 0.37-0.94]; P = 0.0258; std risk: median 40.1 vs 21.6 mo; HR, 0.43 [95% CI, 0.32-0.59]; P < 0.0001) regardless of risk. Additional data will be presented. Conclusions: Adding daratumumab to Vd demonstrates significant efficacy in high-risk RRMM. Among high-risk pts, MRD negativity was only achieved with D-Vd. These findings support use of D-Vd for high-risk RRMM. Clinical trial information: NCT02136134. [Table: see text]

Depth of response and minimal residual disease status in ultra high-risk multiple myeloma and plasma cell leukemia treated with daratumumab, bortezomib, lenalidomide, cyclophosphamide and dexamethasone (Dara-CVRd): Results of the UK optimum/MUKnine trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8001-8001
Author(s):  
Martin F. Kaiser ◽  
Andrew Hall ◽  
Katrina Walker ◽  
Ruth De Tute ◽  
Sadie Roberts ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Plasma Cell ◽  
Residual Disease ◽  
Cell Leukemia ◽  
Ultra High Risk ◽  
Grade 3 ◽  
Minimal Residual

8001 Background: Patients with ultra high-risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with plasma cell leukemia (PCL) continue to have dismal outcomes and are underrepresented in clinical trials. Recently, improved responses with anti-CD38 monoclonal antibody combination therapy have been reported for NDMM patients. We report here outcomes for NDMM UHiR and PCL patients treated in the OPTIMUM/MUKnine (NCT03188172) trial with daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction, augmented high-dose melphalan (HDMEL) and ASCT. With final analysis follow-up surpassed in Feb 2021, we report here early protocol defined endpoints from induction to day 100 post ASCT. Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with PCL (circulating plasmablasts > 20%) were included in OPTIMUM across 39 UK hospitals. Patients received up to 6 cycles of Dara-CVRd induction, HDMEL and ASCT augmented with bortezomib, followed by Dara-VR(d) consolidation for 18 cycles and Dara-R maintenance. Primary trial endpoints are minimal residual disease (MRD) status post ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. Data is complete but subject to further data cleaning prior to conference. Results: Median follow-up for the 107 patients in the safety population was 22.2 months (95% CI: 20.6 – 23.9). Two patients died during induction due to infection. Bone marrow aspirates suitable for MRD assessment by flow cytometry (10-5 sensitivity) were available for 81% of patients at end of induction and 78% at D100 post ASCT. Responses in the intention to treat population at end of induction were 94% ORR with 22% CR, 58% VGPR, 15% PR, 1% PD, 5% timepoint not reached (TNR; withdrew, became ineligible or died) and at D100 post ASCT 83% ORR with 47% CR, 32% VGPR, 5% PR, 7% PD, 10% TNR. MRD status was 41% MRDneg, 40% MRDpos and 19% not evaluable post induction and 64% MRDneg, 14% MRDpos and 22% not evaluable at D100 post ASCT. Responses at D100 post ASCT were lower in PCL with 22% CR, 22% VGPR, 22% PR, 22% PD, 12% TNR. Most frequent grade 3/4 AEs during induction were neutropenia (21%), thrombocytopenia (12%) and infection (12%). Grade 3 neuropathy rate was 3.7%. Conclusions: This is to our knowledge the first report on a trial for UHiR NDMM and PCL investigating Dara-CVRd induction and augmented ASCT. Response rates were high in this difficult-to-treat patient population, with toxicity comparable to other induction regimens. However, some early progressions highlight the need for innovative approaches to UHiR NDMM. Clinical trial information: NCT03188172.

scholarly journals Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study

Leukemia ◽  
2020 ◽  
Vol 34 (7) ◽  
pp. 1875-1884 ◽  
Author(s):  
Nizar J. Bahlis ◽  
Meletios A. Dimopoulos ◽  
Darrell J. White ◽  
Lotfi Benboubker ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase ◽  
Intent To Treat ◽  
Line Of Therapy

Abstract In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with ≥1 prior line received Rd (lenalidomide, 25 mg, on Days 1–21 of each 28-day cycle; dexamethasone, 40 mg, weekly) ± daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35–0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10–5; 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31–0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42–0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.

scholarly journals Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma

2021 ◽  
Author(s):  
Meera Mohan ◽  
Samantha Kendrick ◽  
Aniko Szabo ◽  
Naveen K Yarlagadda ◽  
Dinesh Atwal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Clinical Relapse ◽  
Landmark Analyses ◽  
Minimal Residual

Multiple myeloma (MM) patients frequently attain a bone marrow (BM) minimal residual disease (MRD) negativity status in response to treatment. We identified 568 patients who achieved BM MRD negativity following autologous stem cell transplantation (ASCT) and maintenance combination therapy with an immunomodulatory agent and a proteasome inhibitor. BM MRD was evaluated by next generation flow cytometry (sensitivity of 10-5 cells) at 3 to 6 months intervals. With a median follow up of 9.9 years from diagnosis (range, 0.4 - 30.9), 61% of patients maintained MRD negativity, while 39% experienced MRD conversion at a median of 6.3 years (range, 1.4 - 25). The highest risk of MRD conversion occurred within the first 5 years after treatment and was observed more often in patients with abnormal metaphase cytogenetic abnormalities (95%vs. 84%; P = 0.001). MRD conversion was associated with a high risk of relapse and preceded it by a median of 1.0 year (range, 0 - 4.9). However, 27% of MRD conversion positive patients had not yet experienced a clinical relapse with a median follow-up of 9.3 years (range, 2.2 - 21.2). Landmark analyses using time from ASCT revealed patients with MRD conversion during the first 3 years had an inferior overall and progression-free survival compared to patients with sustained MRD negativity. MRD conversion correctly predicted relapse in 70%, demonstrating the utility of serial BM MRD assessment to complement standard laboratory and imaging to make informed salvage therapy decisions.

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