OAB-002: Daratumumab improves depth of response and progression free survival in transplant-ineligible, high-risk, newly diagnosed multiple myeloma (NDMM)

2021 ◽  
Vol 21 ◽  
pp. S2
Author(s):  
Andrzej Jakubowiak ◽  
Shaji Kumar ◽  
Rohan Medhekar ◽  
Huiling Pei ◽  
Patrick Lefebvre ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Depth Of Response

scholarly journals Cyclophosphamide–bortezomib– dexamethasone compared with bortezomib–dexamethasone in transplantation-eligible patients with newly diagnosed multiple myeloma

2019 ◽  
Vol 27 (2) ◽  
Author(s):  
A. Figueiredo ◽  
H. Atkins ◽  
R. Mallick ◽  
N. Kekre ◽  
A. Kew ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Tertiary Centre ◽  
Depth Of Response ◽  
Cell Mobilization ◽  
Stimulating Factor ◽  
Good Partial Response

Introduction Cyclophosphamide–bortezomib–dexamethasone (CyBorD) is considered a standard induction regimen for transplant-eligible patients with newly diagnosed multiple myeloma (mm). It has not been prospectively compared with bortezomib–dexamethasone (Bor-Dex). We aimed to compare the efficacy of CyBorD and Bor-Dex induction in transplant-eligible patients. Methods In a retrospective observational study at a single tertiary centre, all patients with transplant-eligible mm who received induction with CyBorD or Bor-Dex between March 2008 and April 2016 were enrolled. Progression-free survival (pfs), response, and stem-cell collection for a first autologous stem-cell transplantation (ahsct) were compared. Results Of 155 patients enrolled, 78 (50.3%) had received CyBorD, and 77 (49.7%), Bor-Dex. The patients in the Bor-Dex cohort were younger than those in the CyBorD cohort (median: 57 years vs. 62 years; p = 0.0002) and more likely to have had treatment held, reduced, or discontinued (26% vs. 14.5%, p = 0.11). The stem-cell mobilization regimen for both cohorts was predominantly cyclophosphamide and granulocyte colony–stimulating factor (gcsf). Plerixafor was used more often for the CyBorD cohort (p = 0.009), and more collection failures occurred in the CyBorD cohort (p = 0.08). In patients receiving Bor-Dex, more cells were collected (9.9×106 cells/kg vs. 7.7×106cells/kg, p = 0.007). At day +100, a very good partial response or better was achieved in 75% of the CyBorD cohort and in 73% of the Bor-Dex cohort (p = 0.77). Median pfs was 3.2 years in the Bor-Dex cohort and 3.7 years in the CyBorD cohort (p = 0.56). Conclusions Overall efficacy was similar in our patients receiving CyBorD and Bor-Dex. After ahsct, no difference in depth of response or pfs was observed. Cyclophosphamide–gcsf seems to increase collection failures and hospitalizations in patients receiving CyBorD. Prospective studies are required to examine that relationship.

scholarly journals Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1231-1238 ◽  
Author(s):  
Gareth J. Morgan ◽  
Faith E. Davies ◽  
Walter M. Gregory ◽  
Nigel H. Russell ◽  
Sue E. Bell ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Autologous Transplantation ◽  
Progression Free Survival ◽  
Initial Therapy ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Overall Response ◽  
Depth Of Response

Abstract As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.

Analysis of 179 Patients with Newly Diagnosed Multiple Myeloma (MM) Treated with Novel Agents Followed by Autologous Stem Cell Transplantation (ASCT): a Retrospective Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1343-1343
Author(s):  
Joyce Habib ◽  
Neil Dunavin ◽  
Gary Phillips ◽  
Patrick Elder ◽  
Meaghan Tranovich ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Research Funding ◽  
Progression Free Survival ◽  
Novel Agents ◽  
Genetic Profile ◽  
Newly Diagnosed ◽  
Free Survival

Abstract Abstract 1343 Background: Multiple myeloma (MM) is the second most common hematological malignancy in the United States with an estimated 20,580 new cases in 2009. Over the past decade, the introduction of novel agents (thalidomide, lenalidomide and bortezomib) have played a pivotal role in improving response rates, duration of response, overall survival (OS) and quality of life. In this study we describe a single center experience with novel agents used for induction followed by high dose chemotherapy (HDT) and first autologous stem cell transplant (ASCT) in patients with MM. Method: A retrospective review of the medical records of 179 newly diagnosed patients with MM seen between October 2006 and December 2009 at The Ohio State University was performed. All patients received novel therapy containing thalidomide, bortezomib or lenalidomide as part of an induction regimen followed by ASCT. All patients received melphalan 140mg/m2 or 200mg/m2 as preparative regimen. Kaplan-Meier estimates were used to plot progression free survival and overall survival. Results: Of the 181 patients seen, 2 were excluded because they did not receive a novel agent as part of induction treatment. Of the 179 patients analyzed, median age was 56.8 years (29-80) with 30% of patients older than 60 years. African American represented 19%. Fifty-nine percent were male, 80% had Durie-Salmon (DS) stage III while 25%, 28%, 18% represented International prognostic score (IPS) stage I, II, and III respectively with 27% unknown. Median comorbidity index score was 2 (2-7) and median Karnofsky performance score (KPS) was 90% (70-100). Thirty percent had high risk genetic profile, and 73% received one line of treatment before ASCT. The median time from diagnosis to ASCT was 8.33 months (4-58). The overall response rate (ORR) prior to transplant was 84% (9% complete (CR), 29% very good partial (VGPR), and 46% partial (PR)). The ORR post ASCT was 89% (CR 45%, VGPR 22%, PR 21%). Non relapse mortality was 1% and 3% at 100 days and 1 year respectively. At a median follow up of 31 months (7-90), 69 patients (38%) had relapsed. Median progression free survival (PFS) was 29 months with 1 and 3 years PFS of 79.3% and 61.5% respectively (Fig. 1). The OS was not reached. One and 3 years OS were 93% and 88% respectively (Fig. 1). Univariate analysis showed that time to transplant > 12 months was associated with poor outcome and decreased overall survival (HR 3.30, p = 0.008). High risk genetic profile was also found to be associated with decreased overall survival although this was not statistically significant (HR 2.31, p = 0.070). Multivariate analysis found that only time to transplant > 12 months was an independent predictor of decreased OS. Significant predictors for disease progression were high risk genetic profile and time to transplant > 12 months in patients receiving 2 or more treatments before ASCT. Conclusion: Induction with novel agents followed by HDT and ASCT improves CR rate, in our case from 9% to 45%. Median PFS (29 months) was comparable to other published data. OS was not been reached after a median follow up of 31 months. Predictors of progression include high risk genetic profile and time to transplant > 12 months. The only significant predictor for survival was time to transplant. Our study suggests that an early transplant may improve OS and PFS. An extended analysis will be presented at the meeting. Disclosures: Phillips: NCI/NIH: Research Funding; NCCM Grant: Research Funding; ARRA RC2 Grant: Research Funding. Byrd:Genzyme Corporation: Research Funding.

Lower Plasma Mir-92a Levels Predict Shorter Progression-Free Survival In Newly Diagnosed Symptomatic Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1879-1879
Author(s):  
Seiichiro Yoshizawa ◽  
Tomohiro Umezu ◽  
Junko H Ohyashiki ◽  
Shinsuke Iida ◽  
Kazuma Ohyashiki
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Chromosomal Aberrations ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Newly Diagnosed ◽  
Lower Plasma ◽  
Free Survival ◽  
Cut Points ◽  
Standard Risk

Abstract Background Current prognostic model for multiple myeloma (MM) is based on International Staging System (ISS) and presence of specific chromosomal abnormalities (CAs), especially by fluorescence in situ hybridization (FISH) analysis. MicroRNAs (miRNAs) play important roles in the development and progression in multiple myeloma (MM). Previously, we have described that plasma miRNA profiling has showed considerably lower plasma miR-92a levels in newly diagnosed MM patients (Yoshizawa et al. Blood Cancer Journal 2(1):e53, 2012). The aim of this study was to investigate the impact of plasma miR-92a levels to CAs and to prognosis in patients with newly diagnosed MM. Patients and methods From April 2004 to December 2012, 60 patients with newly diagnosed symptomatic MM (median age, 66 years; range, 34-93 years) were included in this study. We measured plasma miR-92a values (miR-92a/miR-638) by qRT-PCR. They were divided into high-risk and standard-risk by using FISH and conventional cytogenetic studies: high-risk cytogenetics was defined as translocations t(4;14), t(14;16), or del (17p13) detected by FISH, or del (13q) by Q-banding according to IMWG guidelines. All others, including t(11;14), were defined as standard-risk cytogenetics. We analyzed the clinical relevance of plasma miR-92a levels with respects to CAs. Furthermore we identified miR-92a expression cut points with the most impact on outcome to investigate which of the some disease characteristics and its cut-off value had prognostic influence in MM patients. Results Chromosomal aberrations were noted in 26 (43%) MM patients after diagnosis, including 12 patients with t(4;14), 5 with t(11;14), 3 with t(14;16), 2 with del (17p13), 2 with del (13q), and 1 with t(4;14) and del (17p13), 1 with t(11;14) and del (17p13). Between MM patients with and without high-risk cytogenetics, there were no significant differences in β2-microglobulin and albumin levels (P = 0.994 and 0.85, respectively), ISS staging (P = 0.583), age (P = 0.651), sex (P = 0.585), frequency of CRAB symptoms (hypercalcemia, P = 0.755; renal insufficiency, P = 0.75; anemia, P = 0.375; bone lesion, P= 0.65, respectively). The plasma miR-92a level was significantly lower in the newly diagnosed MM with high-risk groups than in those with standard-risk groups (P = 0.015). Patients with plasma miR-92a levels < 0.04 had a significantly shorter progression-free survival (PFS) than patients with plasma miR-92a levels ≥ 0.04 (median PFS: 48 vs 15.8 months, P = 0.011). In addition, some clinical parameters were associated with adverse PFS: high-risk cytogenetics (P = 0.001), high proportions of bone marrow plasma cells (P = 0.043), high levels of serum β2-microglobulin (P = 0.022) and not attaining ≥ very good partial response (VGPR) (P = 0.007). On multivariate analysis, lower miR-92a level was an independent prognostic factor for PFS. Using the same miR-92a cut points, there was a tendency towards significant difference among standard-risk myeloma patients (P = 0.077). Moreover, the combinations of chromosomal aberrations and plasma miR-92a were able to classify newly diagnosed MM patients with three risk groups with different probabilities. Conclusion The plasma miR-92a values vary across high- and standard-risk cytogenetics in newly diagnosed MM patients. We conclude that measurement of plasma miR-92a levels may not only function as novel biomarkers for diagnosis, but may also be helpful for prognostic stratification. Disclosures: Ohyashiki: Janssen Pharmaceutical co.: Research Funding.

Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. 4547-4553 ◽  
Author(s):  
María-Victoria Mateos ◽  
Norma C. Gutiérrez ◽  
María-Luisa Martín-Ramos ◽  
Bruno Paiva ◽  
María-Angeles Montalbán ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Dna Ploidy ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
High Risk Patients ◽  
Risk Patients ◽  
Standard Risk

Abstract Cytogenetic abnormalities (CAs) such as t(4;14), t(14;16) or del(17p), and nonhyperdiploidy are associated with poor prognosis in multiple myeloma. We evaluated the influence of CAs by FISH and DNA ploidy by flow cytometry on response and survival in 232 elderly, newly diagnosed multiple myeloma patients receiving an induction with weekly bortezomib followed by maintenance therapy with bortezomib-based combinations. Response was similar in the high-risk and standard-risk CA groups, both after induction (21% vs 27% complete responses [CRs]) and maintenance (39% vs 45% CR). However, high-risk patients showed shorter progression-free survival (PFS) than standard-risk patients, both from the first (24 vs 33 months; P = .04) and second randomization (17 vs 27 months; P = .01). This also translated into shorter overall survival (OS) for high-risk patients (3-year OS: 55% vs 77%; P = .001). This adverse prognosis applied to either t(4;14) or del(17p). Concerning DNA ploidy, hyperdiploid patients showed longer OS than nonhyperdiploid patients (77% vs 63% at 3 years; P = .04), and this was more evident in patients treated with bortezomib, thalidomide, and prednisone (77% vs 53% at 3 years; P = .02). The present schema does not overcome the negative prognosis of high-risk CAs and nonhyperdiploidy. This trial was registered with www.ClinicalTrials.gov as NCT00443235.

scholarly journals Presence of Multiple High Risk Cytogenetic Abnormalities Is Associated with Rapid Progression and Shorter Survival in Newly Diagnosed Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-23
Author(s):  
Portia Smallbone ◽  
Stephanie Clugston ◽  
Rebecca De Kraa ◽  
Duncan Purtill ◽  
Matthew Wright ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Response Rate ◽  
Progression Free Survival ◽  
Response To Therapy ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
Double Hit

Background: Detection of cytogenetic abnormalities by fluorescent in situ hybridization (FISH) are a critical component of diagnostic workup and prognostication in patients with multiple myeloma. Higher risk cytogenetic abnormalities are defined as t(4;14), t(14;16) and del(17p),1 with 1q21 gain more recently described, and are associated with reduced overall survival and lower response rate.2 Objectives: To ascertain the impact of presence of multiple high risk cytogenetic abnormalities, "double-hit", on clinical characteristics, response to therapy, overall and progression free survival in newly diagnosed patients with multiple myeloma. Methods: We retrospectively analyzed records of 279 patients with multiple myeloma aged over 18 years reviewed and/or treated across two tertiary hospitals (Fiona Stanley Hospital and Royal Perth Hospital) between 1st January 2008 and 31st of December 2019. Karyotyping and FISH on interphase nuclei on bone marrow cells was recorded. High risk cytogenetic abnormalities (HRC) were categorized in accordance with the International Myeloma Working Group (IMWG) definition and included deletion (17p), t(4;14) and t(14;16). Patients were categorized into three groups based on number of HRC present (HRC=0, HRC=1 and HRC&gt;1). Results: Two hundred and thirty four patients had complete data on HRC and were included in the analysis (n=182 for HRC=0, n=44 for HRC=1 and n=8 for HRC&gt;1). Baseline characteristics for the three groups are listed in Table 1. One or more high risk cytogenetic abnormalities (HRC) were detected in 22.2% of patients, with del(17p) and t(4;14) identified most commonly, at 10.7% and 9.3% respectively. All patients in the HRC&gt;1 cohort had del (17p) with 62% (n=5) having concurrent t(14;16) and 38% (n=3) having t(4;14). Females were more likely to have HRC (41.2% in HRC=0 vs 68.1% in HRC=1 vs 50% in HRC=&gt;1, p=0.0055). Patients in the HRC&gt;1 cohort appeared to have higher ISS stage (60% stage III) however this did not meet statistical significance due to low numbers in the HRC&gt;1 cohort. A greater proportion of patients in the HRC&gt;1 cohort (100%) received bortezomib-based therapy (p=0.05). Overall response rate (ORR) was similar between cohorts, 84.8%, 86.0% and 71.43% in HRC=0, HRC=1 and HRC&gt;1 respectively, p=0.95. High risk cytogenetic abnormalities were associated with a worse overall survival (OS) and progression free survival (PFS) compared to patients with standard risk disease. Median overall survival (OS) was 52, 20 and 8 months for HRC=0, HRC=1 and HRC&gt;1 respectively, p&lt;0.0001 Figure 1a. Median PFS was 43, 12 and 6 months for HRC=0, HRC=1 and HRC&gt;1 respectively, p&lt;0.0001 Figure 1b. Conclusions: Patients with multiple high risk cytogenetics, "double hit" myeloma have an exceptionally poor prognosis with earlier relapse and shorter survival than those with a single high risk abnormality. This represents a significant area of unmet need in myeloma therapy and risk adapted treatment intensification strategies need to be evaluated in clinical trials to improve outcomes in this cohort. Disclosures Leahy: Pfizer: Membership on an entity's Board of Directors or advisory committees. Sidiqi:Amgen: Honoraria; Celgene: Honoraria, Other: Travel grant; Janssen: Honoraria.

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 ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 33-33 ◽  
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.

scholarly journals Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma

Blood ◽  
2020 ◽  
Vol 136 (22) ◽  
pp. 2513-2523 ◽  
Author(s):  
Jagoda K. Jasielec ◽  
Tadeusz Kubicki ◽  
Noopur Raje ◽  
Ravi Vij ◽  
Donna Reece ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Cardiac Events ◽  
End Point ◽  
Depth Of Response ◽  
Grade 3

Abstract In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (&lt;10−5 sensitivity). After median follow-up of 56 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 84% for ITT, 85% and 91% for MRD-negative patients, and 57% and 72% for patients with high-risk cytogenetics. For high-risk patients who were MRD negative, 5-year rates were 77% and 81%. Grade 3 to 4 adverse events included neutropenia (34%), lymphopenia (32%), infection (22%), and cardiac events (3%). There was no grade 3 to 4 peripheral neuropathy. Patients with NDMM treated with KRd with ASCT achieved high rates of sCR and MRD-negative disease at the end of KRd consolidation. Extended KRd maintenance after consolidation contributed to deepening of responses and likely to prolonged PFS and OS. Safety and tolerability were manageable. This trial was registered at www.clinicaltrials.gov as #NCT01816971.

scholarly journals Outcomes with early response to first-line treatment in patients with newly diagnosed multiple myeloma

2019 ◽  
Vol 3 (5) ◽  
pp. 744-750 ◽  
Author(s):  
Nidhi Tandon ◽  
Surbhi Sidana ◽  
S. Vincent Rajkumar ◽  
Morie A. Gertz ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Light Chain ◽  
Progression Free Survival ◽  
Early Response ◽  
Stage Iii ◽  
Newly Diagnosed ◽  
Best Response ◽  
Light Chain Disease ◽  
The Impact

Abstract We evaluated the impact of achieving a rapid response in 840 newly diagnosed multiple myeloma patients from 2004 to 2015. Rates of very good partial response (VGPR) or better were 29% (240/840) after 2 cycles of treatment, 42% (350/840) after 4 cycles of treatment, and 66% (552/840) as best response. Early responders after 2 cycles of treatment had higher rates of light chain disease, anemia, renal failure, International Staging System (ISS) stage III disease, and high-risk cytogenetics, especially t(4;14), and were more likely to have received triplet therapy and undergo transplant. Median progression-free survival (PFS) and overall survival (OS) were not different among patients with ≥VGPR and &lt;VGPR after 2 cycles (PFS, 28 vs 30 months, P = .6; OS, 78 vs 96 months, P = .1) and 4 cycles (PFS, 31 vs 29 months; OS, 89 vs 91 months, P = .9), although both were improved, with ≥VGPR as best response (PFS, 33 vs 22 months, P &lt; .001; OS, 102 vs 77 months, P = .003). On multivariate analysis stratified by transplant status, achievement of ≥VGPR after 2 cycles was not associated with improved PFS (hazard ratio [95% confidence interval]; transplant cohort, 1.1 [0.7-1.6]; nontransplant cohort, 1.2 [0.8-1.7]) or OS (transplant cohort, 1.6 [0.9-2.9]; nontransplant cohort, 1.5 [1.0-2.4]). Covariates in the model included high-risk cytogenetics, ISS stage III, triplet therapy, creatinine ≥2 mg/dL, light chain disease, and age. Although patients with high-risk disease are more likely to achieve early response, a rapid achievement of a deep response by itself does not affect long-term outcomes.

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.

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