Maintenance Therapy in Newly Diagnosed and Transplant Ineligible Multiple Myeloma Patients: A Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Abdul Rafae ◽  
Ali Jaan ◽  
Zahoor Ahmed ◽  
Karun Neupane ◽  
Sara Ashraf ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Partial Response ◽  
Adverse Effects ◽  
Maintenance Therapy ◽  
Pooled Analysis ◽  
Newly Diagnosed ◽  
Logit Transformation ◽  
Common Grade ◽  
Grade 3

Introduction: Multiple myeloma (MM) is an incurable plasma cell disorder with more than two-thirds of the newly diagnosed multiple myeloma (NDMM) patients being ≥65 years of age. Recent advancements in the treatment of MM with novel agents and autologous stem cell transplantation (ASCT) have significantly improved survival in those patients. However, the management of NDMM in many elderly patients remains a challenge due to frailty, multiple comorbidities, and their ineligibility for ASCT. Our aim in this study is to review and analyze the safety and efficacy of different maintenance regimes for NDMM patients who are ineligible for ASCT. Methods: A comprehensive literature search was done on four databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). A search was performed without the use of filters and using MeSH terms for multiple myeloma and maintenance therapy (MT). Studies involving transplant-ineligible NDMM patients which reported overall response rate (ORR), complete response (CR), very good partial response (VGPR), or partial response (PR) along with adverse effects were included. A pooled analysis of the extracted data was performed using the "meta" package by Schwarzer et al. in the R programming language (version 4.0.2). The event rates were pooled using the inverse variance method and logit transformation. The between-studies variance was calculated using the DerSimonian-Laird estimator. The random-effects model was used for the analysis. Results: Lenalidomide based MT: Four studies involving 950 transplant-ineligible NDMM patients were included. All patients received lenalidomide (R) based MT following induction therapy. A pooled analysis of these studies showed ORR of 88% (95% confidence interval (CI): 81%-93%, p < 0.01) with 67% of the patients showing ≥VGPR (95% CI: 48%-82%, p <0.01) (Figure 1 A). The most common ≥ grade 3 hematological adverse effects (AE) included neutropenia, anemia, and thrombocytopenia while most common ≥ grade 3 non-hematological AE were infections, diarrhea, and fatigue (Table 1). Bortezomib based MT: Five clinical trials involving 1171 NDMM patients who received bortezomib (V) based MT were included and evaluated in our study (Figure 1 B). Pooled analysis showed ORR of 84% (95% CI: 74%-91%, p <0.01) with 32% patients showing CR (95% CI: 25%-41%, p <0.01). The most common ≥ grade 3 hematological and non-hematological AE's are reported in table 1. Ixazomib based MT: A total of 202 transplant-ineligible NDMM patients were evaluated for a response after receiving ixazomib (I) based MT in 5 clinical trials (Figure 1 C). A pooled analysis of these trials showed an ORR of 86% (95% CI: 69%-94%, p: <0.01) with 60% patients having ≥ VGPR (95% CI: 40%-76%, p <0.01). The most common ≥ grade 3 hematological AE included anemia (9%), neutropenia (15%), and thrombocytopenia (3%). (Table 1) Conclusion: V, R and I based MT has shown promising efficacy with an acceptable safety profile in transplant-ineligible NDMM patients. R based MT has shown superior ORR compared to V or I based MT. However, data from more clinical trials are needed. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Safety and Efficacy of Four Drug Versus Three Drug Regimens Among Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Saad Ullah Malik ◽  
Nazma Hanif ◽  
Priyanka Kumari ◽  
Khadija Noor Sami ◽  
Chase Warner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Standard Of Care ◽  
Drug Regimen ◽  
P Value ◽  
Newly Diagnosed ◽  
Drug Regimens ◽  
Grade 3

Introduction: During recent years there has been a boom in the availability of treatments for multiple myeloma (MM). Based on the status of disease (newly diagnosed or relapsed/refractory), several regimens have successfully improved progression free survival (PFS) and overall survival (OS) in these two types of patients. Triple drug regimen is considered the current standard of care for newly diagnosed MM patients. However, with the advent of four drug regimens, some studies demonstrated a significant improvement in PFS and OS compared to standard of care where as others showed marginal to no difference. Also, it remains unclear whether the benefits of using four drug regimen outweigh the risks. Thus, the aim of our meta-analysis was to compare the efficacy and safety of four drug versus three drug regimens among newly diagnosed multiple myeloma patients. Methods: We built a PICO based search strategy using keywords like "multiple myeloma", "randomized clinical trials" and ran literature search on PubMed, Embase, Wiley Cochrane Library, Web of Science and ClinicalTrials.gov ranging from the date of inception till 16th July, 2020. A pre-validated data extraction sheet was used to extract data on PFS, OS and ≥Grade 3 hematologic adverse events at the longest follow-up. We included only randomized clinical trials (RCTs) comparing four versus three drug regimen in newly diagnosed MM patients. We excluded studies other than RCTs, studies conducted on relapsed refractory MM patients or other plasma cell dyscrasias. A generic variance weighted random effects model (DerSimonian and Laird) was used to derive hazard ratio estimates along with their 95% confidence intervals (CIs) for PFS and OS. Risk ratio along with its 95% CIs was estimated for Grade ≥3 hematologic adverse events. Heterogeneity was assessed with Cochrane Q -statistic and was quantified with I2 test (I2 >50% was consistent with a high degree of heterogeneity). A pre-specified sensitivity analysis was also performed for risk of adverse events. Cochrane Collaboration's tool was used to assess the quality of included RCTs and GRADE was used to rate the quality of evidence. Results: Initial search retrieved 7622 titles. After duplicate removal, 4880 articles were left. Following initial screening, 58 articles were considered for full text review. Of these only 3 studies (n=2277) met inclusion criteria. Four drug regimens included daratumumab, bortezomib, melphalan-prednisone (D-VMP), daratumumab, bortezomib, thalidomide-dexamethasone (D-VTd) and bortezomib and melphalan prednisone and thalidomide (VMPT-VT) respectively. Whereas, three drug regimens were bortezomib, melphalan-prednisone (VMP), bortezomib, thalidomide-dexamethasone (VTd) and bortezomib, melphalan and prednisone (VMP) respectively. There was a significant improvement in PFS when 4 vs 3 drug regimens were compared in patients with newly diagnosed MM (HR: 0.53, 95% CI: 0.46-0.62, p-value:<0.001, I2: 0%). Also, OS improved significantly in four drug regimen group (HR: 0.62, 95% CI: 0.51-0.76, p-value:<0.001, I2: 3.5%). There was no statistically significant difference in any grade ≥3 hematologic adverse events when 4 vs 3 drug regimens were compared (RR: 1.26, 95% CI: 0.93-1.73, p-value:0.14, I2: 93%). Sensitivity analysis after removing D-VTd regimen from any grade ≥3 hematologic adverse events revealed similar results (RR: 1.05, 95% CI: 0.97-1.13, p-value:0.23, I2: 23%) confirming the robustness of analysis. When each hematologic adverse event was looked at separately, there was no difference between 4 vs 3 drug regimen in rates of anemia (RR: 0.99, 95% CI: 0.76-1.28, p-value:0.92, I2: 0%), neutropenia (RR: 1.39, 95% CI: 1.00-1.94, p-value:0.05, I2: 85%) and thrombocytopenia (RR: 1.13, 95% CI: 0.92-1.39, p-value:0.24, I2: 33%). There was low risk of bias and strength of evidence was of moderate. Conclusion: Using four drug regimens, compared to three drug regimens, significantly improves PFS and OS among newly diagnosed multiple myeloma patients without any difference in the risk of ≥3 grade hematologic adverse events. Further randomized clinical trials are required to establish four drug regimen as standard of care for patients with newly diagnosed multiple myeloma. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

A Phase II Study of PS-341 for Patients with High Risk, Newly Diagnosed Multiple Myeloma: A Trial of the Eastern Cooperative Oncology Group (E2A02).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2546-2546 ◽  
Author(s):  
Angela Dispenzieri ◽  
Emily Blood ◽  
David Vesole ◽  
Rafael Fonseca ◽  
Natalie Callander ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
High Risk ◽  
Partial Response ◽  
Progressive Disease ◽  
Response Rate ◽  
Cell Labeling ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Background: Multiple myeloma (MM) is an incurable disease with a anticipated overall survival (OS) ranging from months to decades. Modest improvements in OS have been made with high-dose chemotherapy with peripheral blood stem cell transplant (PBSCT), but to date prognostic factors have a greater impact on OS than do individual therapies. Patients with adverse risk factors such as elevated beta-2 microglobulin (B2M), plasma cell labeling index, deletions of the long arm of chromosome 13 by metaphase cytogenetics (del 13q) require innovative new treatment strategies. Bortezomib has significant activity in patients with both newly diagnosed and relapsed/refractory MM, but its specific role in patients with adverse features has not yet been defined. Methods: Patients with newly diagnosed “high-risk” myeloma (B2M ≥ 5.5., PCLI ≥ 1, or del 13q) and adequate organ and functional status were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients were scheduled to receive bortezomib 1.3 mg/m2 every other week indefinitely. Elective peripheral stem cell mobilization (growth factor alone) was allowed after 4 cycles of bortezomib. Patients relapsing on maintenance schedule were to have the full induction schedule resumed. Responses were by the EBMT criteria but a very good partial response category was included. The primary end-point was the response rate in these high-risk patients (90% power to detect a response rate of 50% or higher). The study decision rule requires that 16 or more responses, among 39 eligible patients, are seen in order to declare this treatment effective. Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled on study. Among the 43 eligible patients, median age was 63; 51% were male. All patients had high risk disease: del 13q (6/41); plasma cell labeling index ≥1% (16/34); and B2M≥5.5 (34/43). Preliminary response data are available for 18 of the 44 cases enrolled, of which 7 had partial response, 1 had minimal response, 1 had no response, 2 had progressive disease, and 5 were unevaluable. Among those patients completing induction therapy and with response information, the median number of cycles of therapy administered is 5, range (0,8). The most common non-hematologic adverse events (AEs) of grade 3 or higher included hyponatremia (9 patients) and diarrhea (6 patients). Mild sensory peripheral neuropathy was common: grade 1, 16 patients; grade 2, 2 patients. Only 1 patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses bortezomib due to heart block and asystole. Two patients had a grade 4, 25 patients had grade 3, and 13 had grade 1 or 2 as the worst grade non-hematologic adverse event. Based on data received by August 1, 2005, 18 patients have gone off study: AEs (2); death (1); progressive disease (9); and other reasons (6). Updated results on the full study population along with FISH data for IgH translocations and deletions of 13q and 17p will be presented at the meeting. Conclusions: Preliminary results suggest that upfront bortezomib has activity in patients with high-risk MM, but further follow-up is required.

Melphalan, Prednisone and Lenalidomide Followed by Lenalidomide Maintenance Displays Treatment Characteristics Favourable to Global Quality of Life in Newly Diagnosed Multiple Myeloma (NDMM) Patients ≥ 65 Years,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3988-3988 ◽  
Author(s):  
Meletios Athanasios Dimopoulos ◽  
Antonio Palumbo ◽  
Roman Hajek ◽  
Martin Kropff ◽  
Maria Teresa Petrucci ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Multiple Myeloma ◽  
Partial Response ◽  
Progressive Disease ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Risk Of Disease ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 3988 Background: Melphalan, prednisone and lenalidomide followed by lenalidomide maintenance (MPR-R) demonstrated higher response rates (ORR; 77% vs. 50%, p <.001; VGPR or better: 32% vs. 12%, p <.001) and significantly reduced the risk of disease progression (hazard ratio [HR] = 0.423, p <.001) vs. MP alone [Palumbo, 2010]. Alongside efficacy considerations, analyses on health-related quality of life (HRQoL) may help more fully establish a regimen's overall treatment profile. HRQoL improvements with MPR-R were observed during MPR induction as well as lenalidomide maintenance, documenting a well-balanced profile in terms of efficacy, tolerability and HRQoL [Dimopoulos, 2011]. Alternative findings on novel NDMM treatment have shown efficacy of melphalan, prednisone and bortezomib (VMP) treatment to be associated with an intermittent deterioration in patients' HRQoL [Dhawan, 2009]. Methods: A mixed effects model was developed based on parameters pre-selected as potentially clinically relevant in impacting HRQoL. Models were run on six domains pre-selected based on clinical relevance: Global QoL, Physical Functioning, Fatigue and Pain (from EORTC QLQ-C30), and Disease Symptoms and Side Effects of Treatment (from EORTC MY20). Cycle 16 was determined as the last observation time point with a statistically meaningful sample size at time of follow-up (May 2010). Following explanatory variables were included: time-dependant covariates at individual HRQoL measurement time points (i.e. cycle 4, 7, 10, 13 and 16), treatment group (MPR-R vs. MP), gender (Female vs. Male), age, baseline QoL, Partial Response (PR) vs. Stable Disease (SD) and Very Good Partial Response or better (≥VGPR) vs. SD, Progressive Disease (PD) and Discontinuation (DC). Neutropenia and anemia, both Grade 3 or 4, were considered the clinically most relevant safety parameters. Main results for Global QoL are reported, with results from other domains found to be comparable. Results: Across all time-dependant covariates, a statistically significant reduction on Global QoL (−4.63; p=.004) was observed at Cycle 4. Being female vs. male significantly reduced Global QoL by -−.07 (p=.026). Each additional life year was found to lower Global QoL b− −0.40 points (p=.034). Baseline Global QoL was also significant, each additional score point leading to +0.30 (p <.001). A response level of ≥VGPR vs. SD increased Global QoL by 9.11 (p=.023); Progressive Disease (PD) reduced Global QoL by -−.34 score points (p <.001). All other pre-defined variables did not significantly impact Global QoL. Clinically meaningful changes for Global QoL in the underlying patient population have been determined to constitute at least a 7-point change [Dimopoulos, 2011]. Progressive disease (reducing Global QoL), respectively ≥VGPR (increasing Global QoL) exerted clinically meaningful changes, as did anemia grade 3–4, which had a clinically meaningful, but not statistically significant negative impact (−9.85; p=.057). Although no significant direct effect of MPR-R over MP on Global QoL was detected in the underlying model, MPR-R displays properties which favor an improved HRQoL profile, including a stronger delay in PD and higher % of VGPR vs. MP patients. Furthermore, certain properties more frequently observed with MPR-R than MP (neutropenia grade 3 or 4 and discontinuation, DC) were shown not to have a significant impact on HRQoL. Anemia grade 3 or 4, exerted a clinically meaningful negative effect but was not significantly more often observed with MPR-R compared to MP (24% vs. 17%, p= 0.091). Conclusions: More patients achieved ≥VGPR when receiving continuous MPR-R treatment than those receiving MP. In the above pooled analysis, ≥VGPR was shown to improve Global QoL in a clinically meaningful and statistically significant way. Furthermore, progression was also shown to negatively impact Global QoL (−8.34; p <.001), with MPR-R significantly reducing the risk of disease progression over MP. Delaying progression with continuous MPR-R therefore helps to maintain a high Global QoL. Disclosures: Dimopoulos: Celgene: Consultancy, Honoraria. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma. Palumbo:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Ortho-Biotech: Honoraria. Hajek:Celgene: Honoraria; Janssen-Cilag: Honoraria; Merck: Honoraria. Petrucci:Celgene: Honoraria. Lewis:Celgene: Employment, Equity Ownership. Millar:Celgene: Consultancy. Zhang:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment, Equity Ownership. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Speakers Bureau.

scholarly journals Pomalidomide Based Regimens for Treatment of Relapsed Multiple Myeloma: A Systematic Review and Meta-Analysis of Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2022-2022
Author(s):  
Adeela Mushtaq ◽  
Ahmad Iftikhar ◽  
Midhat Lakhani ◽  
Fnu Sagar ◽  
Ahmad Kamal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Meta Analysis ◽  
Random Effect Model ◽  
Pooled Analysis ◽  
Cochrane Library ◽  
Significant Heterogeneity ◽  
Grade 3 ◽  
Stratified Analysis

Abstract Introduction Bortezomib, a proteasome inhibitor and lenalidomide (Len), an immunomodulatory drug are the backbone of established treatment regimens for newly diagnosed MM. Patients with dual-refractory (refractory to both bortezomib and lenalidomide) disease have a poor prognosis with overall survival estimated to be less than one year. Pomalidomide (Pom) has distinct anticancer, antiangiogenic and immunomodulatory properties and has demonstrated synergistic antiproliferative activity in combination regimens. The aim of our study is to compare different Pom based regimens to identify the most effective regimen for relapsed refractory multiple myeloma (RRMM) patients. Methods A comprehensive literature search was performed on PubMed, Cochrane library, Web of Science, Embase and AdisInsight databases on 03/29/2018 which identified a total of 1374 studies. We included phase II/III clinical trials on pomalidomide based regimens that have clearly documented efficacy outcomes. All statistical analyses were performed using Comprehensive Meta-analysis (CMA) Version 3. We used the Cochrane Q statistics (p<0.05 considered significant) and I2 index to calculate the degree of heterogeneity of the studies. A random effect model was used if there was significant heterogeneity (p>0.05 or I2 >50%). Studies were classified into subgroups according to the therapeutic regimen: dual and triplet combinations. A separate stratified analysis of triplet regimens based on type of regimen was also performed. Results A total of 35 studies (n = 4623 patients) were included. The most commonly studied regimen was Pom + LoDex (Low dose dexamethasone) with a total of 16 studies on this regimen. All patients included in our study had ≥ 2 prior lines of therapy. Mean number of prior lines of therapy was 6. Most patients were lenalidomide refractory, with 10 patient cohorts of 100% refractoriness and 8 cohorts of ≥ 90% refractoriness. Pooled analysis showed an overall response rate (ORR) of 47.1% across all Pom regimens including both doublet and triplet regimens. An I2 value of 87.3 was found, indicating high heterogeneity across all Pom regimens. With Pom-LoDex, pooled ORR was found to be 35.7% and mean OS 14.37 months. With triplet regimens, pooled ORR was found to be 61.9%. In a separate stratified analysis of triplet regimens based on type of regimen, pooled ORRs with few selected regimens were as follows; Bort-Pom-LoDex (pooled ORR 83.5%, mean PFS 15.7 months [mos]), CFZ-Pom-LoDex (pooled ORR 77.1%, mean PFS 15.3 mos), Pom-LoDex-bendamustine (pooled ORR 74.2%), Pom-Dex-daratumumab (pooled ORR 64.5%), Pom-LoDex-cyclophosphamide (pooled ORR 59.4%, mean PFS 9.5 mos), Pom-LoDex-doxorubicin (pooled ORR 32%). Most frequently reported adverse event with Pom based regimens was myelosuppression. Mean incidences of grade ≥3 hematologic adverse events were neutropenia (47.6%), anemia (26.5%), and thrombocytopenia (20.8%). Mean incidences of grade ≥3 non-hematologic adverse events were infections (29.1%), pneumonia (13.8%) and fatigue (10%). Most of the studies used pomalidomide 4mg daily dosing. Lacy et al. suggested no advantage of 4mg pomalidomide over 2 mg daily dosing. Conclusion From results of pooled analysis, we can infer that triplet combinations of Pom yield almost double response rates (pooled ORR 61.9%) when compared to dual combination of Pom-LoDex (pooled ORR 35.7%). Among three drug combinations, Bort-Pom-LoDex (pooled ORR 83.5%) and CFZ-Pom-LoDex (pooled ORR 77.1%) seem to produce better outcomes. Our study provides useful insight into relative efficacy of various Pom regimens for treatment of RRMM patients. Several trials involving various MoAbs like nivolumab, daratumumab, elotuzumab, isatuximab and pembrolizumab in combination with Pom-LoDex are currently ongoing. Pomalidomide has an acceptable safety profile. Most common treatment emergent adverse events were myelotoxicity and infections that can be effectively managed with supportive care and dose modifications. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of post-ASCT maintenance therapy on outcomes in patients with newly diagnosed multiple myeloma in Connect MM

2018 ◽  
Vol 2 (13) ◽  
pp. 1608-1615 ◽  
Author(s):  
Sundar Jagannath ◽  
Rafat Abonour ◽  
Brian G. M. Durie ◽  
Mohit Narang ◽  
Howard R. Terebelo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Maintenance Therapy ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Second Primary ◽  
Newly Diagnosed ◽  
Serious Adverse Events ◽  
Using Data

Abstract Autologous stem cell transplantation (ASCT) followed by lenalidomide maintenance therapy is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). Clinical trials show progression-free survival (PFS) benefits, with some studies (Cancer and Leukemia Group [CALGB] trial and meta-analysis) also showing overall survival (OS) benefits, but applicability to real-world clinical settings is unclear. Using data from Connect MM, the largest US-based observational registry of NDMM patients, we analyzed effects of maintenance therapy on long-term outcomes in 1450 treated patients enrolled from 2009 to 2011. Patients who received induction therapy and ASCT (n = 432) were analyzed from 100 days post-ASCT (data cut 7 January 2016): 267 received maintenance (80% lenalidomide-based [of whom 88% received lenalidomide monotherapy]); 165 did not. Lenalidomide maintenance improved median PFS and 3-year PFS rate vs no maintenance (50.3 vs 30.8 months [hazard ratio (HR), 0.62; 95% confidence interval (CI), 0.46-0.82; P &lt; .001] and 56% vs 42%, respectively). Improvements in median OS and 3-year OS rate were associated with lenalidomide maintenance vs no maintenance (not reached in either group [HR, 0.54; 95% CI, 0.36-0.83; P = .005] and 85% vs 70%, respectively). Five hematologic serious adverse events were reported with lenalidomide maintenance (pancytopenia [n = 2], febrile neutropenia, anemia, and thrombocytopenia [n = 1 each]) and 1 with no maintenance (thrombocytopenia). Second primary malignancies occurred at rates of 1.38 and 2.19 events per patient-year in lenalidomide maintenance and no maintenance groups, respectively. Survival benefits associated with lenalidomide maintenance previously demonstrated in clinical trials were observed in this community-based Connect MM Registry.

A Multicenter, Open Label Study of Oral Lenalidomide and Prednisone (RP) Followed by Oral Lenalidomide Melphalan and Prednisone (MPR) and Oral Lenalidomide Maintenance In Newly Diagnosed Elderly Multiple Myeloma Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1940-1940 ◽  
Author(s):  
Antonio Palumbo ◽  
Patrizia Falco ◽  
Giulia Benevolo ◽  
Davide Rossi ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Autologous Transplantation ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 1940 The combination of Melphalan-Prednisone-Lenalidomide (MPR) has shown promising results in elderly newly diagnosed myeloma patients. In the transplant setting, low-dose chemotherapy (induction) precedes high-dose chemotherapy (autologous transplantation consolidation). This approach reduces tumor mass, with few side effects, before achieving the maximum cyto-reduction with autologous transplantation. The same approach has been designed for the elderly patients. Accordingly induction with lenalidomide plus corticosteroids precedes consolidation with MPR. A two-stage phase II clinical trial was planned to evaluate the safety and efficacy of Lenalidomide-Prednisone (RP) as induction, followed by Melphalan-Prednisone-Lenalidomide (MPR) as consolidation and Lenalidomide as maintenance in elderly myeloma patients. Unfit patients with newly diagnosed symptomatic myeloma older than 65 years were enrolled. No exclusion criteria were included in the protocol, to avoid the selection of fit elderly subjects only. Patients with low blood count, abnormal performance status, hepatic, renal, cardiac or pulmonary functions were enrolled. Patients received 4 RP courses (Lenalidomide 25 mg/day for 21 days every 4 weeks, plus Prednisone 50 mg three times/week for 4 weeks) followed by 6 MPR cycles (Melphalan 2 mg and Prednisone 50 mg three times/week, for 4 weeks plus Lenalidomide 10–15 mg/day for 21 days every 4 weeks) and maintenance with Lenalidomide alone (10 mg/day for 21 days every 4 weeks). Two different dose-levels of Lenalidomide were tested in combination with MP: 15 mg (dose-level 1) and 10 mg (dose-level 2). Each cohort included 12 patients, with additional 22 patients enrolled at dose-level 2. Patients were evaluated for efficacy and toxicity after completion of at least 2 MPR cycles. Forty-six patients (median age 75, range 65–88) were enrolled. Thirty-six patients were evaluable after a median of 7 cycles and a median follow-up of 8.5 months. During RP induction, the most frequent grade 3–4 hematological adverse events were neutropenia (19%), anemia (11 %), thrombocytopenia (6%). During MPR consolidation, grade 3–4 adverse events were neutropenia (45%), and thrombocytopenia (3%). Neutropenia was increased by the addition of melphalan, but both thrombocytopenia and anemia were reduced. Non-hematological toxicities were more frequent during RP cycles and reduced during MPR cycles (cutaneous rash and infections). After RP induction, at least partial response (PR) rate was 67%, at least very good partial response (VGPR) was 17%. After 2 MPR cycles, PR rate increase to 72%, including 22% of patients who achieved at least a VGPR. Conclusions. Induction with RP followed by consolidation with MPR showed a manageable safety profile and reduced the risk of anemia, thrombocytopenia and non-hematological toxicity in unfit elderly myeloma patients. These data will be updated at the meeting. Disclosures: Palumbo: Celgene Srl: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janseen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide in combination with melphalan for multiple myeloma patients at diagnosis. Guglielmelli:Celgene: Honoraria; Janseen-Cilag: Honoraria. Gay:Celgene: Honoraria. Cavallo:Celgene: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janseen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Combination Therapy Based on Bortezomib for Newly-Diagnosed Multiple Myeloma: a Chinese Experience

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5036-5036
Author(s):  
Li Yang ◽  
Jing-Song He ◽  
WenJun Wu ◽  
Xiujin Ye ◽  
Jimin Shi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Combination Therapy ◽  
Combination Chemotherapy ◽  
Chinese Population ◽  
Conflicts Of Interest ◽  
Malignant Neoplasm ◽  
Chinese Patients ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Abstract 5036 Multiple myeloma (MM) is a malignant neoplasm of plasma. With conventional chemotherapy, the rates of complete remission (CR) or very good partial remission (VGPR) are still low. Little has been reported on Bortezomib-based therapies specifically in the Chinese pateitns with MM. Here we report our results with combination therapy based on bortezomib in the Chinese population. We investigated the efficacy and safety of Bortezomib-based therapies in previously untreated MM patients. Methods: Between June 2006 and June 2010, 61 consecutive newly-diagnosed patients with symptomatic MM were treated with combination therapies based on Bortezomib. Forty-two patients were male and 19 were female. Median age was 59 years (range 37–86 years). Forty-four patients were stage 3 according to the International Staging System, 6 patients were stage 2 and 11 patients were stage 1. The conbinations included dexamethasone, dexamethasone plus subsequent thalidomide and dexamethasone plus cyclophosphamide. In detail, Bortezomib was at the dose of 1.3 mg per square meter IV on days 1, 4, 8, 11 and dexamethasone at 20 mg per square meter IV daily on the day of bortezomib and the day after, with or without daily oral thalidomide that was escalated from 100 mg to 200 mg (BD group or BDT group) or plus cyclophosphamide at 0.2 per square meter IV on days 1 to days 4 (BDC group). Thirty-four patients were in BDT group, 12 in BD group and 15 in BDC group. All patients received a median of three cycles of therapy (range 1–6). The IMWG criteria were used for response evaluation and toxicities were evluated according to the NCI Common Toxicity Criteria version 3. Results: The proportions of patients with very good partial response (VGPR) or better were 38% (13/34), 25% (3/12) and 60% (9/15) in BDT, BD and BDC group, respectively; 44% (15/34), 33% (4/12) and 33% (5/15) achieved partial response (PR). Therefore the overall response (VGPR plus PR) were 82% (28/34), 58% (7/12) and 93% (14/15). Three patients died with severe infection without disease progression. Grade 3–4 toxicities included fatigue (4/34, 1/12 and 4/15), thrombocytopenia (8/34, 3/12 and 5/15), diarrhea (4/34, 2/12 and 2/15) and infection (7/34,3/12,6/15) in BDT, BD and BDC group, respectively. Grade 1–2 neuropathy were occurred in 20 patients (59%), 6 patients (50%) and 9 patients (60%) and grade 3–4 were occurred in 6 (18%), 1 (8%) and 1 (7%) in BDT, BD and BDC group, respectively. Herpes zoster occurred in 6 patients (18%), 1 patients (8%) and 2 patients (13%) respectively. Routine anticoagulation or anti-thrombsis were not used. Only 1 patient suffered from DVT/PE but did well with treatment. Conclusions: Our preliminary experience in Chinese patients indicated that combination chemotherapy based on Bortezomib is highly effective in newly-diagnosed multiple myeloma and BDC or BDT regimens may be more superior than BD in Chinese population. There were relative lower rates of grade 3–4 neuropathy and DVT/PE in the Chinese patients with MM receved combination chemotherapy based on bortezomib. Disclosures: No relevant conflicts of interest to declare.

A 28 Day Schedule for Lenalidomide, Bortezomib, and Dexamethasone in Newly Diagnosed Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2949-2949
Author(s):  
Ajai Chari ◽  
Nitin Roper ◽  
Sundar Jagannath
Keyword(s):  
Multiple Myeloma ◽  
Neuropathic Pain ◽  
Partial Response ◽  
Board Of Directors ◽  
Sensory Neuropathy ◽  
Treatment Schedule ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
D 20

Abstract Abstract 2949 Background: The treatment of patients with newly diagnosed multiple myeloma (MM) with a 3 week cycle of lenalidomide (R), bortezomib (V), and dexamethasone (D) (R 25 mg days 1–14, V 1.3 mg/m2 day 1, 4, 8, 11, and D 20 mg day 1, 2, 4, 5, 8, 9, 11, 12) is associated with unprecedented response rates (Richardson et al. Blood 2010) (see Table 1). Partial response (PR) was 100% and 74% of patients achieved a very good partial response (VGPR) or better with RVD treatment. However, these responses come at the expense of an 80% rate of sensory neuropathy (27% grade 2 and 2% grade 3) and 32% with neuropathic pain (11% grade 2, 3% grade 3). As a result, only 59% of patients received all 3 agents and at least 1 dose modification of bortezomib was required in 44% of patients including 15% for neuropathic pain, 14% for sensory neuropathy, and 8% for fatigue Recent data confirm that a decrease in the dose intensity of bortezomib (for example with weekly dosing) is associated with significantly less toxicity, but importantly (at least in the context of combination chemotherapy) without a decrease in efficacy (Bringhen et al., Blood 2010). In this retrospective study, we examine the efficacy and toxicity of a 28 day RVD treatment schedule for patients with newly diagnosed MM. Methods: All patients with newly diagnosed, symptomatic MM who received front-line RVD on a 28 day schedule where R 25 mg was given days 1–21, V 1.3 mg/m2 was given on day 1, 4, 11, 18 and D 20 or 40 mg was given on day 1, 4, 11, 18 (see Table 2) were selected for this analysis. Patients were excluded if they had received any previous systemic anti-MM therapy (except prior corticosteroids for hypercalcemia or spinal cord compression). Patients who were empirically dose reduced for comorbidities were not excluded. All patients received prophylaxis for venous thromboembolism and VZV. Results: A total of 38 patients met the inclusion criteria for analysis. The median age at start of treatment was 59.5 years. The ISS distribution was Stage I 73% of patients, Stage II 16%, and Stage III 11%. Median treatment length was 4.5 cycles (range 3–12). After four cycles of treatment with VRD, the overall response rate was 97%, which included 63% VGPR or better (24/38) and 34% PR (13/38). 1 remaining patient had an MR (49% reduction in m spike). 32% of patients (n=12/38) went on to stem cell transplantation after four cycles of treatment while the rest were placed on maintenance therapy. With a median follow up of 9 months, no patients have had disease progression. Impressively, the rate of all grades of neuropathy at four cycles was 37% (n=14/38) with 21% (n=8/38) grade 1 sensory neuropathy, 11% (n=4/38) grade 2 neuropathy with pain and 5% grade 3 (n=2/38). There were no other hematologic or non-hematologic grade 3 or 4 toxicities. Conclusion: Despite a decrease in the dose density of bortezomib and dexamethasone, the continued synergy of these agents with a full 21 day course of lenalidomide provides excellent efficacy with reduced rates of toxicity. The 28 day schedule of RVD is an efficacious, convenient, and well tolerated treatment regimen for patients with newly diagnosed symptomatic MM. The subcutaneous administration of bortezomib on this 28 day schedule may allow even further reductions in toxicity without sacrificing efficacy. Disclosures: Chari: Millenium Takeda: speakers bureau (terminated May 2010); Celgene: lecturer. Jagannath:Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Efficacy and Safety Profile of Ixazomib Based Regimens in Relapsed/Refractory Multiple Myeloma: A Meta-Analysis of Clinical Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-21
Author(s):  
Ahmad Iftikhar ◽  
Muhammad Ashar Ali ◽  
Anum Javaid ◽  
Muhammad Abu Zar ◽  
Atif Sohail ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Safety Profile ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Case Series ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Grade 3

Background: Multiple myeloma (MM) is an incurable disease, and clinical trials with newer agents have shown improved patient outcomes. There is a need for effective and tolerable treatment for patients with relapsed/refractory MM (RRMM). Proteasome inhibitors (bortezomib, carfilzomib, ixazomib) remain an integral part of regimens used in RRMM or newly diagnosed (ND) MM. This meta-analysis aims to assess the efficacy and safety of ixazomib (Ixa) based regimens in RRMM. Methods: A comprehensive literature search was performed on PubMed, Cochrane, Embase, Web of Science, and clinicaltrials.gov. We used MeSH and Emtree terms, "ixazomib" AND "multiple myeloma" from the inception of literature till 06/01/2020. We screened 1529 articles and included 3 randomized clinical trials (RCT, N=907) and 8 non-randomized clinical trials (NRCT, N=321). We excluded case reports, case series, review articles, meta-analysis, observational studies, and clinical trials that didn't provide data about the efficacy and safety of Ixa in RRMM. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In 11 clinical trials (N=1228), the age range of patients was 30-91 years. In Phase III RCTs (N=837) comparing Ixa + Lenalidomide (Len) + dexamethasone (Dex) vs. placebo + Len + Dex, risk ratio of overall response rate (ORR), complete response (CR), and very good partial response (VGPR) were 1.14 (95% CI=1.05-1.24, I2=80%), 1.87 (95% CI=1.17-2.99, I2=0), and 1.15 (95% CI=0.95-1.40, I2=0), respectively in favor of Ixa + Len + Dex. (Fig 1-3) Grade 3 or higher treatment-related adverse events (TRAEs) thrombocytopenia, diarrhea, and rash were reported in 20%, 5.7% and 6.4% of the patients in the Ixa group vs. 10%, 2.1%, and 2.8% in the placebo group, respectively. In a Phase II RCT by Kumar et al (N=70) comparing the Ixa dosage, 4 mg Ixa + Dex yielded an ORR of 31%, CR 2.8%, and VGPR 17.1%, while 5.5 mg Ixa yielded improved ORR of 54%, CR 2.8%, and VGPR 25.7%. In a NRCT by Costello et al. (N=6), Ixa + daratumumab (Dara) + Pom + Dex yielded 100% ORR, CR 5% (95% CI=0.17-0.83), and VGPR 50% (95% CI=0.17-0.83). ≥Grade 3 TRAEs were hypertension (16%), and hematological (33%). Among 417 patients from two RCT in single arm who received Ixa + Len + Dex, pooled ORR was 70% (95% CI=0.53-0.82, I2=84%), pooled CR 11% (95% CI=0.8-0.14, I2=0), and pooled VGPR was 29% (95% CI=0.18-0.43, I2=66%). In a NRCT by Dhakal et al. (N=19), Ixa + bendamustine + Dex yielded an ORR 58% (95% CI=0.36-0.77), CR 0, and VGPR 11% (95% CI =0.03-0.34). ≥Grade 3 TRAEs were neutropenia 31%, thrombocytopenia 52%, and diarrhea 10%. In 2 NRCT (N=106), Ixa + cyclophosphamide (Cyc) + Dex yielded a pooled ORR 52% (95% CI=0.42-0.61, I2=0), CR 4% (95% CI=0.01-0.10, I2=0), and VGPR 17% (95% CI=0.11-0.25, I2=0). ≥Grade 3 TRAEs were thrombocytopenia (15%), and upper abdominal pain (4%). In a NRCT by Ludwig et al. (N=90), Ixa + thalidomide (Thal) + Dex yielded an ORR 51% (95% CI=0.41-0.61), CR 9% (95% CI=0.5-0.17), and VGPR 14% (95% CI=0.09-0.23). ≥Grade 3 TRAEs were anemia (17.8%), and infections (16.1%). In a NRCT by Krishnan et al. (N=31), Ixa + Pomalidomide (Pom) + Dex yielded an ORR 48% (95% CI=0.32-0.65) and VGPR 16% (95% CI=0.07-0.33). (Fig 4-6) ≥Grade 3 TRAEs were neutropenia (10%), and lymphopenia (35%). In 2 NRCT by Kumar et al. (N=70) of two drugs combination, Ixa + Dex yielded a pooled ORR 43% (95% CI=0.28-0.59, I2=47%), pooled CR 1% (95% CI=0-0.09, I2=0), and pooled VGPR 24% (95% CI=0.16-0.36, I2=0). ≥Grade 3 TRAEs were hematological (28%), and non-hematological (22.8%). In 2 NRCT of Ixa monotherapy (N=69), pooled ORR was 17% (95% CI=0.10-0.28, I2=0), and pooled CR 6% (95% CI=0.2-0.22, I2=0). (Fig 4-6) ≥Grade 3 TRAEs were anemia (11%), thrombocytopenia (5.4%), and neutropenia (2.7%). Conclusion: Our study provides useful insight into relative efficacy of various Ixa regimens for the treatment of RRMM. The pooled analysis of RCT showed that the combination of Ixa + Len + Dex yielded better response as compared to placebo. In the pooled analysis of outcomes in single arm NRCT, Ixa + Dara + Pom + Dex and Ixa + Len + Dex showed better efficacy outcomes as compared to Ixa + Dex in combination with Thal, Cyc, or Bendamustin. Three drugs Ixa combination regimens had better efficacy as compared to two drugs combination of Ixa + Dex and Ixa monotherapy. Ixa was well tolerated with acceptable safety profile. Additional multicenter, double-blind clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Carfilzomib Based Regimens for Treatment of Newly Diagnosed Multiple Myeloma: A Systematic Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5588-5588
Author(s):  
Maimoona Khan ◽  
Asma Waheed ◽  
Rida Ul Jannat ◽  
Arafat Ali Ali Farooqui ◽  
Muhammad Saad Farooqi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Effect ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Induction Therapy ◽  
Drug Combination ◽  
Alkylating Agents ◽  
Adverse Effect Profile ◽  
Newly Diagnosed ◽  
Grade 3

Background: Carfilzomib (Car), a second-generation proteasome inhibitor (PI), has been approved by the US Food and Drug Administration (FDA) as therapy for relapsed and /or refractory multiple myeloma (RRMM), either as a single agent or in combination with other agents. It has proven to be superior in many ways compared to the the first generation PI, bortezomib, both in terms of superior efficacy and neuropathy related adverse effect profile. Carfilzomib has lower rate of peripheral neuropathy. In this review, we gathered data from trials which studied Carfilzomib for newly diagnosed MM (NDMM). Carfilzomib based two and three drug combination as induction regimens for the management of NDMM is an emerging approach. Through this systematic review, we explore efficacy, adverse effect profile of Car based regimens for NDMM. Methods: Per PRISMA guidelines, a thorough database search was conducted on 06/24/2019 using the following search engines; PubMed, EMBASE, Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov. We included all published trials that used carfilzomib as an induction agent in NDMM patients and had at least response rates after induction. Results: The total number of articles identified with initial search were 1131, out of which 19 articles met our selection / eligibility criteria (n=2286). The overall response rates (ORR) after induction therapy with carfilzomib based regimens was very impressive (range: 84.3% - 100%). Two drug combination using carfilzomib and dexamethasone (n=72) had an ORR of 90% and a greater than very good partial response rate (>VGPR) of 84%. Three drug combinations used for induction therapy included carfilzomib/dexamethasone with immunomodulators (n=391) and alkylating agents (n=308). The combination of carfilzomib/dexamethasone with lenalidomide (n=189, ORR: 97% - 98%, >VGPR: 69% - 98%) and thalidomide (n=202, ORR: 90% - 94%, >VGPR: 66% - 68%) showed the best response. Alkylating agents used in combination with carfilzomib were melphalan (n=98, ORR: 90% - 93%, >VGPR: 58% - 70%), cyclophosphamide (n=192, ORR: 87% - 95%, >VGPR: 39% - 71%) and bendamustine (n=18, ORR; 100%, >VGPR: 89%). Four drug combinations with carfilzomib used were daratumumab/lenalidomide/dexamethasone (n=22, ORR: 100%, >VGPR: 90%, 12m PFS: 95%) and cyclophosphamide / thalidomide / dexamethasone (n=64, ORR; 91%, >VGPR: 69%, 24m PFS: 76%). One trial directly compared carfilzomib/melphalan/dexamethasone (n=478, ORR: 84%, >VGPR: 61%, PFS: 22.3m) with bortezomib/melphalan/dexamethasone (n=477, ORR: 79%, >VGPR: 49%, PFS: 22.1m). Another trial compared the combination of carfilzomib / dexamethasone with lenalidomide (n=315) or cyclophosphamide (n=159) that showed similar ORR (97% vs 91%) though >VGPR rate was better with lenalidomide (75% vs 60%). Efficacy data including progression free survival (PFS) for carfilzomib based regimens is reported in table 1. Most common >grade 3 hematological adverse effects reported were anemia (2% - 35%), lymphopenia (5% - 76%), thrombocytopenia (4% - 28%) and neutropenia (1% - 38%). Most Common >grade 3 non-hematological adverse events included cardiac events (5% - 10%), respiratory disorders (8% - 16%), infections (2% - 9%), hypertension (6% - 17%), renal events (9% - 10%) and hyperglycemia (6% - 23%). (Table 1) Conclusion: The overall efficacy and favorable adverse effect profile of Carfilzomib-based induction regimens seem very promising for the treatment of NDMM. Car is now approved for weekly dosing which is convenient. Due to cardiovascular toxicity seen in upto 10% cases, Car should be used very judiciously in patients with cardiovascular risk factors and heart failure. Several ongoing phase 3 clinical trials are studying Carfilzomib in various combinations will help to establish foundation for future standard therapy as well as next phase of drug development through clinical trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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