Polymorphisms in the Multiple Drug Resistance Protein 1 and in P-Glycoprotein 1 Are Associated with Time to Event Outcomes in Patients with Relapsed and/or Refractory Multiple Myeloma Treated with Bortezomib and Pegylated Liposomal Doxorubicin.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 109-109
Author(s):  
Gabriele Buda ◽  
Deborah Ricci ◽  
Nadine Cohen ◽  
Reyna Favis ◽  
C. Chris Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Gene Polymorphism ◽  
Response Rate ◽  
Multiple Drug Resistance ◽  
Statistical Significance ◽  
Progression Free Survival ◽  
Time To Progression ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Ortho Biotech

Abstract Abstract 109 Background: Single nucleotide polymorphisms (SNPs) in the gene encoding multiple drug resistance protein 1 (ATP-binding cassette, sub-family C member 1 (ABCC1) influence its ability to act as a mediator of anthracycline resistance. The same is true for SNPs in P-glycoprotein 1 (ATP-binding cassette, sub-family B member 1 (ABCB1)), and the latter have been associated with outcome in newly diagnosed patients with multiple myeloma treated with anthracycline-based therapy. We therefore sought to evaluate the role of SNPs in ABCC1 and ABCB1 in the outcome of patients with relapsed and/or refractory multiple myeloma. Methods: The DOXIL-MMY-3001 study was an international, randomized, phase III trial comparing the efficacy of single-agent bortezomib to that of bortezomib with pegylated liposomal doxorubicin (PLD) in patients with relapsed and/or refractory multiple myeloma. Patients treated with bortezomib received this proteasome inhibitor at 1.3 mg/m2 as an intravenous push on days 1, 4, 8, and 11 of every 21-day cycle, while patients on the combination arm received this dose and schedule of bortezomib along with PLD as an infusion at 30 mg/m2 on day 4. Genomic DNA samples were obtained from all subjects in the intention-to-treat cohort who consented to DNA testing under Part 1 of the pharmacogenomic component of the clinical trial protocol. Samples that produced at least one useable genotype were included in this pharmacogenomic analysis. SNPs in ABCC1 (R723Q) and ABCB1 (1236 C>T, 2677 G>W (W = T or A), and 3435 C>T) were correlated with the overall response rate (complete + partial), time to progression, progression-free survival, and overall survival. Results: Genetic transmission patterns differ among racial groups, and since usable genotype and clinical data were available for 301 subjects, 279 of whom were Caucasians, this analysis focused on that group. The ABCC1 gene polymorphism R723Q was not represented in the bortezomib arm, and found in 5 subjects (3.5%) who received bortezomib + PLD. Its presence was significantly associated with a longer time to progression (median of 330 days vs. 129 days; p = 0.0008), a longer progression-free survival (median of 338 days vs. 129 days p = 0.0006), and a superior overall survival (p = 0.0045) in these patients. The ABCB1 gene polymorphism at 3435 (C>T) was associated with progression-free survival (p = 0.0578), response rate (p = 0.0782) and time to progression (p = 0.0923) in patients receiving bortezomib + PLD, though not at the level of statistical significance, and no correlation was found in the bortezomib alone arm. However, in a recessive genetic model, the ABCB1 gene polymorphism at 3435 T allele was significantly associated with a better clinical outcome, specifically time to progression (p = 0.0405), and progression-free survival (p = 0.0186) in patients receiving bortezomib + PLD. Haplotype analysis indicated that the three most frequent haplotypes for ABCB1 may have been associated with response rate in subjects with relapsed multiple myeloma who received bortezomib + PLD treatment (p = 0.0775), though not at the level of statistical significance. Diplotypes that contained 3435T may have been associated with a superior time to progression (p = 0.0819) and progression-free survival (p = 0.0891) in subjects with relapsed multiple myeloma who received bortezomib + PLD when compared to the most frequent diplotype containing 3435C, though not at the level of statistical significance. Conclusions: These findings indicate a potential role for SNPs in both ABCC1 and ABCB1 in modulating the long-term outcome of patients with relapsed and/or refractory multiple myeloma treated with the combination of bortezomib + PLD. Moreover, they support additional prospective studies to determine if such data could be incorporated into an algorithm by which therapy in the relapsed and/or refractory setting could be tailored to each individual patient's own genetic make-up. Disclosures: Ricci: Centocor Ortho Biotech Inc.: Employment. Cohen:Johnson & Johnson Pharmaceutical Research and Development: Employment. Favis:Johnson & Johnson Pharmaceutical Research and Development: Employment. Huang:Centocor Ortho Biotech Inc.: Employment. Rackoff:Centocor Ortho Biotech Inc.: Employment. Zhuang:Centocor Ortho Biotech Inc.: Employment. Sonneveld:Centocor Ortho Biotech Inc.: Membership on an entity's Board of Directors or advisory committees.

Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4445-4451 ◽  
Author(s):  
Michael Wang ◽  
Meletios A. Dimopoulos ◽  
Christine Chen ◽  
M. Teresa Cibeira ◽  
Michel Attal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Efficacy And Safety ◽  
Time To Progression ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Previously Treated ◽  
Survival Studies

AbstractThis analysis assessed the efficacy and safety of lenalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide + dexamethasone led to higher overall response rate (ORR), longer time to progression (TTP), and progression-free survival (PFS) versus placebo + dexamethasone despite prior thalidomide exposure. Among lenalidomide + dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (P = .04), with longer median TTP (P = .04) and PFS (P = .02). Likewise for dexamethasone alone-treated patients (P = .03 for ORR, P = .03 for TTP, P = .06 for PFS). Prior thalidomide did not affect survival in lenalidomide + dexamethasone-treated patients (36.1 vs 33.3 months, P > .05). Thalidomide-naive and thalidomide-exposed patients had similar toxicities. Lenalidomide + dexamethasone resulted in higher rates of venous thromboembolism, myelosuppression, and infections versus placebo + dexamethasone, independent of prior thalidomide exposure. Lenalido-mide + dexamethasone was superior to placebo + dexamethasone, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to inferior TTP and PFS compared with thalidomide-naive patients, these parameters remained superior compared with placebo + dexamethasone; similar benefits compared with placebo + dexamethasone were not evident for thalidomide-exposed patients in terms of overall survival. Studies were registered at http://www.clinicaltrials.gov under NCT00056160 and NCT00424047.

Efficacy of Single-Agent Bortezomib Versus Thalidomide in Patients with Relapsed or Refractory Multiple Myeloma: A Systematic Review.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5160-5160
Author(s):  
Miles Prince ◽  
Michael Adena ◽  
Dell Kingsford Smith ◽  
Judy Hertel
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Response Rate ◽  
English Literature ◽  
Progression Free Survival ◽  
Cochrane Library ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
One Year ◽  
Intent To Treat

Abstract Aim: To perform a systematic review of the efficacy of monotherapy with bortezomib versus thalidomide in patients with relapsed or refractory multiple myeloma. Methods: Published English literature from 1966 to June 2005 (MEDLINE, EMBASE, Cochrane library), publication reference lists, Janssen-Cilag Pty Ltd data-on-file, and abstracts from recent multiple myeloma conferences were reviewed. Prospective studies containing at least a single arm of any treatment group with n ≥ 30 and using continuing or variable thalidomide dosing were included. Studies adding dexamethasone for non-responders were excluded. Outcomes were analysed on an intent-to-treat basis. Statistical pooling was performed where possible for the following outcome measures: primary outcome of response rate, defined by a serum M-protein reduction ≥50% (A) and strict (e.g. EBMT) criteria (B), and for the secondary outcomes of overall survival and progression-free survival. Results: One bortezomib (n=333, APEX, NEJM2005, 352; 2487–98) and 15 thalidomide (n=1007) studies were included. Patient baseline characteristics including age, gender, IgG:IgA, disease duration and β2M were well matched, except that 48% of bortezomib patients had received prior thalidomide. On an intent-to-treat basis, the overall estimate for response rate (A) was 53% for patients receiving bortezomib versus 32% for thalidomide (p<0.001, n=10 studies). For response rate (B) the estimate was 36% for patients receiving bortezomib versus 22% for thalidomide (p<0.001, n=4 studies). One-year survival was 81% for patients receiving bortezomib versus 67% for thalidomide (p<0.001, n=6 studies). Due to differences in disease monitoring and definitions of progression, it was not possible to compare results for progression-free survival. Conclusion: In patients with relapsed or refractory multiple myeloma, bortezomib achieved significantly higher response rates and longer one-year survival than thalidomide, despite 48% of bortezomib-treated patients having received prior thalidomide.

scholarly journals Efficacy of Daratumumab, Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma Among Patients with 1 to 3 Prior Lines of Therapy Based on Previous Treatment Exposure: Updated Analysis of Pollux

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 489-489 ◽  
Author(s):  
Philippe Moreau ◽  
Jonathan L. Kaufman ◽  
Heather J. Sutherland ◽  
Marc Lalancette ◽  
Hila Magen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Statistical Significance ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Refractory Multiple Myeloma

Abstract Introduction: Daratumumab is an anti-CD38 IgGκ monoclonal antibody that has been combined successfully with lenalidomide and dexamethasone. The combination of daratumumab with lenalidomide and dexamethasone (DRd) has been compared with lenalidomide and dexamethasone alone (Rd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM) in a randomized phase 3 study (Dimopoulos MA, et al. N Engl J Med 2016; in press). In a pre-specified interim analysis, the DRd combination demonstrated significantly longer progression-free survival (PFS) in addition to deep and durable responses compared with the Rd arm. We performed subgroup analyses to further examine these efficacy data according to prior treatment exposure. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to Rd (lenalidomide: 25 mg PO on Days 1-21 of each 28-day cycle; dexamethasone: 40 mg PO weekly) with or without daratumumab (16 mg/kg IV qw for 8 weeks, q2w for 16 weeks, then q4w until progression). The primary endpoint was PFS. Pts who were refractory to lenalidomide were not eligible. All analyses were performed in pts who received 1 to 3 prior lines of therapy. Results: Median follow-up was 13.5 months. Pts who were lenalidomide-naive prior to the start of study treatment (DRd, n=226; Rd, n=219) demonstrated significantly longer PFS with DRd vs Rd (median: not reached [NR] vs 18.4 months; HR, 0.36; 95% CI, 0.25-0.52; P<0.0001), with estimated 12-month PFS rates of 83.0% vs 59.9%, respectively. ORR was significantly higher with DRd vs Rd (96% vs 79%), with ≥VGPR rates of 76% vs 47% and ≥CR rates of 44% vs 21%, respectively (P<0.0001 for all). In the lenalidomide-exposed subgroup (DRd, n=46; Rd, n=45), median PFS was NR in both treatment groups (HR, 0.49; 95% CI, 0.22-1.12; P=0.0826); estimated 12-month PFS rates were 84.1% vs 63.1%, respectively. ORR was higher with DRd vs Rd but did not reach statistical significance (87% vs 71%; P=0.0729); however, rates of ≥VGPR (78% vs 38%; P=0.0001) and ≥CR (44% vs 12%; P=0.0011) were significantly improved with DRd vs Rd, respectively. For bortezomib-naive pts (DRd, n=44; Rd, n=45), PFS was significantly longer with DRd vs Rd (median: NR vs 15.8 months; HR, 0.34; 95% CI, 0.13-0.86; P=0.0170), with estimated 12-month PFS rates of 85.4% vs 69.2%, respectively. ORR was significantly higher with DRd vs Rd (98% vs 82%; P=0.0158), with trends toward increased rates of ≥VGPR (74% vs 55%; P=0.0544) and ≥CR (42% vs 23%; P=0.0576). In the bortezomib-exposed pts (DRd, n=228; Rd, n=219), median PFS was NR in DRd vs 18.4 months in Rd (HR, 0.35; 95% CI, 0.24-0.50 P<0.0001); estimated 12-month PFS rates were 82.8% vs 58.7%, respectively. Significant differences in ORR (93% vs 77%), rate of ≥VGPR (77% vs 43%) and rate of ≥CR (44% vs 19%) were observed with DRd vs Rd, respectively (P<0.0001 for all). Among bortezomib-refractory patients (DRd, n=54; Rd, n=49), the PFS benefit of DRd compared with Rd was maintained (median: NR vs 10.3 mo, respectively; HR, 0.46; 95% CI, 0.25-0.85; P=0.0117; Figure). The estimated 12-month PFS rates were 70.8% vs 44.4%, respectively. Similar to bortezomib-exposed pts, ORR (92% vs 68%; P=0.0024), rate of ≥VGPR (75% vs 36%; P=0.0001), and rate of ≥CR (46% vs 13%; P=0.0003) were all significantly higher with DRd vs Rd for bortezomib-refractory pts. Updated data will be presented at the meeting. Conclusions: Among pts who received 1 to 3 prior lines of therapy, significantly longer PFS and higher ORR were observed with DRd vs Rd among pts who previously received bortezomib or were refractory to bortezomib or were lenalidomide-naive. Higher rates of deeper responses were observed in pts who previously received lenalidomide or bortezomib. Follow-up is ongoing to assess PFS in pts who received 1 to 3 prior lines of therapy and previously received lenalidomide. These results further strengthen the significant benefit of combining daratumumab with Rd for RRMM. Figure Progression-free Survival in Bortezomib-refractory Patients who Received 1 to 3 Prior Lines of Therapy Figure. Progression-free Survival in Bortezomib-refractory Patients who Received 1 to 3 Prior Lines of Therapy Disclosures Moreau: Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Kaufman:Pharmacyclics: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Sutherland:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Lalancette:Celgene: Honoraria; BMS: Honoraria. Iida:Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding. Prince:Janssen: Honoraria; Celgene: Honoraria. Cochrane:BMS: Other: Received sponsorship to attend international meetings; Novartis: Other: Received sponsorship to attend international meetings; Celgene: Other: Received sponsorship to attend international meetings; Takeda: Other: Received sponsorship to attend international meetings. Khokhar:Janssen: Employment. Guckert:Johnson & Johnson: Equity Ownership; Janssen: Employment. Qin:Janssen: Employment. Oriol:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A phase 2, open-label, multicenter study of ixazomib plus lenalidomide and dexamethasone in adult Japanese patients with relapsed and/or refractory multiple myeloma

2021 ◽  
Author(s):  
Shinsuke Iida ◽  
Tohru Izumi ◽  
Takuya Komeno ◽  
Yasuhito Terui ◽  
Takaaki Chou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Confidence Interval ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Open Label ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Good Partial Response

Abstract Background TOURMALINE-MM1 was a global study that demonstrated a significant improvement in progression-free survival with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone, in patients with relapsed and/or refractory multiple myeloma. The current study was conducted to evaluate further the efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients. Methods This phase 2, open-label, single-arm, multicenter study enrolled patients aged ≥ 20 years with relapsed and/or refractory multiple myeloma at 16 sites in Japan. Patients refractory to lenalidomide or proteasome inhibitor-based therapy at any line were excluded. The primary endpoint was the rate of very good partial response or better in the response-evaluable analysis set. Secondary endpoints were progression-free survival, overall response rate, duration of response, time to progression, overall survival and safety. Results In total, 34 patients were enrolled. The rate of very good partial response or better was 50.0% (95% confidence interval 31.9–68.1) and the overall response rate was 84.4% (95% confidence interval 67.2–94.7). Median progression-free survival was 22.0 months (95% confidence interval 17.3–not evaluable) and median overall survival was not estimable. The safety profile of ixazomib plus lenalidomide and dexamethasone in this study was similar to that in the TOURMALINE-MM1 study. Conclusions The efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma are comparable with reported TOURMALINE-MM1 study results. Clinicaltrials.gov identifier NCT02917941; date of registration September 28, 2016.

scholarly journals Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14)

2021 ◽  
pp. JCO.21.00443
Author(s):  
Nizar J. Bahlis ◽  
Rachid Baz ◽  
Simon J. Harrison ◽  
Hang Quach ◽  
Shir-Jing Ho ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Phase I ◽  
Phase I Study ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Grade 3

PURPOSE Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab. METHODS This phase I study ( NCT03314181 ) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity. RESULTS Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd. CONCLUSION VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).

The Combination of Pegylated Liposomal Doxorubicin and Bortezomib Significantly Improves Time to Progression of Patients with Relapsed/Refractory Multiple Myeloma Compared with Bortezomib Alone: Results from a Planned Interim Analysis of a Randomized Phase III Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 404-404 ◽  
Author(s):  
Robert Z. Orlowski ◽  
Sen H. Zhuang ◽  
Trilok Parekh ◽  
Liang Xiu ◽  
Jean-Luc Harousseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Progression ◽  
Interim Analysis ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Time To Progression ◽  
Free Survival ◽  
Refractory Multiple Myeloma

Abstract Introduction: Proteasome inhibition with bortezomib (VELCADE®) is a standard of care for patients with relapsed/refractory multiple myeloma (MM) who have received at least one prior therapy. Pre-clinical studies have shown that bortezomib acts synergistically with anthracyclines, and clinical trials have shown encouraging evidence of enhanced anti-myeloma activity for the combination of bortezomib with pegylated liposomal doxorubicin (PLD; DOXIL®). We therefore sought to test the hypothesis that the bortezomib/PLD regimen would improve clinical outcome measures in this patient population. Methods: Between December, 2004 and March, 2006, 646 patients with relapsed or refractory MM after at least one prior line of therapy were randomized on the DOXIL-MMY-3001 study conducted at 144 sites in 18 countries. Patients were eligible if they had not previously received bortezomib, progressed on an anthracycline-containing regimen, or received more than 240 mg/m2 of doxorubicin, or the equivalent amount of another anthracycline. Subjects were randomized in a 1:1 ratio to receive either bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 of every 21-day cycle, or the same dose and schedule of bortezomib but with the addition of PLD at 30 mg/m2 given on day 4 of each cycle. Treatment was to continue for up to a total of 8 cycles unless a complete response (CR) was attained, or disease progression occurred, or unacceptable treatment-related toxicity was noted. Exceptions included patients achieving CR at any time, who were treated with an additional two cycles, and patients experiencing a continued paraprotein response after 8 cycles, who were allowed to continue for as long as treatment was tolerated, and they continued to respond. Disease assessments were to occur at the start of each cycle, beginning at cycle 2, and were made according to the stringent criteria recommended by the European Group for Blood & Marrow Transplantation. Subjects who did not progress after the initial 42-week period were assessed every 6 weeks until disease progression was documented. Results: During the course of the study, an Independent Data Monitoring Committee (IDMC) reviewed safety data every 3 months, and a planned interim analysis (IA) was performed after at least 230 progression events were collected. Upon review, the IDMC concluded that, based on the IA, there was a significant benefit to patients randomized to the bortezomib/PLD arm of the trial in the primary study endpoint, time to progression, as well as in progression-free survival. No survival advantage had yet been demonstrated to date. While there was an increase in adverse events associated with the combination therapy, this increase was judged to be acceptable in the context of the benefits. In light of these results, the IDMC recommended that study results be communicated. Toxicity, time to progression, and progression free survival data will be available for presentation at the time of the annual meeting. Conclusions: At the IA, PLD plus bortezomib was significantly more effective than bortezomib monotherapy for patients with previously treated multiple myeloma.

Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 772-778 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Progression Free Survival ◽  
Prior Treatment ◽  
Once Daily ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Treatment Regimens ◽  
Common Grade ◽  
Grade 3

Abstract Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.

scholarly journals Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

2020 ◽  
pp. JCO.20.02259
Author(s):  
Paul G. Richardson ◽  
Albert Oriol ◽  
Alessandra Larocca ◽  
Joan Bladé ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

scholarly journals Carfilzomib Based Treatment Strategies in the Management of Relapsed/Refractory Multiple Myeloma with Extramedullary Disease

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1035 ◽  
Author(s):  
Xiang Zhou ◽  
Patricia Flüchter ◽  
Katharina Nickel ◽  
Katharina Meckel ◽  
Janin Messerschmidt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Serological Response ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Extramedullary Disease ◽  
Heavily Pretreated ◽  
Pretreated Patients

Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40–80) years. Twenty (44%) and 25 (56%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59%. Extramedullary response was evaluable in 33 patients, nine (27%) of them achieved partial remission (PR) (ORR = 27%). In 15 (33%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95% CI, 3.5–6.5) and ten (95% CI, 7.5–12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS (p = 0.004) and OS (p = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients.

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