Comparison of Different Upfront Transplant Strategies in Multiple Myeloma - a Large Registry Study from Chronic Malignancies Working Party of EBMT

Introduction Although many new drugs became available to treat multiple myeloma (MM), high-dose chemotherapy with auto-HCT remains the gold standard. Further intensification to improve disease control has been assessed in several trials. However, no clear consensus has emerged. Further evidence is therefore required to guide clinicians in choosing between single auto, tandem auto and auto-allo approaches. Materials and Methods We performed a retrospective analysis of MM patients (20-65 years) undergoing their first auto-HCT in EBMT centres (2002-2015). Our primary end-points were Progression-Free Survival (PFS) and Overall Survival (OS). We used 3 different statistical methods to avoid time bias and to account for time-dependent effects. We defined tandem transplants (auto-auto2 or auto-allo) given within 9 months in absence of progression. Single- and tandem-transplant groups were compared by a landmark analysis (1). In addition, two different dynamic prediction models (2, 3) were applied to predict long-term outcomes in all patients according to the treatment actually received while avoiding the loss of information that occurs in landmark analysis. The models incorporated a horizon time of 5 years for OS and PFS during the first 3 years following auto1. Since the effects of tandem transplants vary over time, these were split into "Recent", the first 100 days following the 2nd transplant, and "Past" for the longer term (2, 3), respectively. Age, disease status and calendar year of transplant at auto1 were also analysed. Furthermore, the third model incorporated the long-term time-varying effect of auto-allo or auto-auto2 and possible associated interactions with patients' characteristics. Results A total of 24,936 patients who received an auto as first transplant were included; 3,683 of these patients proceeded to an elective tandem auto and 878 to an auto-allo transplant. The median age of the entire cohort was 57.0 years (range 18.1.-65.0). 18% were in complete remission (CR) at first auto. The Tandem auto-allo group was younger (51.7 years). Both tandem groups (auto-auto and auto-allo) had fewer patients in CR at first auto (9% and 8%, respectively). There was no difference in CR rates at second transplant in the tandem groups (18% and 19%, respectively). In the tandem auto-allo group, 72% had HLA identical sibling donors and 25% matched unrelated donors. Reduced intensity conditioning was performed in 85% of the allogeneic transplants. The median follow-up of the entire cohort was 66.3 months. At 60 months following first auto, the PFS was 24.8% and OS 63.1%. All three statistical methods found that younger age and being in CR at first transplant were associated with superior PFS and OS. The long term results of the different transplant strategies were as follows: Landmark analysis at 4 months resulted in a reduction in the number of transplants analysed. Auto-allo only had an advantage in terms of very long term PFS (figure 1) and not for OS (not shown).Dynamic prediction (table 1, curves not shown) revealed that the tandem groups were superior regarding PFS in comparison to single auto (auto-allo and auto-auto: HR 0.56 and 0.85, both p<0.001; corresponding to a 21% and 6% gain of PFS probability, respectively). For OS, the tandem groups were just slightly superior (auto-allo and auto-auto: HR 0.78 and 0.87, both p<0.001; corresponding to a 7 % and 4% gain in OS probability, respectively).Finally, dynamic prediction with time-varying effect and interactions revealed that auto-auto was superior, especially for patients in CR at first auto. In essence, auto-auto was the best treatment strategy for this group in terms of OS; for PFS, auto-allo remained the best long-term strategy (figure 2). Summary We here present a very large cohort of patients who have undergone auto and allo transplantation as first-line treatment for MM. Younger age and being in CR at first transplant were consistently found to be positive prognostic factors for PFS and OS. Tandem auto-allo was superior to single and tandem auto for long-term PFS. However, this PFS advantage only translated into a minor OS benefit for tandem auto-allo even when analysis was restricted to patients who were not in CR at the time of the first auto-HCT. Disclosures Schönland: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant. Blaise:Pierre Fabre medicaments: Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria; Molmed: Consultancy, Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Gribben:Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Stelljes:MDS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Amgen: Honoraria; Jazz Pharmaceuticals: Honoraria. Bloor:Abvie, Gilead, Novartis, Autolus, Celgene, etc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational grant. Beksac:Celgene: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hayden:Amgen: Honoraria; Alnylam: Honoraria. Kröger:Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding.

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Long-Term Survivorship with Active Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-120152 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1912-1912

Author(s):

Brett Grieb ◽

Jithma Prasad Abeykoon ◽

Saurabh Zanwar ◽

S. Vincent Rajkumar ◽

Martha Q. Lacy ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Short Term ◽

Advisory Committees ◽

Entire Cohort ◽

Long Term Survivors

Abstract Background The survival of patients with multiple myeloma (MM) has improved significantly over the past two decades with the introduction of novel treatment agents. However, MM is still largely considered an incurable malignancy with a relapsing-remitting course. A follow-up of at least 10 years from active disease is required to determine whether a plateau in progression-free survival has been attained. Prior literature has used 10 years as a cutoff for "long-term survivorship". In this study, we have assessed the biological disease characteristics and outcomes of long-term survivors with MM (≥10 years from active disease). Methods All patients with active MM evaluated at the Mayo Clinic, Rochester between January 1, 1999 and July 1, 2008 were included in the study after approval of the Institutional Review Board. Patients with smoldering multiple myeloma were excluded. The overall survival (OS) was calculated from the time of symptomatic disease requiring treatment. Patients were then divided into two cohorts: (1) long-term survivors, which included patients who had an overall survival of at least 10 years; and (2) short-term survivors, which included patients who had an overall survival of less than 5 years from the diagnosis of active MM. The baseline characteristics between these two groups were compared using Wilcoxon, chi-square, and Fisher's exact test as applicable. All time-to-event analyses were performed using the Kaplan-Meier method and the survival curves were compared using Log-Rank test. Results During the time frame of the study, 2,125 patients were identified who fulfilled the diagnostic criteria for active MM. The median follow-up for the entire cohort was 12.6 years (95% CI: 12.5-13.4).The median OS for the entire cohort was 4.4 years (95% CI: 4.2-4.7 years). Three-hundred and ninety nine (18.7%) patients survived at least 10 years whereas 872 patients (41%) survived less than 5 years from the date of initial diagnosis. The median OS was 14.1 years for the long-term survivors (95% CI: 13.9-14.6 years) and 2.1 years for the short-term survivors (95% CI: 1.8-2.2 years). The clinical features at diagnosis comparing long-term survivors and short-term survivors are shown in Table 1. Among long-term survivors (n=399), based on the available data regarding remission and ongoing treatment status, 331 patients were categorized into 6 cohorts (Table 2). The MM specific survival data of these 6 cohorts is depicted in Table 2.Figure 1 shows survival outcomes from the 10-year landmark. Of the 6 cohorts, 38 patients in Cohort 1 and 19 patients in Cohort 2 (total 57; 17% of long term survivors, ~3% of the entire cohort ) have been off therapy for at least 5 years and remain in remission, representing a distinct group of patients with 100% 15-year survival. Conclusion In our large database with prolonged follow-up, long-term survivors appear to have distinct baseline characteristics, but also constitute a heterogenous group of patients with disparate outcomes. A small subset (17% of long-term survivors) was identified that may represent patients closest to being considered as 'operationally cured'. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Teva: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; Apellis: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; janssen: Consultancy; celgene: Consultancy; Prothena: Honoraria; annexon: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding.

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Carfilzomib (CFZ), a Novel Proteasome Inhibitor for Relapsed or Refractory Multiple Myeloma, Is Associated with Minimal Peripheral Neuropathic Effects.

Blood ◽

10.1182/blood.v114.22.430.430 ◽

2009 ◽

Vol 114 (22) ◽

pp. 430-430 ◽

Cited By ~ 10

Author(s):

Ravi Vij ◽

Luhua Wang ◽

Robert Z Orlowski ◽

A. Keith Stewart ◽

Sundar Jagannath ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Board Of Directors ◽

Proteasome Inhibitor ◽

Research Funding ◽

Class Effect ◽

Advisory Committees ◽

Ortho Biotech ◽

Grade 3

Abstract Abstract 430 Background: Peripheral neuropathy (PN) is a feature of multiple myeloma (MM) itself as well as a debilitating side effect and major dose-limiting toxicity of thalidomide (THAL) and bortezomib (BTZ) (Chaudry et al, J Peripher Nerv Syst. 2008). Although the mechanism of BTZ-induced PN (BIPN) is unknown, PN may not be a proteasome inhibitor class effect. Carfilzomib (CFZ) is a highly selective proteasome inhibitor with activity in relapsed or refractory MM. CFZ overcomes BTZ-resistance in vitro (Kuhn et al, Blood 2007), lacks the off-target activities of BTZ (Kapur et al, Blood 2008), and does not cause neurotoxicity in long-term chronic (e.g. up to 9 months) animal toxicology studies (Kirk et al, Blood 2008). In Phase I and 1b/2 trials (total n=138), CFZ was not associated with dose-limiting PN. Here we report on the experience of CFZ treatment from two ongoing Phase 2 trials in relapsed or refractory MM. Methods: Patients with relapsed or refractory MM received CFZ, 20 mg/m2 IV, Days 1, 2, 8, 9, 15, and 16 in a 28-day cycle for up to 12 cycles on studies PX-171-003 and PX-171-004. Neuropathy history, neurological physical exam and PN-related quality of life data (FACT-GOG/NTx v 4.0 scores) were collected at screening. Prospective neurological exams and subjective reporting of PN using the FACT-GOG/Ntx subscale v.4 questionnaire occurred every 2 cycles until study discontinuation to proactively assess for PN. Adverse Event (AE) data were also collected. AEs reported as ‘neuropathy peripheral', ‘neuropathic pain', ‘neuropathy', and ‘peripheral sensory neuropathy' were included as PN. AE reports of ‘paraesthesias' and ‘dysesthesias' were counted separately. Results: To date, baseline data are availabel for 136 patients. At screening, 73 (54%) patients had active PN, including 64 (47%) with Grade (G) 1 and 9 (7%) with G2. 111 (82%) patients had a history of PN which was attributed to prior chemotherapy, 86 cases of which were attributed to either THAL or BTZ. THAL was implicated in 57 cases, BTZ in 45 cases, and both THAL and BTZ in 17 cases. For 27 of these patients, PN was the primary reason for THAL or BTZ discontinuation. The mean number of CFZ doses was 27 (4.5 four-week cycles) and 27 (20%) patients completed at least 8 cycles. Peripheral neuropathy AEs (all grades) were reported in 21 (15%) patients; 12 (9%) cases were considered possibly related to CFZ. Grade ≥ 3 PN was reported in only 3 (2%) patients. In one patient, the Grade 3 neuropathy lasted from treatment days 2 to 3 (i.e., < 36 hours) and resolved; the patient continued on CFZ at full dose for 30 days before discontinuing study due to progressive MM. In a second patient, Grade 3 neuropathy occurred on study day 91. The dose was reduced from 20 mg/m2 to 15 mg/m2, at the same twice-weekly frequency; the PN resolved to G1 and the patient continued on therapy until day 133. The third patient had G3 PN that occurred from days 260-281 and resolved to G1 while still on full dose CFZ. This patient completed the full 12-cycle protocol (∼1 year CFZ treatment). Paraesthesias and dysesthesia were reported in 10 (7%) patients; all were G1 or 2. There were no missed doses or CFZ treatment discontinuations due to PN, paraesthesias or dysesthesias. Comparative FACT-GOG/Ntx subscale scores were availabel for 95 patients. There was no statistically significant change in FACT-GOG/NTx scores from baseline to the end of the study. Neurological exams did not identify any additional peripheral neuropathy beyond those reported as AEs. Conclusions: In MM patients receiving CFZ therapy, reports of PN, paraesthesias and dysesthesia are generally mild and do not result in missed doses or CFZ discontinuation, allowing long-term treatment and prolonged disease control. These data, along with the experience from other clinical trials, indicate that PN is not a class effect of proteasome inhibitors. Disclosures: Vij: Proteolix: Consultancy, Research Funding. Wang:Proteolix, Inc.: Research Funding. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Belch:Ortho Biotech: Honoraria, Research Funding. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Le:Proteolix, Inc.: Employment. Cruickshank:Proteolix, Inc.: Employment. Bennett:Proteolix: Employment. Molineaux:Proteolix, Inc.: Employment, Equity Ownership. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Obesity In Young Adulthood Is Associated With Early Onset Multiple Myeloma In African Americans

Blood ◽

10.1182/blood.v122.21.1872.1872 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1872-1872

Author(s):

Amie E. Hwang ◽

Sikander Ailawadhi ◽

Leon Bernal-Mizrachi ◽

Todd M Zimmerman ◽

Christopher Haiman ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

African American ◽

African Americans ◽

Board Of Directors ◽

Research Funding ◽

Clinical Characteristics ◽

Age At Diagnosis ◽

Advisory Committees ◽

Younger Age

Abstract Introduction African-American ethnicity, male sex, older age and obesity are accepted risk factors for multiple myeloma (MM). Obesity early in life is a risk factor for many cancers, including MM; most studies have focused on populations of European origin. African-Americans have a higher prevalence of obesity than other populations, and may have a distinct genetic contribution to this condition. We established a multi-center collaborative study to investigate possible explanations for the excess risk of MM among African-Americans. The aim of the present case-case analysis was to determine whether body mass index (BMI) was associated with risk factors and clinical characteristics at presentation in African-American MM patients. Methods Patients diagnosed with active MM since January 1, 2009 were recruited from nine outpatient centers and three Surveillance, Epidemiology, End-Results Program (SEER) population-based cancer registries. Information on weight and height at 20 years of age and at 5 years prior to diagnosis was obtained from questionnaires. Clinical information collected included age at diagnosis, stage, percent plasmacytosis on bone marrow biopsy, β2 microglobulin level, Ig serotype, light vs. heavy chain disease, and presence of lytic bone lesions. BMI (ht/wt2) was categorized into 3 levels (normal <25, overweight 25-29, obese >30) according to World Health Organization standard. The Pearson chi-square test was used to test the association between BMI category, and risk factors and clinical characteristics. Mean ages at diagnosis across BMI categories were compared using linear regression and a t-test for trend calculated. Results To date, 1,044 African-American MM patients have been enrolled and of those, 1,014 provided a DNA sample. At present, 970 patients have completed a questionnaire, clinical records have been abstracted for 823 patients, and 509 patients have some information on gender, age at diagnosis, weight, height and clinical characteristics.The mean age at diagnosis was 59. Increasing BMI at age 20 was associated with younger age at diagnosis (p= 0.0004), whereas BMI at 5 years prior to diagnosis was not associated with age at diagnosis (p=0.9477). Among men, mean age at diagnosis decreased with increasing BMI at age 20 (p= 0.0125) (Table 1a) and at 5 years prior to diagnosis (p=0.0252) (Table 1b). Among women, the trend was signficant at age 20 (p=0.0018) (Table 1a) but not at 5 years prior to diagnosis (p= 0.7094) (Table 1b). Increasing BMI was not significantly associated with any other clinical characteristics. Conclusion/Discussion In a large collection of African-American MM patients, we observed a strong association between increasing BMI at age 20 and younger age at diagnosis. A similar trend was observed in men only at 5 years prior to diagnosis, consistent with previous reports. Obesity is one of the few known potentially modifiable risk factors for MM. Younger age at diagnosis reflects an earlier accumulation of either or both genetic and environmental risk factors. Obesity at an early age may influence MM risk through shared biological pathways such as interleukin-6 and insulin-like growth factor, by contributing to chronic B-cell activation, thereby increasing susceptibilty for MM later in life. The significance of the gender difference for the association closer to diagnosis is unclear and requires additional study. Disclosures: Terebelo: Amgen: Honoraria; Millennium: Honoraria. Mehta:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Zonder:Skyline: Consultancy. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Lonial:Celgene Corporation: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

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Differences in Presentation and Survival Outcomes for African American Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-119948 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5647-5647 ◽

Cited By ~ 1

Author(s):

Nisha Joseph ◽

Vikas A. Gupta ◽

Craig C Hofmeister ◽

Charise Gleason ◽

Leonard Heffner ◽

...

Keyword(s):

African American ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Newly Diagnosed ◽

Long Term Outcomes ◽

Advisory Committees ◽

Entire Cohort ◽

Significant Difference

Abstract Background : Though the incidence of MM is two- to threefold higher in the African American (AA) population compared to Caucasians, reported long term outcomes are less favorable presumably due to inequities in access to healthcare. Little is known about the biology or disease presentation among AAs. We have conducted a retrospective analysis of our institutional data of 1000 patients treated with RVD induction therapy, specifically assessing differences in presentation, disease biology, and outcomes in AA patients. Methods: A total of 1000 newly diagnosed MM patients were treated with RVD induction therapy [R - 25 mg/day (days 1-14), V - 1.3 mg/m2 (days 1, 4 8, 11) and D - 40 mg once/twice weekly as tolerated every 21 days] from January 1st 2005 until August 31st 2016. Dose-adjustments were made based on the treating physician's discretion and patient tolerability. Demographic and outcomes data for the patients were obtained from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Of the 1000 patients included in the analysis, 564 (56.4%) of patients were white (W), and 339 (33.9%) were AA, consistent with the demographic representation of the state of GA and our institutional referral population. Median age of this cohort was 61 years (range 16-83), 57 for AA patients (range, 24-83) compared to 62 (range, 16-81) in white patients, suggesting the onset is earlier among AA which has been previously reported in population based studies. Other notable characteristics include: 42.5%M/57.5% F for AA cohort and 61.7%M/38.3%F for white cohort. In regard to stage, AA: 73.9% stage I/II, 26.1% stage III; W: 77.1% stage I/II, 22.9% stage III, showing no difference in prognostic staging at presentation. There was no statistically significant difference in the presenting labs between AA and whites except for hemoglobin, with more AA patients presenting with Hgb≤9.9 g/dL (45.7% AA vs 32.5% W, p <.0001). In terms of prevalence of high-risk cytogenetics, there was no significant difference between the two cohorts in: complex karyotype 16% white/14.4% AA; t(14;16) 2.4% W/2.8% AA; t(4;14) 4.7% W/5.0% AA; t(11;14) 11.7% W/15.9% AA; or del1p 6.5%W/7.8%AA. However, there were significant differences found in the rates of: amp 1q 19.2% W/10.6% AA, (p<.0001), del13 28.3% W/19.6% AA (p=.003), and del17p 11.7% W/7.2% AA (p=.019), all three significantly less frequent in AAs. Median time to transplant for the entire cohort was 5 months (range, 1-124), and median time to best response was 3 months (range, 0-39). There was no significant difference in the number of patients who underwent ASCT (84% W vs 82% AA, p=.241), nor in ≥VGPR rates post-induction and 100 days post-ASCT: 69.9% W vs 64.5% AA (p=.056) and 88.1% W vs 86.7% in AA patients (p=.317), respectively. Median PFS for the entire cohort was 63 months, 62 months (54-69.9) for white patients versus 65 months (53-76.9) for AA patients (p=0.403). At a median follow up of 38 months, median OS has not yet been reached. Conclusions: This is the largest reported cohort of myeloma patients treated with RVD induction, with one-third of the patients representing the AA population. In our dataset, AAs are diagnosed 5 years younger, with lower hemoglobin at presentation and lower rates of amp1q, del13 and del17p when compared to whites. When offered the same induction regimen and opportunity for ASCT, AAs tend to experience the same survival benefits as their white counterparts. The lack of significant difference in PFS or OS suggests standardization and improved access to care could lead to better long-term outcomes in the AA population. Disclosures Hofmeister: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:Genentech: Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Kite Pharma: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Kaufman:BMS: Consultancy; Janssen: Consultancy; Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Roche: Consultancy. Lonial:Amgen: Research Funding. Nooka:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Real-World Outcomes with Bortezomib-Containing Regimens and Lenalidomide Plus Dexamethasone for the Treatment of Transplant Ineligible MM Patients: A Multi-Institutional Report from the National Myeloma Canada Research Network (MCRN) Database

Blood ◽

10.1182/blood-2018-99-117363 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2008-2008 ◽

Cited By ~ 1

Author(s):

Victor Jimenez-Zepeda ◽

Donna E Reece ◽

McCurdy R Arleigh ◽

Esther Masih-Khan ◽

Eshetu G Atenafu ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Small Sample ◽

Research Network ◽

National Database ◽

Categorical Variables ◽

Advisory Committees ◽

Entire Cohort

Abstract Introduction: Bortezomib-containing regimens (BCRs) have been the standard frontline approach for the treatment of transplant ineligible multiple myeloma (TIMM) patients in Canada for many years. Based on recent randomized clinical trial results lenalidomide and dexamethasone (Ld) has become another provincially funded option in Canada in the same therapeutic space. We aimed to compare the effect of BCRs and Ld for the treatment of TIMM using the newly-formed Myeloma Canada Research Network Multiple Myeloma Database (MCRN-MM-DB) project. This web-based centralized platform can track and characterize real-world outcomes of patients treated at major Canadian institutions and includes both legacy data dating back to 2007 (from 4 centres) as well as ongoing prospective data collection (from 11 centres) analyzed up to 01/07/18. Patients and Methods: The primary objective was to assess the ORR, PFS and OS for TIMM patients treated with CyBorD/CyBorP, Ld, VMP or VD/VP, each given as reported previously but with dose-adjustments at the discretion of the treating physician to maintain patients on therapy. The two-sided Fisher exact test was used to test for differences between categorical variables. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test; a p value of <0.05 was considered significant. Results: 842 TIMM patients were evaluated. Clinical characteristics are shown in Table 1. Median OS and PFS for the entire cohort were 54.1 and 20.4 months, respectively. ORR and ≥VGPR better rates were 83% and 52% for the entire cohort. A ≥VGPR rate of 53%, 46%, 56% and 51% were observed for patients treated with CyBorD/P, VMP, Ld and VD/VP, respectively (p=0.3). The median PFS was longer for Ld patients (25 months) compared to CyBorD/CyBorP, VMP and Vd/VP (19.3, 20.5 and 13.7 months, respectively), (p=0.03, Fig 1a); there was no significant difference in PFS between the 2 different alkylating-agent containing regimens when combined with bortezomib + steroids (CyBorD/P vs VMP, p =0.9). Median OS was 51, 59.5, 29.4 and 66.5 months for those patients treated with CyBorD/CyBorP, VMP, VD/VP and Ld, respectively (p=0.07, Fig 1b). When the OS and PFS for CyBorD/P (typically given for a fixed duration of 9 cycles) were compared with Ld in a subset analysis, the p-values were 0.08 and 0.008, respectively. Conclusions: 1) OS was not significantly different in patients treated with either a bortezomib-containing triplet that includes an alkylator + steroid or continuous Ld. 2) The BCR triplets and Ld were more efficacious than the bortezomib + steroid doublet (VD/VP) for both OS and PFS although, the small sample size and adverse factors, such as frailty and comorbidities, may have influenced the findings. 3) The results in the real-world setting, i.e., a median PFS in the range of 1.5-2 years and median OS of 4.5-5.5 years, confirm triplet-based BCRs and Ld as current valid standards of care for frontline therapy in TIMM. 5) This study confirms the utility of a large comprehensive national database to benchmark current results for comparison with newer regimens as they are introduced into the Canadian therapeutic landscape. Disclosures Arleigh: Celgene: Honoraria; Janssen: Honoraria. Sebag:Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Leblanc:Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Louzada:Janssen: Honoraria; Celgene: Honoraria; amgen: Honoraria; pfizer: Honoraria. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria.

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Long-Term Molecular Results Of The Gimema VEL-03-096 Trial: Molecular Remission Achievement and Loss Are Major Outcome Predictors

Blood ◽

10.1182/blood.v122.21.2077.2077 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2077-2077

Author(s):

Simone Ferrero ◽

Marco Ladetto ◽

Daniela Drandi ◽

Federica Cavallo ◽

Elisa Genuardi ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Salvage Treatment ◽

Clinical Relapse ◽

Molecular Remission ◽

Advisory Committees ◽

Risk Of Relapse

Abstract Background and aims The extensive use of new drugs in multiple myeloma (MM) allowed the achievement of unprecedented levels of cytoreduction and major advantages in survival rates, though almost all patients still relapse after a successful treatment. PCR-based minimal residual disease (MRD) studies are powerful prognostic tools, able to indentify patients at high risk of relapse. Thus, there is a growing interest in MRD to modulate therapy also in MM, as already happens in other lymphoid neoplasms. However available reports have a too short follow-up to be conclusive. In particular some points need to be addressed: 1) which is the long-term outcome of patients achieving molecular remission (MR) in the absence of further treatment? 2) What is the prognostic impact of MR loss? 3) How long is the window between MR loss and clinical relapse? These issues have been addressed based on the mature results of the GIMEMA VEL-03-096 trial [EudraCT Number 2004-000531-28], which currently has a median follow-up (mFU) of 93 months. Patients and methods Inclusion criteria and treatment schedule have been already reported [Ladetto et al., J Clin Oncol 2010]. MRD was assessed on bone marrow at diagnosis, study entry, after two VTD courses, at the end of treatment and then every six months up to clinical relapse. Patients underwent MRD detection using both qualitative nested PCR and Real Time Quantitative (RQ)-PCR, employing immunoglobulin heavy chain-derived patient specific primers, as described [Voena et al., Leukemia 1997; Ladetto et al., Biol Bone Marrow Transpl 2000; van der Velden et al., Leukemia 2007]. MR was defined as negative MRD results by nested-PCR or less than 1EE-04 by RQ-PCR. Loss of MR was defined as an increase of MRD levels of at least one log in consecutive samples at whenever timepoint. For survival analysis duration of response (DOR), progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS) rates were used, as detailed in IMWG criteria [Rajkumar et al., Blood 2011]. Results Thirty-nine patients were enrolled. So far 27 serological progressions, 22 clinical relapses needing salvage treatment and 12 deaths (two non-MM-related) were observed. Median PFS was 60 months, median TNT 67 months and OS at mFU was 64%. 270 of the planned samples for MRD monitoring (86%) were actually received by the centralized lab. Currently, 26 MR and 11 MR losses have been registered. The achievement of MR was strongly associated with a better outcome, in terms of median DOR (62 vs 9 months, p<0.001), PFS (67 vs 22 months, p<0.001), TNT (108 vs 30 months, p<0.001) and resulted significant for OS, too (72% vs 48% at mFU, p=0.04, Figure 1A-B). Moreover, patients with ongoing MR, MR loss or not achieving MR at all showed increasing risk of relapse, respectively (DOR not reached vs 38 vs 9 months, PFS 92 vs 63 vs 22 months, TNT not reached vs 72 vs 30 months, each p<0.001, Figure 2). Interestingly, the time lag between MR loss and clinical relapse for patients achieving and then loosing MR was comparable to that between end of consolidation and clinical relapse for patients never obtaining MR (TNT 19 vs 11 months p=0.34). Finally, analyzing the relationship between MR achievement, MR loss and need for a salvage treatment, of the 26 patients who obtained MR only 11 (42%) received a retreatment at a median time of 42 months (range: 22-87 months). Of these 11 clinical relapses, 7 were anticipated by a molecular relapse (64%), occurring at a median time of 9 months (range: 2-39 months). The 4 relapses not anticipated by MR loss occurred in cases with inadequate follow-up sampling or at least two years after the end of the planned molecular follow-up. Conclusions Besides confirming the strong prognostic value of PCR-based MRD monitoring in MM, our long-term results indicate the following: 1) the 42 months TNT of patients achieving MR underlines the excellent disease control of MM patients once obtained MR; 2) the occurrence of MR loss heralds relapse, with a TNT from MR loss comparable to TNT of patients not achieving MR; 3) there is a 9 months lag between MR loss and need for salvage treatment. These observations will have increasing relevance considering that ongoing methodological developments will allow effective MRD monitoring in the vast majority of MM patients. Disclosures: Off Label Use: Bortezomib and thalidomide as post-transplant consolidation during first-line treatment of multiple myeloma. Ladetto:Celgene: Research Funding, Speakers Bureau; Jannsen Cilag: Research Funding, Speakers Bureau; Mundipharma: Research Funding, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Cavallo:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Jannsen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Caravita:Celgene: Honoraria, Research Funding; Jannsen Cilag: Honoraria. Guglielmelli:Celgene: Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Jannsen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

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Characteristics of a Comprehensive, Continuously Updated Longitudinal Database for Multiple Myeloma

Blood ◽

10.1182/blood-2021-148399 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4969-4969

Author(s):

C. Anthony Blau ◽

Grace Nam ◽

Leena Chhun ◽

Cheng Zheng ◽

Jayne Piboonvaranggoon ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Control ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Disease Stage ◽

Publicly Traded ◽

Advisory Committees ◽

Multi Agent

Abstract Introduction: Despite the availability of many effective agents, multiple myeloma is characterized by repeated cycles of treatment response and relapse, and remains incurable in almost all patients. Efforts to optimize treatment are complicated by variation in disease biology and by the combinatorial complexity inherent in assembling, sequencing and administering multi-agent regimens. Determining which strategies provide maximal therapeutic benefit requires deploying a variety of multi-agent regimens in a range of settings and assessing long-term outcomes; information that cannot be readily discerned from clinical trials. Here we present results from a real-world database that comprehensively tracks all treatments and responses in patients with multiple myeloma. Methods: Since March 2017, All4Cure has hosted an online platform for patients with multiple myeloma, clinicians and researchers that has been initially focused in the Pacific Northwest. Medical records from consenting patients are collected and information regarding all treatments and responses graphically displayed on their de-identified dashboards. A discussion panel allows for asynchronous communication between members of All4Cure's community of patients, clinicians and researchers (currently numbering over 1600 participants). There is no charge to patients who participate in All4Cure, and clinicians and researchers are neither charged nor paid for their participation. A summarized real-world database describes the lines of therapy that each patient has received, treatment start and stop dates, and responses in accordance with International Myeloma Working Group (IMWG) criteria. Results: The overall profile of patients with multiple myeloma enrolled in All4Cure (N=555) was benchmarked against myeloma patients from the National Program of Cancer Registries (NPCR) (diagnosis year 2017; N=25,895). Patients in all 50 States and D.C. were included in the comparison, and those with monoclonal gammopathy of undetermined significance (MGUS) were not considered. Myeloma patients enrolled in All4Cure are younger at diagnosis or start of treatment (median 61 versus between 65 and 69), more likely to be white (90.3% versus 73.5%), and more likely to reside in Washington State (41.2% versus 2%) compared to the NPCR cohort, reflecting participation influenced by geographic location as described above. After enrollment, All4Cure patients are followed longitudinally throughout the entirety of their disease course, with fewer than 2% having been lost to follow up. To gain insights uniquely available from the All4Cure database and to inform the future direction for our research, we focus our exploratory data analysis on the All4Cure cohort of patients who started treatment in June 2015 or later (N=299). Despite the relatively recent start of the All4Cure database, this timeframe allows up to 6 years of observation following the start of treatment, since the survival rates for the first 1-2 years of treatment are generally very high. Consistent with prior knowledge, increasing age and disease stage are associated with increased morality, as are high-risk cytogenetics such as 17p-, t(4:14) and t(14;16). We further explored the potential impact of early lines of therapy on long-term disease control. While the current literature is mixed on the merits of aggressive treatments in early lines of therapy in terms of overall survival, insights from our data suggest that more aggressive front-line therapies (such as SCT) are associated with improved disease control over time, although this is evolving with the impact of novel therapies and in particular the use of triplet and now quadruplet induction regimens and adapting treatment to achieve measurable residual disease (MRD) negativity. Conclusions: Even with the current limitations regarding the size and representativeness of All4Cure's database, these preliminary results support the validity of this approach for gaining insight into the treatments and outcomes of patients with multiple myeloma in real-world settings. Disclosures Blau: Oncopeptides: Other: Oncopeptides is an All4Cure customer. Blau: All4Cure: Current equity holder in publicly-traded company. Richter: Tisch Cancer Institute: Icahn School of Medicine at Mount Sinai: Current Employment; Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive biotechnologies: Speakers Bureau; BMS, Karyopharm, Antengene: Membership on an entity's Board of Directors or advisory committees. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Richardson: Secura Bio: Consultancy; Protocol Intelligence: Consultancy; Sanofi: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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Carfilzomib and Dexamethasone Vs Bortezomib and Dexamethasone in Patients with Relapsed Multiple Myeloma: Results of the Phase 3 Study Endeavor (NCT01568866) According to Age Subgroup

Blood ◽

10.1182/blood.v126.23.1844.1844 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1844-1844 ◽

Cited By ~ 3

Author(s):

Antonio Palumbo ◽

Meletios A. Dimopoulos ◽

Philippe Moreau ◽

Wee-Joo Chng ◽

Hartmut Goldschmidt ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Odds Ratio ◽

Research Funding ◽

Phase 3 ◽

Advisory Committees ◽

Younger Age ◽

Grade 3 ◽

Support Research

Abstract Introduction: Carfilzomib is a selective proteasome inhibitor that is approved in the United States and other countries for the treatment of relapsed and refractory multiple myeloma. The randomized, open-label, multicenter, phase 3 study ENDEAVOR (NCT01568866) met its primary end point, demonstrating a statistically and clinically significant improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) compared with bortezomib and dexamethasone (Vd) (median 18.7 vs 9.4 months; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.44-0.65; 1-sided P <0.001) (Dimopoulos et al, J Clin Oncol 2015;33:abstr 8509; Dimopoulos et al, Haematologica 2015;100[s1]:abstr LB2071). Herein we present results of a preplanned subgroup analysis of efficacy and safety outcomes of the ENDEAVOR study according to age. Methods: Adult patients with relapsed multiple myeloma (RMM; 1-3 prior regimens) were eligible. Patients in the Kd arm received K (30-min intravenous [IV] infusion) on days (D) 1, 2, 8, 9, 15, and 16 (20 mg/m2 on D1, 2 [cycle 1]; 56 mg/m2 thereafter) and dexamethasone (20 mg) on D1, 2, 8, 9, 15, 16, 22, and 23 of 28-day cycles. The Vd arm received V (1.3 mg/m2; IV or subcutaneously) on D1, 4, 8, and 11 and dexamethasone (20 mg) on D1, 2, 4, 5, 8, 9, 11, and 12 of 21-day cycles. Treatment was administered until disease progression or unacceptable toxicity. The primary end point of the study was PFS; secondary end points included overall survival, overall response rate (ORR), duration of response (DOR), safety, and rate of peripheral neuropathy (PN). The present analyses evaluated outcomes in patients grouped according to age (ie, <65, 65-74, and ≥75 years of age). Results: A total of 929 patients were enrolled (intent-to-treat population; <65 years: Kd, n=223; Vd, n=210; 65-74 years: Kd, n=164; Vd, n=189; ≥75 years: Kd, n=77; Vd, n=66). Baseline patient and disease characteristics were generally well balanced between treatment arms within each age subgroup. PFS was improved with Kd vs Vd within each age subgroup (<65 years: median, not estimable vs 9.5 months [HR, 0.58; 95% CI, 0.44-0.77]; 65-74 years: median, 15.6 months vs 9.5 months [HR, 0.53; 95% CI, 0.38-0.73]; ≥75 years: median, 18.7 months vs 8.9 months [HR, 0.38; 95% CI, 0.23-0.65]) (Table). Kaplan-Meier PFS curves by age subgroup are shown in the Figure. ORRs in each age group were also higher in the Kd arm compared with the Vd arm in each subgroup (<65 years: 74% vs 61% [odds ratio, 1.82; 95% CI, 1.21-2.74]; 65-74 years: 77% vs 66% [odds ratio, 1.80; 95% CI, 1.12-2.89]; ≥75 years: 84% vs 59% [odds ratio, 3.75; 95% CI, 1.71-8.24]). Rates of grade ≥3 adverse events of interest, including hypertension are shown in the Table. Grade ≥3 hypertension, dyspnea, cardiac failure, renal failure were more common with Kd vs Vd within each age subgroup. Rates of grade ≥2 PN were lower in the Kd arm across all subgroups compared with the Vd arm (<65 years: 6% vs 27% [odds ratio, 0.17; 95% CI, 0.09-0.32]; 65-74 years: 8% vs 34% [odds ratio, 0.17; 95% CI, 0.09-0.32]; ≥75 years: 3% vs 43% [odds ratio, 0.035; 95% CI, 0.008-0.16]). Adverse events leading to treatment discontinuation occurred at similar frequencies in the Kd and Vd arms in the two younger-age subgroups (<65 years: 17% vs 15%; 65-74 years: 22% vs 22%), but at a higher frequency in the Vd arm for the oldest-age subgroup (≥75 years: 26% vs 35%). Deaths within 30 days post-treatment due to adverse events occurred at similar rates in the Kd and Vd arms within each age subgroup (<65 years: 3% vs 3%; 65-74 years: 5% vs 3%; ≥75 years: 4% vs 5%). Conclusions: Kd demonstrated clinically meaningful improvement in PFS and ORR compared with Vd within all age subgroups examined, with a trend toward a greater improvement in the eldest-age subgroup (≥75 years) than in the two younger-age subgroups (<65 and 65-74 years). The eldest-age subgroup in the Kd arm had an increased incidence of select grade ≥3 adverse events of interest, including cardiac failure and hypertension, compared with the younger-age subgroups in the Kd arm. Hypertension is a recognized but manageable complication in elderly patients and should be monitored. Overall, results suggest that Kd has a favorable benefit-risk profile in patients with RMM, irrespective of age. Disclosures Palumbo: Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Dimopoulos:Janssen: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Genesis: Honoraria; Janssen-Cilag: Honoraria. Moreau:Novartis, Janssen, Celgene, Millennium, Onyx Pharmaceuticals: Consultancy, Honoraria. Goldschmidt:Janssen, Celgene, Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria; Amgen, Takeda: Consultancy; BMS: Consultancy, Research Funding; Chugai, Millennium: Honoraria, Research Funding. Hájek:Janssen-Cilag: Honoraria; Celgene, Amgen: Consultancy, Honoraria. Facon:Onyx/Amgen: Membership on an entity's Board of Directors or advisory committees. Ludwig:Janssen Cilag: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Celgene Corporation: Honoraria, Speakers Bureau; Takeda: Research Funding. Niesvizky:Celgene, Millennium, Onyx: Consultancy, Speakers Bureau. Oriol:Celgene, Janssen, Amgen: Consultancy, Speakers Bureau. Rosiñol:Celgene, Janssen: Honoraria. Gaidano:Celgene: Research Funding; Morphosys, Roche, Novartis, GlaxoSmith Kline, Amgen, Janssen, Karyopharm: Honoraria, Other: Advisory Boards. Weisel:Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Support; Janssen: Consultancy, Honoraria, Other: Travel Support, Research Funding; Onyx: Consultancy, Honoraria; Novartis: Other: Travel Support; Takeda: Other: Travel Support; Noxxon: Consultancy. Gillenwater:Onyx, Amgen: Employment, Other: Stock. Mohamed:Onyx/Amgen: Employment, Other: Stock. Feng:Amgen/Onyx: Employment, Equity Ownership. Joshua:Celgene: Membership on an entity's Board of Directors or advisory committees.

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Updated Progression-Free Survival (PFS) and Overall Survival (OS) with Melflufen and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Results from the Phase 2 Study O-12-M1

Blood ◽

10.1182/blood-2019-124828 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1839-1839 ◽

Cited By ~ 1

Author(s):

Sara Bringhen ◽

Peter M. Voorhees ◽

Torben Plesner ◽

Ulf-Henrik Mellqvist ◽

Brandi Reeves ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Peptidase Activity ◽

Efficacy And Safety ◽

Advisory Committees ◽

Equity Ownership

Background: Patients with multiple myeloma (MM) who have relapsed after conventional treatment have limited therapeutic options for long-term disease control. Melflufen is a lipophilic peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells through peptidase activity. In the first report of efficacy and safety for the phase 1/2 study O-12-M1 (median follow-up, 28 months), melflufen and dexamethasone demonstrated an overall response rate of 31%, a median PFS of 5.7 months, and a median OS of 20.7 months, with acceptable safety for patients with RRMM (Richardson PG, et al. Blood. 2017; Abstract 3150). Here, updated OS and PFS results from the O-12-M1 study are reported, with 18 months of additional follow-up of the patients who were still participating in long-term follow-up at the time of the final database lock in November 2017. Methods: Eligible patients had RRMM, measurable disease, and ≥2 prior lines of therapy, including bortezomib and lenalidomide. Patients must have had progressive disease (PD) on or within 60 days of completion of last therapy. Patients received melflufen 40 mg intravenously on day 1 of each 28-day cycle and oral dexamethasone 40 mg weekly for up to 8 cycles or longer at the discretion of the investigator and sponsor. Treatment continued until PD or unacceptable toxicity. Patients were followed up for 2 years after PD or start of subsequent therapy. PFS and OS were secondary end points in this study. Time to next treatment (TTNT), an exploratory end point defined as the time from start of melflufen and dexamethasone to first subsequent therapy or death, was retrospectively reviewed. Results: As of 15 May 2019, 45 patients were treated. Median age was 66 years (range, 47-78); 60% of patients had International Staging System stage II/III at study entry, and 44% had high-risk cytogenetics [del(17p), t(14;16), t(4;14), t(14;20), or gain(1q)]. The median time since initial diagnosis was 5.0 years (range, 1-21). Patients received a median of 4 prior lines of therapy (range, 2-14). All patients were exposed to IMiDs, 98% to proteasome inhibitors (PIs), 93% to alkylators (any dose of melphalan, cyclophosphamide, or bendamustine), and 80% to melphalan; 87% were refractory to last line of therapy, and 91%, 67%, and 7% were single (IMiD or PI), double (IMiD and PI), and triple (IMiD, PI, and daratumumab) refractory, respectively. After a median follow-up of 30.1 months, median PFS was 5.7 months (95% CI, 3.7-9.3; 98% events). Median OS was 20.7 months (95% CI, 13.6-not reached; 58% events; Figure). Updated PFS, OS, and TTNT data will be presented. No new adverse events (AEs) were reported. Conclusion: Melflufen and dexamethasone resulted in sustained long-term benefits (median OS, 20.7 months) and no new AEs with 1.5 years of additional follow-up of patients with late-stage, heavily pretreated RRMM who have relapsed on conventional therapy including bortezomib and lenalidomide. Further trials are ongoing to evaluate efficacy and safety of melflufen, including the phase 3 study OCEAN (OP-103; NCT03151811) of melflufen plus dexamethasone versus pomalidomide plus dexamethasone in patients with RRMM refractory to lenalidomide. Figure Disclosures Bringhen: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Voorhees:Novartis: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TeneoBio: Consultancy, Research Funding; Amgen: Research Funding; GSK: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Plesner:AbbVie: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy; Janssen: Consultancy, Research Funding. Mellqvist:Amgen, Janssen, Oncopeptides, Sanofi, Sandoz, Takeda: Honoraria. Reeves:Celgene: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria. Byrne:Oncopeptides: Consultancy; Takeda: Consultancy. Nordström:Oncopeptides: Employment, Equity Ownership. Harmenberg:Oncopeptides: Consultancy, Equity Ownership. Obermüller:Oncopeptides: Employment. Richardson:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This is a Phase 1/2 investigational study of melflufen in RRMM

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Biomarkers of Bone Remodeling in Multiple Myeloma Patients to Tailor Bisphosphonate Therapy

Blood ◽

10.1182/blood.v120.21.3965.3965 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3965-3965

Author(s):

Chirayu Patel ◽

Andrew Yee ◽

Tyler A. Scullen ◽

Neeharika Nemani ◽

Loredana Santo ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Dose ◽

Board Of Directors ◽

Bone Remodeling ◽

Research Funding ◽

Advisory Board ◽

T Test ◽

Advisory Committees ◽

Paired T Test

Abstract Abstract 3965 Background: Aminobisphosphonates (aBP) are standard of care for myeloma-related bone disease and are recommended every 3–4 weeks. Multiple myeloma patients may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures secondary to altered bone remodeling due to long-term aBP therapy. Monthly dosing of aBP is based on early studies that documented the suppression of N-telopeptide (NTX), a marker of bone resorption, for 4–8 weeks following a single dose of aBP. However, it is unclear whether NTX or other bone biomarkers are predictive of skeletal related events (SRE) or what the impact of cessation of aBP therapy has on bone remodeling. Methods: We studied markers of bone turnover after a single dose of zoledronic acid in myeloma patients in remission (NCT00577642). All patients had received 8–12 doses of aBP (pamidronate/zoledronic acid) prior to study inclusion. Patients were not receiving active anti-myeloma therapy besides maintenance therapy. Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronic acid on study. A secondary objective was the identification and correlation of other markers of bone remodeling with NTX changes. High throughput cytokine arrays of validated and potential surrogate markers of bone remodeling were performed. Bone marrow biopsies at start and end of protocol during which time aBPs were not administered were performed. Patients were removed from study if NTX crossed a threshold value (50 nMol), based on correlation of NTX levels with bone-related morbidity and mortality. Results: Twenty-nine patients were enrolled in a 6-month period. Cytokine array data is available in 28 patients. All patients had suppressed NTX levels, except one patient who had an increase in NTX levels associated with a SRE and disease progression. To identify other surrogate as yet unexplored cytokines that may serve as better markers in addition to NTX to monitor aBP activity, thirty cytokines were curated from the literature based on their possible role in bone remodeling and tested using custom designed cytokine arrays. Positive hits were confirmed by ELISA. GDF-15, which correlates with poor prognosis in myeloma and is thought to be produced by bone marrow mesenchymal stem cells, decreased in 24 of 28 patients (two-sided paired T test, p<0.001). However, decorin, a proteoglycan produced by osteoblasts that seems to have anti-myeloma properties based on knockdown studies, decreased in 20 of 28 patients at 6 months as compared to beginning of study (two-sided paired T test, p<0.001). In addition, there was evidence that there is some recovery of osteoblast function with cessation of aBP, with increased osteopontin and osteoprotegerin levels in at least half of the patients. Although these results were not significant in aggregate, when complemented with ELISA results of bone-specific alkaline phosphatase showing an increase in 18 of 28 patients (two-sided paired T test, p<0.001), they signify that oversuppression of osteoblasts by long-term aBP may be reversible. Effects on osteoclasts and osteoblasts are being confirmed by immunohistochemistry on BM biopsies. Conclusion: Our data suggest that suppressed NTX levels are predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP is reversible in myeloma. Importantly, the role of other surrogates such as decorin and GDF-15 need further validation and are the subject of ongoing studies. Taken together, this evidence may provide rationale for less frequent aBP dosing in multiple myeloma patients to help lower the incidence of long term toxicities such as ONJ and stress fractures, by allowing limited recovery of bone remodeling without adverse effects on multiple myeloma progression. Disclosures: Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Bristol Myers Squibb: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Onyx: Advisory Board, Advisory Board Other; Novartis: Advisory Board Other. Schlossman:Celgene: Membership on an entity's Board of Directors or advisory committees. Anderson:Onyx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Raje:Onyx: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding.

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