Evaluation of Atypical Low Energy Fractures in Patients Affected by Multiple Myeloma Treated with Bispohosphonates

Abstract Abstract 5134 BACKGROUND: Bisphosphonates (BP) are standard supportive care in patients affected by symptomatic multiple myeloma (MM) with skeletal lesions. Despite the long term use of BP in the clinic, many of the effects of this category of drugs and their optimal schedule of administration are still matter of debate. In the recent past the identification of osteonecrosis of the jaw induced clinicians and researchers to reevaluate the schedule of administration of BP in myeloma, questioning about their effects on other cells than osteoclasts. Therefore a better definition of risks and benefits of anti-catabolic agents may help addressing future studies in this field. Recently a growing number of publications alerted orthopedics and endocrinologists about a rare but serious event called “atypical low energy fractures” (LEF) in patients affected by osteoporosis treated with long term BP (1–3). LEF refer to stress fractures, mainly localized in the subtrochanteric region, spontaneous or secondary to minor trauma, often preceded by local pain, with specific radiologic patterns and sometimes delayed healing. Localizations in bones different than femur have been reported. Still debated is the association with BP and the pathophysiology of this condition. So far three cases of fractures with the characteristics of LEF have been described in MM patients. METHODS: in order to evaluate the possible existence of other cases of LEF in patients with MM we started a retrospective survey in hematological centers, collecting the cases of MM followed by each center between January 2005 and December 2010, and any case of atypical fracture not related to MM or major trauma. Inclusion criteria for LEF were so defined: diagnosis of MM; treatment with BP; fractures induced by minor trauma or spontaneous, not associated with MM localization; radiological aspect of stress fracture; +/− prodromic pain. Central revision of patients history and radiology will be conducted with the support of an orthopedic in the patients with atypical fractures, followed by bone histomorphometry on bone marrow biopsy. RESULTS: The study is ongoing. At present seven centers reported a total of 1065 patients affected by MM followed between 2005 and 2010 and five cases of suspect LEF. The first patient is a woman diagnosed with anaplastic myeloma in 2002, apparently in complete remission after 4 lines of treatment. In June 2008 the patient was diagnosed with an atraumatic left fracture of the fifth metatarsal bone, followed by a right metatarsal fracture one month later and second right metatarsal stress fracture in 2011. The fractures were not related to myeloma localization. Other four cases of fractures are under investigation in other two center. CONCLUSIONS: MM patients are exposed to high rate of bone fractures related to the hematological disease and at the best of our knowledge the frequency of stress fractures in this population is unknown. With the present study, over a population of more than one thousand patients, we observed five cases of possible LEF that will undergo detailed analysis through central revision of patients history, radiology and bone histomorphometry with the aim to identify individual risk factors. Despite LEF is a rare and still controversial condition, the identification of individual risks to develop fractures not secondary to MM, may help clinicians tailoring the treatment for bone disease, much needed in an era of new drug discoveries for bone treatment. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria.

Download Full-text

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

Blood ◽

10.1182/blood-2019-128795 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 324-324 ◽

Cited By ~ 1

Author(s):

Stefan O. Schönland ◽

Simona Iacobelli ◽

Linda Koster ◽

Didier Blaise ◽

Michael Potter ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Time Varying ◽

Advisory Committees ◽

Dynamic Prediction ◽

Landmark Analysis ◽

Entire Cohort ◽

Younger Age

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

Long-Term Use of Lenalidomide Plus Low-Dose Dexamethasone (Rd) in Chinese Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): MM-024 Expanded Access Program (EAP)

Blood ◽

10.1182/blood.v124.21.5737.5737 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5737-5737

Author(s):

Xin Du ◽

Jie Jin ◽

Zhen Cai ◽

Fangping Chen ◽

Dao-bin Zhou ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Low Dose ◽

Median Number ◽

Upper Respiratory Tract ◽

Advisory Committees ◽

Grade 3 ◽

Cutoff Date

Abstract Introduction: In China, the Rd regimen is approved for use in multiple myeloma (MM) pts who have received ≥ 1 prior treatment (Tx). This approval was based on the efficacy and safety of Rd demonstrated in the MM-021 study, a phase 2 multicenter registration trial in which 199 pts were enrolled (Hou, J Hematol Oncol 2013). MM-024 is both an EAP and an extension study that was initiated in order to provide continued Rd regimen for pts enrolled in the MM-021 study. Updated safety and efficacy information from the EAP is presented here. Methods: Eligible pts had participated in MM-021, were still on Tx for ≥ 1 year (yr) and were progression-free. Pts received the same regimen of Rd as in MM-021 (lenalidomide 25 mg/day on days 1–21, and low-dose dexamethasone 40 mg/day on days 1, 8, 15, and 22 of each 28-day cycle). The starting doses of Rd were the same as the last doses received in MM-021 unless dose adjustments were required prior to rollover, as per protocol. Tx was continued until progressive disease (PD) or withdrawal due to toxicities, and pts were followed-up for a maximum of 5 yrs (which included 1 yr spent in the MM-021 study). The primary endpoint was safety, including the incidence of second primary malignancy (SPM). Secondary endpoints included progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Results: By the cutoff date (May 5th, 2014), of the 41 pts who entered the Tx phase of the EAP, 21 are still receiving Tx with a median number of 22 cycles. A total of 20 pts discontinued Tx: 18 discontinued due to PD; 1 due to death (related to lung infection); and 1 was lost to follow-up. Median follow-up was 37.5 months (mos) from initial enrolment in the MM-021 study. Median age was 59 yrs (range 47–74) and 34% of pts were aged > 65 yrs. Most pts (78%) had Durie-Salmon stage III disease at baseline. All pts had received prior Tx for MM, including thalidomide and bortezomib; 7.3% of pts had undergone surgery and 2.4% of pts had received radiation therapy. The median number of prior Tx was 3 (range 1–11); 76% of pts had received prior bortezomib, 68% had received prior thalidomide, and 46% had received both. Median duration of Rd Tx was 21.6 mos (range 13.1–37.5) and 22% of pts have received > 25 mos of the regimen. All efficacy endpoints were measured from the enrolment date of the MM-021 study. Median PFS and median TTP were both 36.0 mos. Median OS has not been reached due to the low number of deaths. Overall, 48.8% of pts had grade 3–4 treatment-emergent adverse events (TEAEs); the most common TEAEs were anemia (51.2%), decreased neutrophil count (48.8%), upper respiratory tract infection (41.5%), neutropenia (31.7%), cough (24.4%), diarrhea (22.0%), and pyrexia (22.0%). Grade ≥ 3 TEAEs included neutropenia (14.6%), anemia (4.9%), thrombocytopenia (2.4%), and pneumonia (7.3%). No TEAEs led to Tx discontinuation; however, TEAEs led to lenalidomide dose reduction (14.6%), interruption (39%), or both (14.6%). Updated efficacy, survival, and SPM analysis will be presented at the meeting. Conclusions: After 37.5 mos of follow-up, median PFS was 36 mos, compared with the median PFS of 7.5 mos in the MM-021 final analyses (cutoff date January 4th, 2013). This indicates that long-term use of Rd is well tolerated and continues to be an effective Tx in Chinese pts with RRMM who have received multiple prior Tx. Disclosures DeMarco: Celgene Corporation: Employment. Zhang:Celgene Corporation: Employment. Mei:Celgene Corporation: Employment. Hou:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

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.

Download Full-text

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

Download Full-text

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.

Download Full-text

Bortezomib Induction and Maintenance in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up of the HOVON-65/GMMG-HD4 Trial

Blood ◽

10.1182/blood.v126.23.27.27 ◽

2015 ◽

Vol 126 (23) ◽

pp. 27-27 ◽

Cited By ~ 22

Author(s):

Pieter Sonneveld ◽

Hans-Juergen Salwender ◽

Bronno Van Der Holt ◽

Laila el Jarari ◽

Uta Bertsch ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Negative Impact ◽

Newly Diagnosed ◽

Advisory Committees ◽

Long Term Follow Up ◽

Support Research

Abstract Background: We reported better PFS and OS in transplant eligible patients with newly diagnosed Multiple Myeloma (MM) who were treated with bortezomib during induction and maintenance, when compared with standard treatment in the HOVON-65/GMMG-HD4 trial. (P. Sonneveld et al., J Clin Oncol 30:2946-2955, 2012). Here the long-term follow up data are presented. Methods: 827 eligible patients were randomized to induction therapy with VAD (vincristine, doxorubicin, dexamethasone) or PAD (bortezomib, doxorubicin, dexamethasone) followed by high-dose melphalan (once or twice) and autologous stem cell transplant. Maintenance consisted of daily thalidomide (T) 50 mg (VAD arm) or 2-weekly bortezomib (B) 1.3 mg/m2 (PAD arm) for 2 years. The primary endpoint was progression-free survival (PFS) adjusted for ISS stage. Results: After a median follow up of 91.4 months (maximum 119) 410 patients are alive. Response rates were VAD/HDM/T: CR 25%, ≥VGPR 56%, ≥PR 83%; PAD/HDM/B: CR 37%, ≥VGPR 76%%, ≥PR 91%, The median duration of maintenance therapy was 14 months (thalidomide) and 23 months (bortezomib), respectively. Main reasons for discontinuation were toxicity (T: 31%; B: 11%), disease progression (T: 33%; B: 36%) or normal completion (T: 28%; B: 48%). Of 827 patients in the analysis, 206 are alive without progression/relapse. PFS was significantly better in the bortezomib arm, i.e. median 34 versus 28 months (HR=0.77, 95% CI=0.65-0.90, p=0.001). Median overall survival (OS) was 90 months in the bortezomib arm vs 83 months in the control arm, but 42% at 9 years in both arms. We used the restricted mean survival time (RMST) method to compare OS between the two treatment arms In univariate analysis. The difference in RMST8y was 4.8 months (95% CI 0.2-9.5, p=0.04) in favor of the bortezomib arm. A landmark analysis in patients who had received HDM starting at 12 months showed a significant PFS advantage of bortezomib in all patients (p=0.02), in patients in VGPR/PR (p=0.02) but not in CR (p=0.19). For OS there was no advantage for bortezomib in either group. PFS at 60 months in bortezomib treated patients was not different when single vs double HDM/ASCT was administered, i.e. 28% vs 27%. However, OS at 60 months was 71% vs 60% in favor of double HDM/ASCT (p=0.04). Subgroup analysis was performed based on presence/absence of adverse FISH (CA) in 395 patients treated with double HDM/ASCT. PFS at 60 months for each abnormality (CA or no CA) in bortezomib vs standard arm is given in Table 1 Table 1.PFS at 60 months, %OS at 60 months, %FISHnBortezomib armpStandard armBortezomib armpStandard Armt(4;14) yes/no50/29516% vs 27%0.048% vs 24%52% vs 75%0.0133% vs 64%add(1q) yes/no113/23116% vs 32%0.00510% vs 28%57% vs 79%0.00143% vs 70%del(17p) yes/no39/31222% vs 27%0.475% vs 24%65% vs 72%0.4818% vs 66% These data show that bortezomib treatment combined with double HDM/ASCT significantly improves PFS and OS in patients with del(17p) and almost abrogates the negative impact of this CA. In t(4;14) and add(1q) some improvement is observed, however the negative impact remains significant. In high-risk patients presenting with elevated creatinine >2 mg/dL bortezomib significantly improved PFS at 60 months (32% vs 5%) (p=0.001) and OS at 60 months (66% vs 21% months (p<0.001)). OS at 8 years was 46% vs 12%. Finally, OS from progression/relapse was not different between patients treated in the bortezomib vs standard arm (OS at 72 months: 33% vs 35%, p=0.73) Conclusions: We conclude that bortezomib leads to a significant and lasting improvement of PFS and OS. Bortezomib significantly reduces the high-risk impact of del(17p) and renal impairment on survival. This trial was registered as NTR213; EudraCT no. 2004-000944-26.and supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research and an unrestricted grant from Janssen. The GMMG group received grants for this trial by Novartis, AMGEN, Chugai and Roche. Disclosures Sonneveld: SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Blau:MSD: Honoraria; Celgene: Honoraria, Research Funding; AMGEN: Honoraria; JAZZ pharm: Honoraria; BMS: Honoraria; Shire: Honoraria; Baxalta: Honoraria; Janssen: Honoraria, Research Funding. Zweegman:celgene: Honoraria, Research Funding; takeda millennium: Honoraria, Research Funding; onyx: Honoraria. Weisel:Noxxon: Consultancy; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Support; BMS: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding. Broijl:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Scheid:Janssen: Honoraria; Celgene: Honoraria. Potamianou:Janssen: Employment. Hose:Takeda: Other: Travel grant; EngMab AG: Research Funding. Kersten:takeda millennium: Research Funding; janssen: Honoraria, Research Funding; roche: Honoraria, Research Funding. Duehrsen:Alexion: Honoraria; janssen: Honoraria. Lokhorst:Janssen: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Amgen: Honoraria. Goldschmidt:celgene: Honoraria, Research Funding; janssen: Honoraria, Research Funding; novartis: Honoraria, Research Funding; chugai: Honoraria, Research Funding; onyx: Honoraria, Research Funding; millennium: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

Download Full-text

Lenalidomide and Vorinostat Maintenance after Autologous Transplant in Multiple Myeloma- Long Term Follow-up

Blood ◽

10.1182/blood-2018-99-116460 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2155-2155

Author(s):

Nidhi Sharma ◽

Nita Williams ◽

Ashley E. Rosko ◽

Don M. Benson ◽

Maria Chaudhry ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Mhc Class I ◽

Research Funding ◽

Nk Cell ◽

Advisory Committees ◽

Autologous Transplant ◽

Long Term Follow Up

Abstract Introduction: Post autologous transplant maintenance therapy with lenalidomide for patients with multiple myeloma (MM) is standard of care (McCarthy et al, NEJM, 2012). Vorinostat (SAHA, Zolinza) is a HDAC inhibitor and preclinical data suggested that HDAC-I's increase MHC class I and class II expression, rendering tumor cells more susceptible to host innate immune killing. Lenalidomide activates NK cells via PP2A inhibition and induces CD56 expression in CD16+CD56- cells thereby enhancing NK cell-mediated ADCC. Initiating lenalidomide to enhance NK cell activity against tumor cells in the early post autologous transplant period may be particularly effective when the NK:myeloma cell ratios favor NK killing, especially if administered after increased MHC class I expression induced by HDAC-I pretreatment. We hypothesized that the combination of vorinostat and lenalidomide would be both tolerable and effective in the post-transplant setting. We have published the initial report of this combination (Sborov, BJH, 2015). We now present the long term follow up. Methods: This was a non-randomized, open-label phase I trial for patients with myeloma who have received high dose IV melphalan followed by autologous peripheral blood stem cell transplant (ASCT) following the three-and-three up-and-down phase I design. Vorinostat was administered beginning at 200 mg starting day +90 after HSCT for days 1-7 and 15-21 of a 28-day cycle combined with lenalidomide 10 mg days 1-21 of a 28-day cycle until progression or clinically significant toxicity. The initial dose of lenalidomide could be increased from 10 mg after cycle 1 and escalated as tolerated up to 25 mg. Results: Sixteen patients were enrolled after autologous transplant with a median age 58 y.o. (range 41-67), with a median number of prior therapies at enrollment of 2 (range 1-8) and mean ISS stage 1.5 (range 1-3). Twelve patients had trisomies on CD138-selected FISH, one patient had normal cytogenetics, and three patients had high risk features [complicated karyotype, t(4;14), or abnormal chromosome 1]. All patients started with 10 mg of lenalidomide and 14 patients received more than one cycle of therapy. 11/14 (78%) were able to escalate the lenalidomide dose. 4/11 (36%) were able to escalate to 25 mg of lenalidomide. The tolerability, toxicities and adverse events have been previously reported (Sborov, BJH, 2015). With a median follow up of 84 months (range 17 - 88), 9 patients (56%) have progressed and 5(31%) have died due to disease progression. Seven patients (44%) remain in complete remission with 5 currently on continued maintenance more than 72 months from ASCT. The median progression-free survival (PFS) is 46.5 months (range 2 - 88) and the median overall survival (OS) has not been reached (17 to NR) (Figure 1). Conclusions: The combination of lenalidomide and vorinostat is well tolerated, with prolonged PFS and OS. Details on the current seven patients still in remission and on continued maintenance will be presented at the meeting. Disclosures Hofmeister: Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

Download Full-text