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

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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Alliance A061202. a Phase I/II Study of Pomalidomide, Dexamethasone and Ixazomib Versus Pomalidomide and Dexamethasone for Patients with Multiple Myeloma Refractory to Lenalidomide and Proteasome Inhibitor Based Therapy: Phase I Results

Blood ◽

10.1182/blood.v126.23.375.375 ◽

2015 ◽

Vol 126 (23) ◽

pp. 375-375 ◽

Cited By ~ 14

Author(s):

Peter M. Voorhees ◽

Flora Mulkey ◽

Hani Hassoun ◽

Claudia E. Paba-Prada ◽

Yvonne A. Efebera ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Phase I ◽

Board Of Directors ◽

Proteasome Inhibitor ◽

Research Funding ◽

Refractory Disease ◽

Advisory Committees ◽

Grade 3 ◽

Experienced Grade

Abstract BACKGROUND: Pomalidomide-dexamethasone (Pom-Dex) represents an important therapeutic advance for the treatment of patients with relapsed/refractory multiple myeloma (MM). Nonetheless, patients with lenalidomide (Len) and bortezomib (double) refractory disease have a median progression-free survival of only 3.7 months with the combination, thus highlighting the need for further progress. Ixazomib, a novel, oral proteasome inhibitor, has pharmacodynamic properties that may allow for improved proteasome inhibition at the tumoral level and has synergistic activity in combination with IMiDs in preclinical MM models. Clinical studies have demonstrated activity as a single agent in relapsed/refractory MM and in combination with Len-Dex in newly diagnosed patients. We therefore evaluated the safety and preliminary efficacy of the combination of Pom, ixazomib and Dex in patients with Len and proteasome inhibitor (PI) refractory MM in the phase I portion of Alliance study A061202. METHODS: Key eligibility criteria included: relapsed or relapsed/refractory disease; ≥2 prior lines of therapy; double refractory disease (progression on or ≤60 days from the last dose of a Len- and PI-based therapy); ECOG performance status (PS) ≤2; absolute neutrophil count ≥1.0 x 109/L, platelets ≥50 x 109/L, creatinine clearance ≥50 mL/min; and ≤grade 2 peripheral neuropathy. Patients were treated with escalating doses of Pom and ixazomib utilizing a standard 3 + 3 dose escalation design in combination with standard dose Dex (Table 1). Patients received 2 - 4 mg of Pom on days 1 - 21; ixazomib 3 - 4 mg on days 1, 8 and 15; and Dex 40 mg (20 mg for those >75 years of age) on days 1, 8, 15 and 22 of a 28-day cycle. Patients were treated until disease progression or the development of unacceptable toxicity. RESULTS: Out of 17 evaluable patients, the median age was 64 (range 47 - 77) and the median time from diagnosis 5.5 years (range 3.3 - 8.3). Sixty-five percent, 24% and 12% had ISS stage 1, 2 and 3 disease at the start of treatment, respectively, and 65% had high-risk cytogenetics (gain of 1q, del[17p] and/or high-risk IgH translocation). All patients had an ECOG PS of 0 or 1 (59% and 41%, respectively). Of 14 patients with complete prior treatment data available, 100% had received prior Len, bortezomib and Dex, 71% alkylating agents (cyclophosphamide or low dose melphalan), 71% autologous stem cell transplant and 29% carfilzomib. Eighty-two percent were refractory to sequential Len- and bortezomib regimens, whereas 6% were refractory to a prior Len/proteasome inhibitor combination (12% not reported). Two dose limiting toxicities have occurred to date, 1 each at dose levels 3 and 4 (Table 1). Grade 3 and 4 neutropenia, thrombocytopenia and lymphopenia attributable to protocol therapy have been seen in 29%/6%, 12%/6% and 29%/0% of patients, respectively. Twelve percent of patients have experienced grade 3 infection, regardless of attribution, but none have experienced ≥grade 4 infection. The incidence of therapy-related peripheral neuropathy was 24%, none of which was ≥grade 3 in severity. Other common, therapy-related adverse events have included fatigue (53%), nausea (24%), constipation (18%), diarrhea (29%), rash (18%), tremor (24%), anxiety (18%), insomnia (29%) and edema (24%), all of which were ≤grade 2 in severity. Fifty-three percent of patients had at least 1 of the 3 medications dose reduced, and 35% experienced dose delays. To date, 1 patient has discontinued therapy due to adverse events and 1 due to refusal of further therapy. Of 13 patients receiving >1 cycle of therapy, the best overall response rate was 62% (7 partial responses, 1 very good partial response). CONCLUSIONS: The Pom, ixazomib and Dex combination has demonstrated an acceptable toxicity profile thus far with encouraging preliminary efficacy. Updated results of the phase I portion of the study will be presented at the meeting, including the maximum tolerated dose that will be used in the randomized, phase II portion of the study, in which the 3-drug combination will be compared with Pom-Dex in double refractory MM patients. ClinicalTrials.gov Identifier: NCT02004275. Supported by U10CA180821, U10CA180882. Table 1. Dose Level Pomalidomide Dose (mg) Ixazomib Dose (mg) DLT Evaluable DLTs 1 2 3 3 None 2 3 3 3 None 3 4 3 6 1 febrile neutropenia 4‡ 4 4 4 1 grade 4 thrombocytopenia lasting 8 days ‡enrollment into dose level 4 is complete. Disclosures Voorhees: Janssen, Celgene, GlaxoSmithKline, Onyx Pharmaceuticals and Oncopeptides: Consultancy, Research Funding; Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Millennium/Takeda and Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: We will discuss the use of Ixazomib, an agent that is not FDA approved, in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma.. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.

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Baseline Peripheral Neuropathy Does Not Impact the Efficacy and Tolerability of the Novel Proteasome Inhibitor Carfilzomib (CFZ): Results of a Subset Analysis of a Phase 2 Trial In Patients with Relapsed and Refractory Multiple Myeloma (R/R MM)

Blood ◽

10.1182/blood.v116.21.3031.3031 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3031-3031 ◽

Cited By ~ 4

Author(s):

Thomas Martin ◽

Seema B. Singhal ◽

Ravi Vij ◽

Michael Wang ◽

A. Keith Stewart ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Board Of Directors ◽

Proteasome Inhibitor ◽

Research Funding ◽

Response Rate ◽

Single Agent ◽

Advisory Committees ◽

Ortho Biotech ◽

New Onset

Abstract Abstract 3031 Background: Treatment-induced peripheral neuropathy (TIPN) can be a debilitating side-effect as well as a therapy-limiting complication in multiple myeloma (MM). Thalidomide (THAL) and bortezomib (BTZ) are two therapies frequently associated with TIPN in MM. Carfilzomib (CFZ) is a novel and highly selective epoxyketone proteasome inhibitor that differs from BTZ both structurally and mechanistically. CFZ overcomes BTZ-resistance in vitro, lacks the off-target activities of BTZ in preclinical studies, and does not cause neurotoxicity in long-term (6–9 month) chronic animal toxicology studies (Kirk et al. Blood, 2008). Single-agent CFZ produces durable responses in relapsed or refractory (R/R) MM without dose-limiting PN. Here we report on the clinical experience with single-agent CFZ in the Ph 2b PX-171-003-A1 trial in patients (pts) with R/R MM and Grade (G) 1/2 PN at study entry. Methods: Pts received CFZ at 20 mg/m2 IV, on Days 1, 2, 8, 9, 15, and 16 in a 28-day cycle (C) for the first C followed by 27 mg/m2 thereafter for up to 12 C. Pts completing 12 C were eligible to enter an extension study. Responses and progression were determined according to the International Myeloma Working Group (IMWG) criteria and were assessed by an Independent Review Committee (IRC). PN data were collected for all pts on study and included neuropathy history, neurological physical exam and PN-related quality of life data (FACT-GOG/NTx v 4.0 scores) collected at screening. Prospective neurological exams and subjective reporting of PN occurred every 2 cycles until study discontinuation to proactively assess for PN. Adverse event (AE) data were also collected, with AEs reported as ‘neuropathy peripheral', ‘neuropathic pain', ‘neuropathy', and ‘peripheral sensory neuropathy' included as PN. AE reports of ‘paraesthesias' and ‘dysesthesias' were counted separately. Results: Of the 266 pts with R/R MM in PX-171-003-A1, 237 (89%) had a history of PN which was attributable to prior anti-myeloma therapy, including THAL (108 pts/41%), BTZ (134 pts/50%), or both BTZ and THAL (17 pts/6.4%). 206 of the 266 (77%) had G1/2 PN at baseline and a median disease duration of 5.9 years. This subset with active PN at baseline had received a median of 5 prior lines of therapy (range 1–20), with a median 13 anti-myeloma agents, and a median of 2 prior BTZ- and 1 prior THAL- containing regimens. Prior therapies included 100% BTZ, and 100% either THAL (77%) or prior lenalidomide (95%). Responses in the subset of pts with baseline PN were nearly identical to those seen in the full study population with an overall response rate (ORR; ≥ partial response [PR]) of 24% and a clinical benefit response rate (CBR; ≥ minimal response [MR]) of 36%. The median duration of response (≥PR) was 7.4 mo (95% CI 5.6–not reached) and median duration of MR was 6.3 months in both the overall and PN-baseline cohorts. OS and TTP data will also be reported. The most common treatment-emergent ≥G3 adverse events regardless of relationship to study drug were primarily hematologic and were as follows: thrombocytopenia (24%), anemia (21%), lymphopenia (11%), pneumonia (9%), neutropenia (9%), fatigue (7%), hypercalcemia (7%), and hyponatremia (6%). Although 77% of pts had G1/2 PN at baseline, new onset PN was infrequent with PN AEs of any grade reported in 31 (15%) pts and G3 PN reported in only 1 (0.4%) pt. New onset or worsening of paraesthesias (6.8%) and dysesthesias (0%) was also infrequent. Conclusions: Analysis of the subset of pts (77%) with active PN (G1/2) in this single-agent Ph 2 trial of CFZ in pts with R/R MM demonstrated that PN has no impact on depth or durability of responses, or on the tolerability of CFZ, in heavily pretreated pts with multiply relapsed and refractory MM. Reports of new or worsening PN were very uncommon, and paraesthesias and dysesthesia were generally infrequent and mild. CFZ can be given to pts with baseline PN with little risk of exacerbation; prolonged therapy is possible in this population. Disclosures: Martin: Celgene: Honoraria; Onyx: Consultancy. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Vij:Onyx: Honoraria. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Stewart:Millennium: Consultancy; Celgene: Honoraria. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Chang:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

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Updated Results of Bortezomib-Naïve Patients in PX-171-004, An Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory Myeloma (MM).

Blood ◽

10.1182/blood.v114.22.302.302 ◽

2009 ◽

Vol 114 (22) ◽

pp. 302-302 ◽

Cited By ~ 4

Author(s):

Luhua Wang ◽

David Siegel ◽

Jonathan L. Kaufman ◽

A. Keith Stewart ◽

Andrzej J Jakubowiak ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Impaired Renal Function ◽

Single Agent ◽

Advisory Committees ◽

Ortho Biotech ◽

The Mean ◽

Grade 3 ◽

Dose Modifications

Abstract Abstract 302 Background: Carfilzomib (CFZ) is a proteasome inhibitor with unique target selectivity and an irreversible binding mechanism that results in sustained proteasome inhibition. In preclinical studies, CFZ lacks non-proteasome off-target activities associated with bortezomib (BTZ) (Kapur et al, Blood 2008). This may account for observed differences in tolerability with CFZ (e.g. minimal neuropathy and myelosuppression), permitting consecutive day dosing and treatment over an extended period of time. We previously observed higher response rates in multiple myeloma (MM) patients without prior BTZ exposure (BTZ-naïve) compared to those with relapsed disease following BTZ therapy (BTZ-treated). Here we present updated data on the BTZ-naïve cohort from PX-171-004, an ongoing Phase 2 study of single-agent CFZ in MM patients with relapsed or refractory disease following 1–3 prior therapies. Methods: Patients with relapsed or refractory (e.g, < 25% response or disease progression during last treatment) MM were enrolled and stratified into two cohorts: BTZ-naïve and BTZ-treated. CFZ 20 mg/m2 IV was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. The primary endpoint was Overall Response Rate [≥ Partial Response (PR)] per International Uniform Response Criteria for Multiple Myeloma. Secondary endpoints included Clinical Benefit Response [CBR = ORR + Minor Reponse (MR)] and safety. Results: Fifty-seven BTZ-naive patients have been enrolled and 56 subjects have received at least one dose of CFZ. Prior therapies included alkylators (81%), stem cell transplant (SCT) (77%), thalidomide (THAL) (67%), lenalidomide (LEN) (42%), and anthracyclines (23%). Ten (18%) patients had received both LEN and THAL and 18 (32%) patients were refractory to their most recent regimen prior to study entry. At baseline, 30 (53%) patients had an ECOG score ≥ 1, 21 (37%) had neuropathy Grade ≥ 1, 12 (21%) had impaired renal function (CrCl < 60 mL/min) and 10 (18%) had diabetes. The mean time from diagnosis was 4 years (range 0.7–24). To date, the mean number of CFZ doses administered was 29.2 (∼5 four-week cycles; range 2–72 doses, 1–12 cycles). Fifty-one patients initiated therapy and were evaluable for response per protocol. The ORR was 45% (23/51 patients) and included 1 CR, 4 VGPR and 18 PR. An additional 9 (18%) patients had MR and 10 (20%) had stable disease (SD) for ≥ 6 weeks. The most common (>25%) adverse events (AEs) were fatigue (59%), nausea (41%), dyspnea (36%), and anemia (29%), and were primarily ≤ Grade 2. Grade 3/4 AEs occurring in ≥ 5% of patients were thrombocytopenia (9%), fatigue (9%), neutropenia (7%), lymphopenia (7%), anemia (5%), pneumonia (5%) and hyperglycemia (5%). One (1.7%) patient had febrile neutropenia. Dose modifications were rarely required. Peripheral neuropathy (PN) of any grade was infrequent (7 patients, 12%) with a single case of Grade 3 PN (2%) in a pt with a history of THAL-induced PN that lasted 41 days. The CFZ dose was reduced and the event resolved to Grade 1 while on CFZ and prior to study discontinuation. Of the12 patients with impaired renal function at baseline, none required dose modifications due to renal AE. Overall, 5 patients have completed the full 12-cycle protocol and another 5 (9%) have completed ≥ 9 cycles; 17 patients (30%) are continuing on study. Conclusions: The 45% ORR (CBR 63%) is noteworthy for a single-agent regimen in patients with tumor progression despite therapy with novel combinations. CFZ can be safely administered to patients with significant comorbidities (e.g. peripheral neuropathy, leukopenia, renal dysfunction, diabetes) when other anti-myeloma agents may not be well tolerated. Enrollment to PX-171-004 is continuing and, based on the safety profile, subjects are now permitted to dose escalate to 27 mg/m2. Disclosures: Wang: Proteolix: Honoraria, Research Funding. Off Label Use: testing testing. 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. 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. Kukreti:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. McDonagh:Proteolix: Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Le:Proteolix, Inc.: Employment. Bennett:Proteolix: Employment. Kunkel:Proteolix: Consultancy, Employment. Kauffman:Proteolix, Inc.: Employment. Vij:Proteolix, Inc.: Consultancy, Research Funding.

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Bortezomib, Melphalan, Prednisone and Thalidomide Followed by Maintenance with Bortezomib and Thalidomide (VMPT-VT) for Initial Treatment of Elderly Multiple Myeloma Patients: Updated Follow-up and Impact of Prognostic Factors

Blood ◽

10.1182/blood.v116.21.620.620 ◽

2010 ◽

Vol 116 (21) ◽

pp. 620-620 ◽

Cited By ~ 6

Author(s):

Antonio Palumbo ◽

Sara Bringhen ◽

Maide Cavalli ◽

Roberto Ria ◽

Massimo Offidani ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Weekly Infusion ◽

Risk Of Disease ◽

Grade 3

Abstract Abstract 620 Background. The combination of bortezomib-melphalan-prednisone (VMP) is a new standard of care for elderly newly diagnosed multiple myeloma. This phase 3 study compared the 4 drug combination bortezomib-melphalan-prednisone-thalidomide followed by maintenance bortezomib-thalidomide (VMPT-VT) with VMP alone. Methods. Patients (N=511) older than 65 years were randomized to receive nine 6-week cycles of VMPT-VT (N=254; induction: bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, thalidomide 50 mg d 1–42; maintenance: bortezomib 1.3 mg/m2 every 14 days and thalidomide 50 mg/day) or VMP (N=257) alone. In March 2007, the protocol was amended: both VMPT-VT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 d 1,8,15,22, all cycles). The primary end point was progression-free survival (PFS). Results. All patients have been evaluated in intention-to-treat. Patient characteristics were similar in both groups, median age was 71 years. The response rates were superior in the VMPT-VT group with a complete remission (CR) rate of 38% vs 24% (p=0.0008). After a median follow-up of 26.1 months, the 3-year PFS were 55% in patients receiving VMPT-VT and 38% in those receiving VMP (HR 0.65, 95% CI 0.49–0.85, P=0.002, Table). The 3-year time-to-next-therapy were 69% with VMPT-VT and 55% with VMP (HR 0.60, 95% CI 0.42–0.85, P=0.004). The 3-year overall survival was 86% with VMPT-VT and 84% with VMP (HR 0.88, 95% CI 0.53–1.45, P=0.62). The achievement of CR was a strong predictive factor of longer PFS in both groups (P=0.0001): in VMPT-VT arm, 3-year PFS was 66% in patients who obtained CR and 47% in those achieving PR; in VMP arm, it was 70% and 30%, respectively. The PFS benefit of VMPT-VT was seen consistently across different subgroups defined by creatinine clearance, LDH and bortezomib schedule; by contrast, in patients older than 75 years (HR 0.87; 95% CI 0.54–1.43, P=0.59) and in those at increased risk of disease progression, defined as presence of cytogenetic abnormalities [t(4;14) or t(14;16) or del17p] and ISS 3 (HR 1.35; 95% CI 0.45–4.06, P=0.60), VMPT-VT seemed not to add any significant PFS advantage to VMP. Grade 3–4 neutropenia (38% vs. 28%, p=0.02), cardiological events (10% vs. 5%, p=0.04) and thromboembolic events (5% vs. 2%, p=0.08) were more frequent among patients assigned to the VMPT-VT group; treatment-related deaths were 4% with VMPT-VT and 3% with VMP. In both groups, the once-weekly infusion of bortezomib significantly reduced the incidence of severe sensory peripheral neuropathy from 16% to 3% (p<0.0001). One hundred and forty-nine VMPT-VT patients were assessable for maintenance treatment. After a median duration of maintenance of 14.4 months, the PR rate was 90%, including 45% CR. The 1-year landmark analysis of PFS in patients completing the 9 induction cycles, showed a 2-year PFS of 63% in the VMPT-VT group and 40% in the VMP group, demonstrating that maintenance with VT reduced the risk of disease progression of 51% (HR 0.49, 95% CI 0.33–0.72, p=0.0003, Figure). This advantage was less evident in patients older than 75 years (HR 0.97, 95% CI 0.52–1.78, P=0.91) and in those with high-risk of disease progression, defined as presence of cytogenetic abnormalities and ISS 3 (HR 1.31, 95% CI 0.22–7.85, p=0.77). Continuous therapy with VT had favourable safety profile: 3% of patients experienced grade 3–4 hematological toxicity, 5% grade 3–4 peripheral neuropathy and 7% discontinued due to adverse events. Conclusion. In summary the current results indicate that: 1. VMPT-VT prolonged PFS with an unprecedented 3-year PFS of 55% in elderly patients; 2. once-weekly infusion of bortezomib improved safety without affecting outcome; 3. higher dose-intensity regimens seemed to be less effective in frail patients (≥ 75 years) and 4. maintenance therapy with VT further improved PFS with a good safety profile. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bringhen:Celgene: Honoraria; Janssen-Cilag: Honoraria. Patriarca:Celgene: Honoraria; Janssen Cilag: Honoraria; Roche: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Petrucci:Celgene: Honoraria; Janssen Cilag: Honoraria. Musto:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase II Study of Elotuzumab in Combination with Pomalidomide, Bortezomib, and Dexamethasone in Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2019-124870 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3169-3169 ◽

Cited By ~ 4

Author(s):

Andrew J. Yee ◽

Jacob P. Laubach ◽

Erica L. Campagnaro ◽

Brea C. Lipe ◽

Omar Nadeem ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

Board Of Directors ◽

Proteasome Inhibitor ◽

Research Funding ◽

Refractory Disease ◽

Advisory Committees ◽

Grade 3 ◽

Line Of Therapy

Background Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). A recent study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone vs. bortezomib and dexamethasone in relapsed or refractory MM (Richardson PG et al., Lancet Oncol 2019). We therefore studied elotuzumab with pomalidomide, bortezomib, and dexamethasone (elo-PVD) in relapsed and refractory MM. Methods The primary objective was to determine the overall response rate (ORR). Patients with relapsed and refractory disease and ≥1 prior lines of treatment (including lenalidomide and a proteasome inhibitor) were eligible to participate. Prior treatment with pomalidomide was permitted. Elotuzumab was weekly for the first 2 cycles and then every other week. Pomalidomide was given on days 1-21; bortezomib was on days 1, 8, 15; and dexamethasone was weekly. Each cycle was 28 days. Results The trial has completed accrual in September 2018 with 48 patients receiving treatment. The median age was 64 (range 40-80), and median number of prior regimens was 3 (range 1-9); 25% had high risk FISH. All patients had prior lenalidomide and proteasome inhibitor (bortezomib 96%, 29% carfilzomib) and were refractory to their last line of therapy. Other prior therapies included: autologous stem cell transplant (48%), pomalidomide (33%), daratumumab (25%), and isatuximab (4%). 46 patients were assessable for response (2 patients did not complete cycle 1 and were not evaluable for response: 1 due to rapid disease progression; 1 stroke. The median length of follow up was 18.8 months (range 0.5-23.4): 16 patients continue on study; 27 patients discontinued for progressive disease; 3 patients discontinued for adverse events (AEs) (sepsis, pneumonia, stroke); 1 patient underwent auto SCT; and 1 patient was lost to follow up. Best ORR was 61% (PR = 16, VGPR = 10, CR = 2). ORR for patients with prior anti-CD38 antibody, 46%; carfilzomib, 46%; pomalidomide, 43%. Median PFS was 9.8 months (95% CI 6.8-Inf). In patients with 1 prior line of therapy, ORR was 74% and median PFS was not reached (95% CI 12-Inf); 18 month PFS was 68%. Grade ≥ 3 hematologic AEs included anemia (10%), neutropenia (29%), and thrombocytopenia (15%). Additional common grade ≥ 3 AEs included lung infection (27%) and hypophosphatemia (15%). Common non-hematologic AEs all grades included fatigue (grade 1-2 only, 70%), upper respiratory infection (grade 1-2, 56%; grade 3, 2%), diarrhea (grade 1-2 only, 42%), constipation (grade 1-2 only, 35%), hyperglycemia (grade 1-2, 46%; grade 3, 4%), and sensory neuropathy (grade 1-2 only, 31%), with 2 possibly related deaths (sepsis, pneumonia). Conclusions Elo-PVD is one of the first trials of a quadruplet regimen in relapsed and refractory MM incorporating a monoclonal antibody. In patients with refractory disease, elo-PVD shows encouraging responses. With the limitations of cross trial comparisons and small patient numbers, for patients with 1 prior line of treatment and refractory disease, a PFS at 18 months of 68% with elo-PVD compares favorably with a median PFS of 17.8 months in a similar subgroup of PVD in the OPTIMISMM trial (Dimopoulos MA et al., ASH 2018). Patients who received prior pomalidomide, carfilzomib, and/or anti-CD38 monoclonal antibody also benefited. Treatment was well-tolerated with manageable toxicity and with attention to infectious AEs. Disclosures Yee: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Nadeem:Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy. O'Donnell:Celgene: Consultancy; Amgen: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Branagan:Pharmacyclics: Consultancy; Janssen: Consultancy; Surface Oncology: Consultancy. Lohr:Celgene: Research Funding; T2 Biosystems: Honoraria. Anderson:Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Richardson: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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; 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; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. OffLabel Disclosure: The combination of elotuzumab, pomalidomide, bortezomib, and dexamethasone is an off-label use in relapsed and refractory multiple myeloma.

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Phase 1/2 Study of Oral MLN9708, A Novel, Investigational Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v118.21.479.479 ◽

2011 ◽

Vol 118 (21) ◽

pp. 479-479 ◽

Cited By ~ 1

Author(s):

Jesus G. Berdeja ◽

Paul G. Richardson ◽

Sagar Lonial ◽

Ruben Niesvizky ◽

Ai-Min Hui ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Board Of Directors ◽

Proteasome Inhibitor ◽

Research Funding ◽

Stem Cell Transplant ◽

Phase 1 ◽

Cell Transplant ◽

Advisory Committees ◽

Grade 3 ◽

Dose Reductions

Abstract Abstract 479 Background: MLN9708 is an investigational, oral, potent, reversible, and specific 20S proteasome inhibitor, which immediately hydrolyzes to MLN2238, the biologically active dipeptidyl leucine boronic acid. In preclinical studies, MLN2238 has shown faster proteasome dissociation and greater tissue penetration than bortezomib. Current phase 1 data indicate that oral administration of single-agent MLN9708 was generally well tolerated, with no grade ≥3 peripheral neuropathy, and showed signs of antitumor activity in some patients with relapsed and/or refractory MM. Bortezomib in combination with lenalidomide and dexamethasone demonstrated a 100% partial response or better (≥PR) rate in patients with previously untreated MM, providing the rationale for evaluating oral MLN9708 in place of bortezomib in this combination. Here we report phase 1 data from the first combination study of MLN9708 (ClinicalTrials.gov: NCT01217957). Methods: Primary phase 1 objectives were to determine the safety, tolerability, and maximum tolerated dose (MTD) of weekly MLN9708 in combination with lenalidomide and dexamethasone; secondary objectives included characterization of the pharmacokinetic (PK)/pharmacodynamic (PD) profile of MLN9708, assessment of PK interaction and response. Adults aged ≥18 years with ECOG performance status of 0 to 2, and adequate renal, hepatic, and hematologic function were eligible. Patients with grade ≥2 peripheral neuropathy or prior/concurrent deep vein thrombosis (DVT)/pulmonary embolism were excluded. Patients received oral MLN9708 weekly on days 1, 8, and 15, lenalidomide 25 mg on days 1–21, and dexamethasone 40 mg on days 1, 8, 15, and 22, for up to twelve 28-day cycles. Patients received thromboprophylaxis with aspirin or low molecular weight heparin. Transplant-eligible patients could undergo stem cell transplant after six cycles. MLN9708 dose escalation, from a starting dose of 1.68 mg/m2, followed a 3+3 scheme based on the occurrence of dose-limiting toxicities (DLTs) in cycle 1. Adverse events (AEs) were evaluated according to NCI-CTCAE v4.0. Response was assessed according to modified EBMT criteria. Results: At data cut-off (June 29, 2011), 10 patients have been enrolled and treated: three each at 1.68, 2.23, and 2.97 mg/m2 and one at 3.95 mg/m2; median age was 66 years (range 59–77). Patients completed a median of 3 cycles (range 1–6), with three having received 6 cycles; treatment is ongoing in six patients. A DLT of grade 3 fainting was observed in a patient treated at 3.95 mg/m2. The MTD has not yet been reached; the current cohort is receiving 3.95 mg/m2. Drug-related AEs included rash in four patients (two maculopapular, two erythematous); vomiting and fatigue in three patients each; and diarrhea, constipation, and nausea in two patients each. Grade 1 treatment-related peripheral neuropathy was reported in one patient. Serious AEs were seen in four patients: one at 3.95 mg/m2 (DLT of grade 3 fainting), one at 2.23 mg/m2 (grade 3 DVT) unrelated to MLN9708, and two unrelated at 1.68 mg/m2 (grade 3 hypotension; grade 3 gastrointestinal hemorrhage resulting in discontinuation). Two patients required lenalidomide dose reductions to 15 mg due to erythematous rash; no dose reductions were required for MLN9708 or dexamethasone. There were no on-study deaths. Of nine response-evaluable patients, all nine achieved ≥PR, including three very good PR (VGPR) and one complete response. Time to response was rapid; all responders achieved a ≥50% decrease in M-protein in cycle 1, and best response was reached by the end of cycle 4. No patient has progressed to date. One patient with confirmed VGPR discontinued at cycle 6 to undergo stem cell transplant. Conclusions: MLN9708 administered weekly in combination with lenalidomide and dexamethasone appears to be generally well tolerated in previously untreated MM patients at the MLN9708 dose levels studied, with evidence of antitumor activity in the dose-escalation cohorts. Evaluation continues to determine the MTD of MLN9708 in this combination. Updated results, PK data, assessment of PK interaction, and PD data will be presented. Disclosures: Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding. Hui:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding.

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Ixazomib-Based Induction Followed By Single-Agent Ixazomib Maintenance in Transplant Ineligible, Newly Diagnosed Multiple Myeloma Patients: Updated Results of the EMN10-Unito Trial

Blood ◽

10.1182/blood-2020-134671 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-28

Author(s):

Roberto Mina ◽

Alessandra Larocca ◽

Paolo Corradini ◽

Nicola Cascavilla ◽

Anna Marina Liberati ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Induction Phase ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3

INTRODUCTION. The proteasome inhibitor (PI) Ixazomib, approved for the treatment of relapsed/refractory multiple myeloma (MM), represents an appealing option for the management of elderly patients, due to its oral administration and the lack of peripheral neuropathy. We previously presented preliminary results of the phase II EMN10-Unito study investigating Ixazomib in combination with dexamethasone (Id), Cyclophosphamide-dexamethasone (ICd), Thalidomide-dexamethasone (ITd) or Bendamustine-dexamethasone (IBd) as induction therapy followed by single-agent Ixazomib maintenance in transplant-ineligible newly diagnosed (ND) MM patients. Here we present updated results of the study with a longer follow-up. METHODS. Transplant-ineligible NDMM patients ≥65 years were enrolled. Treatment consisted of 9 28-day induction cycles of Ixazomib 4 mg on days 1,8,15 and dexamethasone 40 mg on days 1,8,15,22 or Id plus either Cyclophosphamide 300 mg/m2 orally on days 1,8,15 or Thalidomide 100 mg/day or Bendamustine 75 mg/m2 iv on days 1,8; followed by Ixazomib maintenance (4 mg on days 1,8,15) for up to 2 years. The primary endpoint was the selection of the most effective induction regimen considering a 2-year progression-free survival (PFS) ≥65% as satisfactory; secondary endpoints were very good partial response (VGPR), PFS2, overall survival (OS) and adverse events (AEs) during induction and maintenance. RESULTS. 171 patients (Id 41, ICd 59, ITd 60 and IBd 11) with a median age of 74 years were enrolled and started treatment. Two of the four investigational arms were prematurely closed due to low-enrollment (IBd arm, 11 patients enrolled) and high risk of inefficacy (Id, 41 patients enrolled). Median follow-up was 27 months. After the induction phase, ICd and ITd resulted in higher ≥ PR (75%-84% vs. 57%; p<0.05) and VGPR (46%-48% vs 24%; p<0.05) rates as compared to Id. The median PFS was 10.3 months with Id, 17.9 with ICd, 12.3 with ITd, and 13.8 with IBd, with a 2-year PFS probability of 31%, 39%, 27% and 40%, respectively. Median OS was not reached in either arm, without significant differences in the 2-year OS across arms (Id: 85%; ICd: 75%; ITd: 78%; IBd: 89%). Grade 3-4 non-hematological AEs were more frequent in the ITd arm (45%) as compared to the Id (17%), ICd (17%) and IBd (36%) arms, as well as the risk of treatment discontinuation due to AEs: ITd 17% vs Id 10%, ICd 12%, IBd 9%. Overall, 102 patients (60%) completed the induction phase and proceeded to ixazomib maintenance (median follow-up from start of maintenance: 18 months). The best response during maintenance was PR in 26%, VGPR in 29%, and complete response (CR) in 26% of patients; 18% of patients improved the response obtained during induction by at least one IMWG category. The median PFS from start of maintenance was 15 months. The median duration of maintenance was 12 months. All grades AEs occurred in 39% of patients during maintenance, while grade 3-4 AEs occurred in 10% of patients. Grade 1-2 peripheral neuropathy (PN) was reported in 15% of patients, without grade 3-4 events. Overall, 15% required at least one dose reduction of ixazomib and 12% discontinued ixazomib maintenance due to AEs. CONCLUSIONS. Safety and efficacy data suggest that Id combined with cyclophosphamide was the most promising induction strategy compared to the other investigated combinations. Continuous treatment with single-agent Ixazomib confirmed its efficacy and tolerability in elderly NDMM patients. Disclosures Mina: Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:GSK: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Corradini:KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria. Liberati:CELGENE: Honoraria; BIOPHARMA: Honoraria; ARCHIGEN: Honoraria; BEIGENE: Honoraria; BMS: Honoraria; AMGEN: Honoraria; FIBROGEN: Honoraria; INCYTE: Honoraria; VERASTEM: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; JANSSEN: Honoraria. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Bringhen:Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including ixazomib, dexamethasone, cyclophosphamide, thalidomide and bendamustine).

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Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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A Phase I Study of Bendamustine Combined with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.1856.1856 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1856-1856 ◽

Cited By ~ 1

Author(s):

Suzanne Lentzsch ◽

Amy O’Sullivan ◽

Silvana Lalo ◽

Carrie Kruppa ◽

Diane Gardner ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Board Of Directors ◽

Dose Level ◽

Research Funding ◽

Advisory Board ◽

Clinical Activity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 1856 Poster Board I-882 Background: Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia. Conclusions: Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation. Disclosures: Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

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A Randomized Phase 2 Trial of Bortezomib–Dexamethasone Versus Bortezomib–Dexamethasone with Added Cyclophosphamide or Lenalidomide in Multiple Myeloma Patients Achieving Stable Disease After Four Cycles of Bortezomib–Dexamethasone Administered as Second-Line Treatment.

Blood ◽

10.1182/blood.v114.22.4937.4937 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4937-4937

Author(s):

Meletios A. Dimopoulos ◽

Huw Roddie ◽

Meral Beksac ◽

Lotfi Benboubker ◽

Romualdas Jurgutis ◽

...

Keyword(s):

Renal Function ◽

Board Of Directors ◽

Research Funding ◽

Safety Data ◽

Phase 2 ◽

Advisory Committees ◽

Ortho Biotech ◽

Function Group ◽

Grade 3 ◽

Renal Function Group

Abstract Abstract 4937 Bortezomib (Velcade®) plus dexamethasone (Vel/Dex) is known to be effective and well tolerated in patients with multiple myeloma (MM). As demonstrated in the frontline setting, the addition to Vel/Dex of cyclophosphamide (VCD) or lenalidomide (Revlimid®; VRD) may lead to improved efficacy, but may be associated with increased toxicities; however, few studies have prospectively assessed Vel/Dex as second-line therapy. This randomized, open-label, parallel-group, phase 2 study in patients who have relapsed after or are refractory to primary MM therapy is designed to evaluate the safety and efficacy of an additional 4 cycles of Vel/Dex, VCD, or VDR in patients achieving stable disease (SD) after 4 cycles of Vel/Dex. Bortezomib-naïve patients aged ≥18 years, with measurable MM, KPS ≥60, life expectancy ≥6 months, adequate hematologic and hepatic function, and without grade ≥2 peripheral neuropathy (PN) received 4 3-week cycles of Vel/Dex (Vel 1.3 mg/m2 IV on days 1, 4, 8, and 11, and Dex 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12). Patients then received a further 4 cycles of therapy as follows: patients achieving at least a partial response (PR) received Vel/Dex; patients with SD underwent central randomization to receive Vel/Dex, VCD, or VRD; patients with progressive disease (PD) discontinued treatment. Here we report efficacy and renal function improvement in patients who had the opportunity to complete the initial 4 cycles of Vel/Dex as of April 2009, and safety data for patients who received at least 1 dose of study drug. Response was assessed by IMWG uniform response criteria based on measurement of serum and urine M-protein prior to treatment on day 1 of each cycle, at end of treatment, and monthly thereafter. Renal function as defined by calculated glomerular filtration rate (GFR; Cockcroft–Gault formula) was assessed prior to treatment on day 1 of cycles 1–5. Adverse events (AEs) were graded using NCI CTCAE v3.0. A total of 122 patients have been enrolled; by data cut-off (July 21 2009), 24 (20%) had not completed a single treatment cycle and are excluded from the safety population (N=98). Eighteen had received <4 cycles at data cut-off. Of the remaining 80 who were eligible for response, 63 had completed 4 cycles, 6 discontinued prior to completing 4 cycles (due to PD in 3 patients, death in 1, drug-related AEs in 2), 9 were not under treatment at data cut-off, and 2 had died. Their median age was 62 years (range 34–86), 55% were male, 21.3% had KPS ≤70; median time from prior therapy was 18.6 months. Response rate in the efficacy population was 41/80 (51%) after 4 cycles, including 8% CR. Median times to first and best response were 37 and 57 days, respectively. Patient renal function (by GFR) at baseline, median improvement in GFR, and responses achieved by the 10 patients in whom GFR improved by at least one renal function group are shown in the Table. Among the 98 patients who received at least one treatment dose, mean cumulative doses of bortezomib and dexamethasone were 14.6 mg/m2 (4.9, 4.5, 4.4, and 4.3 mg/m2 in cycles 1–4) and 478 mg (151.8, 145.6, 145.4, and 144.0 mg for cycles 1–4), respectively. Most patients (90%) reported AEs, including 39% with grade 3/4 AEs and 23% with serious AEs, within the first 4 cycles. The most common grade 3/4 AEs included thrombocytopenia (13%), anemia (7%), and pneumonia (6%). AEs resulting in dose reductions/treatment stop were seen in 21%/10% of patients. Incidence of sensory PN and PN was 29% (3% grade 3/4); most PN events were reversible, with 68% resolving within a median 53 days. Updated efficacy and safety data for the first 4 cycles of Vel/Dex for all patients enrolled by July 31 will be presented. Table: Improvement in renal function (as measured by GFR)* Renal function group at baseline, n† <15 mL/min 3 15–<30 mL/min 6 30–<60 mL/min 33 ≥60 mL/min 36 Median GFR (median improvement from previous cycle), mL/min At baseline 58.3 After cycle 1 64.4 (4.8) After cycle 2 68.9 (2.9) After cycle 3 68.6 (9.9) After cycle 4 73.5 (9.4) Renal improvement by at least 1 grade, n (response achieved) 10 <15 to 15–<30 mL/min 1 (1 CR) 15–<30 to 30–<60 mL/min 1 (1 PR) 30–<60 to ≥60 mL/min 8 (2 CR, 1 VGPR, 3 PR, 2 SD) * 1 patient only had a baseline GFR measurement and was not included in the renal analysis † 1 patient had no baseline GFR measurement Disclosures Dimopoulos: Ortho Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Beksac:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Langer:Celgene: Consultancy; Ortho Biotech: Consultancy. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees.

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