ALBERT

Description: Abstract 631 Introduction: In relapsed and/or refractory MM, the combination of carfilzomib (CFZ) with lenalidomide (Len), and low-dose dexamethasone (Dex) (CRd) has shown very promising efficacy (78% ≥partial response [PR], 40% ≥very good partial response [VGPR], and 24% CR/nCR) and good tolerability including a low rate of peripheral neuropathy (Wang et al, ASCO, 2011). In a Phase I/II study of newly diagnosed MM, the regimen was well tolerated in the Phase I portion of the study up to a maximum dose of CFZ 36 mg/m2, Len 25 mg, and Dex 40 mg, and very active with 96% ≥PR, 70% ≥VGPR, and 55% CR/nCR (Jakubowiak et al, ASH 2010). The lack of overlapping toxicities has allowed these agents to be used at full doses and for extended periods. Here we report the results for all patients (pts) enrolled in both phases of this first prospective trial of CFZ combination in new MM. Methods: In the initial eight 28-day cycles, pts were treated with CFZ at 20 mg/m2, 27 mg/m2 (Phase I), and 36 mg/m2 (Phase I and II), given IV on days 1, 2, 8, 9, 15 and 16, Len at 25 mg PO (days 1–21), and Dex at 40/20 mg PO weekly (cycles 1–4/5–8). Pts achieving ≥PR could proceed to stem cell collection (SCC) using growth factors alone (protocol recommendation) and autologous stem cell transplant (ASCT) after 4 cycles. Per protocol, ASCT candidates were offered the option to continue CRd treatment after SCC. After 8 cycles, pts received 28-day maintenance cycles of CFZ (days 1, 2, 15, 16), Len days 1–21, and Dex weekly at the doses tolerated at the end of 8 cycles. Responses were assessed by IMWG criteria with the addition of nCR. Results: Enrollment was completed (53 pts): 4 pts at CFZ 20 mg/m2, 13 at CFZ 27 mg/m2 and 36 at CFZ 36 mg/m2 (18 in Phase I and 18 in Phase II). Median age was 59 years (range 35–81; 23 pts ≥65), 60% had ISS stage II/III, and 33% (of 49 with available data) had unfavorable cytogenetics: del 13 or hypodiploidy by metaphase, or t(4;14), t (14;16), del 17p by FISH. As of June 30, 2011, toxicity data (cycles 1–8) were available for 51 pts. Hematologic toxicities were reversible and included Grade (G) 3/4: anemia (18%), neutropenia (12%), and thrombocytopenia (10%). The most common non-hematologic toxicities (all G) were hyperglycemia (76%), hypophosphatemia (61%), and infection (53%). G3/4 non-hematologic AEs included hyperglycemia (24%), DVT/PE while on ASA prophylaxis (10%), infection (6%), and mood alteration (2%). PN was limited to G1/2 sensory (24%). Forty-five pts continue treatment with 22 pts in the maintenance phase. Six pts discontinued treatment: 2 proceeded to ASCT, 1 due to toxicity, and 3 due to events unrelated to treatment or per pt wish. The majority of pts did not require dose modifications, either in the initial (31%) or in the maintenance (25%) phase. After a median of 8 cycles (range 1–20), the best responses per IMWG criteria for 49 response-evaluable pts (all pts who completed 1+ cycle) are shown in the Table. Responses were rapid with 46/49 pts achieving at least PR after 1 cycle, and improved with the duration of treatment reaching 100% ≥PR after 4 cycles and 100% ≥VGPR, 79% CR/nCR after 12 cycles. Responses were deep even at the 2 lower dose levels with the majority of pts at 36 mg/m2 still early in treatment. Responses in pts with unfavorable cytogenetics were similar to response rates in all remaining pts and included a 100% ≥PR in 6 pts with del 17p. Twenty-four pts proceeded to SCC after a median of 5 cycles of CRd (range 4–9); using growth factors only in 23 pts and cyclophosphamide and growth factors in 1 pt, with a median 6.55 × 106 CD34+ cells/kg collected (range 3.75–9.6); all resumed CRd treatment. After a median of 9.5 months of follow-up, only 1 pt has progressed, and all are alive Conclusions: CRd is highly active and well-tolerated allowing the use of full doses for an extended time in newly-diagnosed MM pts with limited need for dose modification. Responses are rapid and improve over time reaching 100% ≥VGPR and early time-to-event data are very encouraging. These results compare favorably to the best frontline regimens in MM. Disclosures: Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria. Off Label Use: Use of the investigational agent carfilzomib, proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; OrthoBiotec.Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Hussein:Celgene Corporation: Employment. Leveque:Onyx Pharmaceuticals: Employment. Vij:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau.

Description: This phase 1/2 trial evaluated combination lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (RVDD) in newly diagnosed multiple myeloma (MM) patients. Patients received RVDD at 4 dose levels, including the maximum tolerated dose (MTD). Patients with a very good partial response or better (≥ VGPR) after cycle 4 proceeded to autologous stem cell transplantation or continued treatment. The primary objectives were MTD evaluation and response to RVDD after 4 and 8 cycles. Seventy-two patients received a median of 4.5 cycles. The MTDs were lenalidomide 25 mg, bortezomib 1.3 mg/m2, pegylated liposomal doxorubicin 30 mg/m2, and dexamethasone 20/10 mg, as established with 3-week cycles. The most common adverse events were fatigue, constipation, sensory neuropathy, and infection; there was no treatment-related mortality. Response rates after 4 and 8 cycles were 96% and 95% partial response or better, 57% and 65% ≥ VGPR, and 29% and 35% complete or near-complete response, respectively. After a median follow-up of 15.5 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated 18-month PFS and OS were 80.8% and 98.6%, respectively. RVDD was generally well tolerated and highly active, warranting further study in newly diagnosed MM patients. This trial was registered at www.clinicaltrials.gov as NCT00724568.

Description: Background NDDM patients (pts) treated with CRd in a phase 1/2 trial (NCT01029054) demonstrated high rates of complete response (CR, 62%) and stringent complete response (sCR, 55%) that correlated with excellent estimated 2-year progression-free survival (PFS; 94%) and overall survival (OS; 98%) (Jakubowiak et al, Blood, 2012; Jakubowiak et al, J Clin Oncol, 2013 abstract 8543). However, the correlation between risk factors or response rates and long-term treatment outcomes could not be demonstrated at that time, owing to a limited number of events. In this post hoc, retrospective analysis, we present an evaluation of outcomes based on pretreatment characteristics (including cytogenetics and gene expression profiling [GEP]) and their relationship to response and minimal residual disease (MRD) status. Methods Pts received 28-day cycles of carfilzomib (CFZ) 20-36 mg/m2 intravenously (days [d]1, 2, 8, 9, 15, 16), lenalidomide (LEN) 25 mg orally (PO; d1-21), and dexamethasone 40/20 mg PO weekly (cycles 1-4/5-8). For cycles 8-24, CRd was given with a modified CFZ schedule (d1, 2, 15, 16), and single-agent LEN was administered after cycle 24. Pts had the option to receive stem cell transplantation after cycle 4. Response was assessed by IMWG criteria, with the addition of near CR. Cytogenetic high-risk disease was assessed by IMWG criteria. RNA isolated from purified plasma cells at pretreatment was available in a subset of pts. GEP was performed using gene expression microarrays (Affymetrix U133 Plus 2.0 GeneChips), and a 92-gene signature (SKY92) was evaluated; pts in the subset were categorized as either SKY92 standard or high risk. MRD analysis was performed using multiparameter flow cytometry (MPF). Results As of May 31, 2013, 53 pts had received a median of 24 CRd cycles (range 2-24); 24 pts continued LEN maintenance for a median of 12 months (range 3-15). Thirty-four pts (64%) achieved at least a CR, and 29 pts (55%) achieved a sCR. Cytogenetic data were available for all but 2 pts: 33% of pts had high-risk disease, of which 47% had del p53. After a median follow-up of 31 months (range, 16-43), the estimated 3-year PFS and OS rates for all pts were 79% and 96%, respectively. There was a trend toward lower estimated PFS rate in pts with high-risk cytogenetics vs pts with standard-risk cytogenetics (69% vs 88%, P=.081; 10 pts had disease progression). Estimated OS rate was also lower in pts with high- vs standard-risk cytogenetics (83% vs 100%); although the number of events assessed was very low (2 pts have died), the difference was determined to be statistically significant (P=.041). There was a trend in the high- vs standard-risk groups toward a lower CR rate (53% vs 71%, respectively) and sCR rate (41% vs 62%, respectively), although the differences did not reach statistical significance (P=.233 and P=.234, respectively, using Fisher's exact test). A subset of 15 pts were analyzed by GEP, including 6 of 10 pts with disease progression. Based on GEP, 4 of 15 pts (27%) had SKY92 high-risk disease. All 4 pts relapsed, of which 2 pts had high-risk cytogenetics. In comparison, 2 of 11 pts (18%) with SKY92 standard-risk disease relapsed, of which 2 pts had high-risk cytogenetics. Twenty-five pts with CR/sCR (including 7 pts [28%] with high-risk cytogenetics) were evaluated for MRD; 22 pts (84%) were MRD-negative. Pts who achieved sCR at any time during CRd treatment showed a trend toward longer estimated 3-year PFS and OS compared with those who did not achieve sCR (PFS, 87% vs 68%, respectively, log-rank P=.222; OS, 100% vs 91%, log-rank P=.107). Among pts with MRD-negative disease, estimated 3-year PFS was 84%; OS was 100%. Conclusions CRd treatment in pts with NDMM resulted in excellent estimated 3-year PFS and OS rates after a median follow-up of 31 months, which compare favorably with historical results for both standard- and high-risk pts. Pts with high-risk cytogenetics by IMWG criteria or with SKY92 high-risk disease demonstrated a trend toward inferior PFS and OS compared with pts with standard-risk cytogenetics or SKY92 standard-risk disease, indicating that CRd treatment may not completely overcome the effect of poor disease characteristics on survival outcomes. However, our results suggest that achievement of sCR and having MRD-negative disease may be associated with superior PFS and OS. Follow-up analyses of MRD using MPF and deep-sequencing in pts with sCR are ongoing; results will be reported at the meeting. Disclosures: Off Label Use: Carfilzomib is a selective proteasome inhibitor that is approved in the US for the treatment of relapsed and refractory multiple myeloma (≥2 prior therapies including an immunomodulatory agent and a proteasome inhibitor, having progressed ≤60 days of completion of the last treatment). Lenalidomide is an immunomodulatory agent approved in combination with dexamethasone for patients with relapsed multiple myeloma (≥1 prior therapy). McDonnell:University of Chicago Medicine (Myeloma Program Coordinator) : Employment. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Merck: Honoraria; Ortho Biotech: Membership on an entity's Board of Directors or advisory committees; Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom Worldwide: Membership on an entity's Board of Directors or advisory committees; OptumHealth Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Vij:Onyx: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Lilly: Honoraria; BMS: Honoraria; Millenium: Speakers Bureau. Faham:Sequenta, Inc,: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lee:Sequenta, Inc,: Employment, Equity Ownership. van Beers:Skyline Diagnostics: Employment. van Vliet:Skyline Diagnostics: Employment. Jakubowiak:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen-Silag: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding.