ALBERT

Description: Abstract 862 Background: Carfilzomib (Cfz) is a novel, irreversible proteasome inhibitor that has demonstrated promising single-agent activity and favorable toxicity profile, including very low rates of peripheral neuropathy and neutropenia in relapsed/refractory multiple myeloma (MM). Combining Cfz with Lenalidomide (Revlimid®, Len), and Dexamethasone (Dex) into CRd shows an additive anti-MM effect in preclinical studies and lack of overlapping toxicity allowing for the use of these agents at full doses and for extended duration of time in relapsed/refractory MM (Niesvizky et al, ASH, 2009). This Phase I/II study was designed to determine the maximum tolerated dose (MTD) of CRd and to assess safety and evaluate efficacy of this combination in newly diagnosed MM. Methods: In Phase I, dose escalation follows the TITE-CRM algorithm, with Cfz as the only escalating agent starting at 20 mg/m2 (level 1), maximal planned dose 27 mg/m2 (level 2), and 15 mg/m2, if needed (level -1), given IV on days 1, 2, 8, 9, 15, 16 in 28-day cycles. Len is used at 25 mg PO (days 1–21), and Dex at 40/20 mg PO weekly (cycles 1–4/5-8) for all dose levels. Based on toxicity assessment, the study was amended to add dose level 3 with Cfz at 36 mg/m2 and the number of pts in the Phase I was increased to 35. A total of 36 pts are planned to be treated at the MTD in Phase I/II. Pts who achieve ≥ PR can proceed to stem cell collection (SCC) and autologous stem cell transplant (ASCT) after ≥ 4 cycles, although per protocol design, ASCT candidates are offered to continue CRd treatment after SCC. After completion of 8 cycles, pts receive 28-day maintenance cycles with Cfz (days 1, 2 15, 16), Len days 1–21, and Dex weekly at the doses tolerated at the end of 8 cycles. Responses are assessed by IMWG criteria with the addition of nCR. Results: The study has enrolled 24 pts to date, 4 pts at level 1 (Cfz 20), 14 at level 2 (Cfz 27) and at 6 at level 3 (Cfz 36). Toxicity data are available for 21 pts, of which 19 have completed at least the first cycle required for DLT assessment; 2 pts were removed during the first cycle for events unrelated to study therapy (1 at level 1 and 1 at level 2), and 3 are currently within their first cycle of treatment. There was a single DLT event at dose level 2 (non-febrile neutropenia requiring dose reduction of Len per protocol) and the MTD has not been reached. Hematologic toxicities were reversible and included Grade (G) 3/4 neutropenia in 3 pts, G3/4 thrombocytopenia in 3, and G3 anemia in 2. There have been additional G3 non-hematologic AEs including 1 case of DVT while on ASA prophylaxis, 1 fatigue, 1 mood alteration, and 5 glucose elevations; the last 2 AEs were related to Dex. There was no emergence of peripheral neuropathy (PN), even after prolonged treatment, except in 2 pts who developed G1 sensory PN. Twenty-three pts continue on treatment, most (20 pts) without need for any dose modifications. After a median of 4 (range 1–8) months of treatment, preliminary response rates by IMWG in 19 evaluable pts who completed at least 1 cycle are: 100% ≥ PR, 63% ≥ VGPR, 37% CR/nCR, including 3 pts with sCR. Responses were rapid with 17 of 19 pts achieving PR after 1 cycle and improving responses with continuing therapy in all pts. To date, 7 pts proceeded to SCC using growth factors only, with a median 6.3 × 106 CD34+ cells/kg collected (range 4.1–8.2), after a median of 4 cycles of CRd (range 4–8); all resumed CRd treatment after SCC. After a median of 4 months of follow-up, none of evaluable pts progressed and all are alive. Conclusion: CRd is well tolerated and highly active in newly diagnosed MM with ≥ PR of 100%, including 63% ≥VGPR and 37% CR/nCR. Accrual is ongoing, with updated toxicity and efficacy data to be presented at the meeting. The results of this study represent the first report of treatment of frontline myeloma with Cfz to date, and provide additional support to recently initiated Phase 3 trial of CRd vs. Rd in relapsed MM. Disclosures: Jakubowiak: Bristol-Myers Squibb: 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; Centocor OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Jagannath:Millennium: Honoraria; OrthoBiotech (Canada): Honoraria; Celgene: Honoraria; Merck: Honoraria; Onyx Pharmaceuticals: Honoraria; Proteolix, Inc: Honoraria; Imedex: Speakers Bureau; Medicom World Wide: Speakers Bureau; Optum Health Education: Speakers Bureau; PER Group: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Millennium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Stockerl-Goldstein:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Barrickman:Celgene: Employment, Equity Ownership. Kauffman:Onyx Pharmaceuticals: Employment, Equity Ownership. Vij:Proteolix: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Abstract 132 Background: The RVD combination of Lenalidomide (Revlimid®, Len), Bortezomib, (Velcade®, Bz), and Dexamethasone (Dex) and the VDD combination of Bz, pegylated liposomal doxorubicin (Doxil®, PLD), and Dex are among the most active in newly diagnosed multiple myeloma (MM). Pre-clinical studies suggest that combining 4 drugs from RVD and VDD into RVDD may produce even higher activity. The aims of this Phase I/II trial were to determine the maximum tolerated dose (MTD) of the RVDD regimen and to assess its safety and evaluate efficacy in newly diagnosed MM. Methods: Patients (Pts) received Len 15–25 mg (days 1–14), Bz 1.3 mg/m2 (days 1, 4, 8, 11), Dex 20/10 mg (cycles 1–4/5–8; days of and after Bz), PLD 20 or 30 mg/m2 (day 4) at 4 dose levels for up to eight 21-day cycles. In the Phase I portion of the study, pts were assigned to dose levels 1-4 according to the TITE-CRM algorithm. Responses were assessed by modified European Group for Blood and Marrow Transplantation (EBMT) and Uniform Criteria. Pts who achieved at least partial response (PR) could proceed to autologus stem cell transplant (ASCT) after ≥ 4 cycles. After 8 cycles, pts could continue treatment using 21-day maintenance cycles with Len (days 1–14), Bz (day 1 and 8), and Dex (days of and after Bz) at the doses tolerated by the end of initial treatment. Results: The study has enrolled 68 pts to date (median age 61; 52% ISS II/III), 42 pts in phase I (including 6 pts treated at the MTD) and 26 pts in phase II, for a total of 32 of 38 planned pts at the MTD. Pts received a median of 4 cycles (range 1–16); 48 completed at least 4 cycles, 11 completed all 8 cycles, and 34 have discontinued/completed therapy. Seven patients remain on maintenance therapy. Toxicity data are available for 55 pts. In the phase I, 4 pts were assigned to level 1 (Len/PLD 15/20), 11 to level 2 (Len/PLD 20/20, 21 to level 3 (Len/PLD 25/20), and 6 to level 4 (Len/PLD 25/30). Two pts were not evaluable for DLT per protocol criteria and were replaced; 1 at level 2 and 1 at level 3, leaving 40 pts evaluable for DLTs. There were no DLTs at level 1, 2 at level 2, 3 at level 3, consisting of 2 grade (G) 3 asymptomatic neutropenia on day 1 cycle 2, 1 G3 elevation of transaminases, 1 G3 drug fever, and 1 grade 3 hypophosphatemia and none at level 4. Based on the pre-determined definition of maximum tolerated dose (MTD) and probability estimates of DLTs of 4.7% for level 1, 9.7% for level 2, 13.7% for level 3, and 17.9% for level 4, the maximum planned dose level 4 was selected as the MTD for the phase II portion of the study as the closest to, but not exceeding, a target rate of 20% of DLTs. Overall, toxicities have been manageable with G3/4 toxicities in 3–18% of all pts including neutropenia (18%), thrombocytopenia (7%) , infections (16 %) , DVT (2%). There was 4% G3 and no G4 peripheral neuropathy reported, 24% G 1/2 palmar-plantar erythrodysesthesia, and no treatment-related mortality. Response rates in 57 pts evaluable for response were as follows: 96% ≥ PR, 58% ≥ VGPR, and 30% CR/nCR. In 48 pts who completed 4 cycles, defined in the protocol for efficacy assessment, response rates were: 98% ≥ PR, 58% ≥ VGPR and 29% CR/nCR; at MTD ≥PR is 100%. Response rates were not statistically different in a subset of pts (24) with 13q deletion or t(4;14) or t(14;16) or 17p del, with PR, VGPR, and CR/nCR rates 92%, 67%, and 33%, respectively. Twenty four pts proceeded to stem cell collection with 7.5 × 106 CD34+ cells/kg collected after a median of 4 cycles of RVDD (range 3–10). After a median of 6 months of follow-up, median progresssion-free survival and overall survival have not been reached. Conclusion: RVDD is well tolerated in newly diagnosed MM and appears highly active with ≥ PR of 96%, including 58% ≥VGPR, which is unaffected by adverse cytogenetic status. Pts treated at the MTD ,which was determined as Len 25 mg, Bz 1.3 mg/m2, Dex 20 mg, and PLD 30 mg/m2, and completed at least 4 cycles, show 100% ≥PR. Stem cell mobilization and collection was successful in all pts, with unremarkable transplant course reported to date. Updated toxicity and efficacy data will be presented at the meeting. Disclosures: Jakubowiak: Bristol Myers-Squibb: 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; Centocor OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Reece:Ortho Biotech: Honoraria, Research Funding. Lonial:Novartis: Consultancy; Gloucester: Research Funding; Bristol Myers - Squibb : Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy. Zimmerman:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Centocor: Speakers Bureau. Schlossman:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Laubach:Novartis: Advisory Board. Raje:Celgene, Norvartis, Astrazeneca: Research Funding. Anderson:Millennium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Barrickman:Celgene: Employment, Equity Ownership. Tendler:Johnson and Johnson: Employment, Equity Ownership. Esseltine:Johnson and Johnson: Equity Ownership; Milllennium: Employment, Equity Ownership. Kelley:Bristol-Myers Squibb: Equity Ownership. Anderson:Millennium: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Richardson:Bristol Myers-Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, 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: Abstract 1937 Background: Three-drug combinations with bortezomib (Bz) and/or either thalidomide or lenalidomide (Len) are highly active in frontline MM and appear superior to at least some 2-drug combinations with these agents. In an attempt to further improve treatment outcomes, we developed the 4-drug RVDD regimen of lenalidomide (Revlimid®, Len), Bz (Velcade®), pegylated liposomal doxorubicin (Doxil®, PLD), and dexamethasone (Dex), which demonstrates high activity in newly diagnosed MM. Here we present final results of this Phase I/II trial. Methods: Patients (Pts) received eight 3-week cycles with Len 15–25 mg (days 1–14), Bz 1.3 mg/m2 (days 1, 4, 8, 11), Dex 20/10 mg (cycles 1–4/5-8; days of and after Bz), PLD 20 or 30 mg/m2 (day 4) at 4 dose levels and the maximum tolerated dose (MTD; Phase II). Responses were assessed by modified EBMT and IMWG criteria with the addition of nCR. Pts could proceed to autologous stem cell transplant (ASCT) or continue treatment, which after 8 cycles consisted of 21-day maintenance cycles with Len (days 1–14), Bz (day 1 and 8), and Dex (days of and after Bz) at the doses tolerated by the end of initial treatment. The primary objectives were to evaluate MTD and VGPR rate at the end of 4 and 8 cycles. Results: The study enrolled 72 pts with a median age 60 (range 29–77); 53% ISS II/III; 46% any of the del 13q, t(4;14), t(14;16), or del 17p, of which 37 were treated at the MTD (including 6 in Phase I). Pts received a median of 4.5 cycles (range 2–31); 70 pts completed at least 4 cycles and 20 at least 8 cycles. Five pts developed DLTs, including 2 pts grade (G) 3 asymptomatic neutropenia, 1 G3 elevation of transaminases, 1 G3 drug fever, and 1 G3 hypophosphatemia. Based on the pre-determined definition of MTD, the maximum planned doses of Len 25 mg, Bz 1.3 mg/m2, PLD 30 mg/m2, and Dex 20/10 mg were selected as the maximum tolerated dose (MTD) for the Phase II portion of the study as the closest to, but not exceeding, a target rate of 20% DLTs. The most common toxicities (all grades) were fatigue (83%), infections (72%), constipation (69%), and sensory neuropathy (65%) of which 8%, 14%, 1%, and 6% were G3, respectively. Other G3/4 toxicities included neutropenia (19%), infections (16 %), thrombocytopenia (11%), hyperglycemia (10%), and DVT/PE (3%). There was 25% G1/2 palmar-plantar erythrodysesthesia and 1 pt experienced G1 asymptomatic and reversible decrease in ejection fraction attributed to PLD. Importantly, there was no treatment-related mortality. The best response rates for all pts were as follows: 96% ≥ PR, 66% ≥ VGPR, and 38% CR/nCR. At the end of 4 and 8 cycles, defined in the protocol for efficacy assessment, response rates were: 96% and 95% ≥ PR, 57% and 65% ≥VGPR and 29% and 35% CR/nCR; at the MTD ≥PR was 96%, ≥VGPR 66%, and CR/nCR 34%. Response rates were not statistically different in a subset of pts with any of del 13q, t(4;14), t(14;16), or del 17p. Forty-seven (65%) pts proceeded to ASCT, after collection of a median 6.7 × 106 CD34+ cells/kg (range 1.9–17.7). At 3 months post ASCT, ≥ VGPR and CR/nCR rates improved in 45 evaluable pts from 64% to 84% and from 38% to 60%, respectively. After a median of 15.5 months of follow-up, the estimated 18-month PFS for all pts is 84% and overall survival 99%. Conclusion: RVDD is generally well tolerated and highly active with rapid reduction of MM tumor burden seen (≥ PR 96%, ≥VGPR 57% and CR/nCR rate 29% at the completion of 4 cycles). Response rates further improved after additional treatment, both in pts who continued RVDD treatment (’VGPR 65%, CR/nCR 35%) and pts who proceeded to ASCT (≥VGPR 84%, and CR/nCR 60%), although some additional toxicity was noted. Whether the incorporation of a 4th agent in the form of PLD has made an impact in this pt population remains to be defined. At equivalent time points (i.e. at the completion of 4 and 8 cycles), the ≥VGPR and CR/nCR rates as well as the current estimated PFS appear to compare favorably to RVD, which provides the rationale for consideration of further studies with this regimen, including potential randomized trials in this setting. Disclosures: Jakubowiak: Bristol-Myers Squibb: 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; Centocor OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Reece:Celgene: Unrestricted educational lectures, research funding, ad hoc advisory boards. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau. Zimmerman:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Campagnaro:NIH: Research funding for NIH K12 CA076917. Raje:Celgene: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Acetylon: Research Funding. Anderson:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barrickman:Celgene: Employment, Equity Ownership. Tendler:Johnson & Johnson Pharmaceutical Services: Employment, Equity Ownership. Esseltine:Millennium: The Takeda Oncology Company: Employment; Johnson & Johnson: Equity Ownership. Anderson:Millennium: 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; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.