ALBERT

Description: INTRODUCTION: Perifosine (peri) is an oral, signal transduction modulator with multiple pathway effects including inhibition of Akt and activation of JNK. In vitro, peri + bortezomib (Velcade®, Vel) shows additive cytotoxicity against MM cells with peri inhibiting Vel induced Akt activation. Peri with dexamethasone (dex) has activity in patients (pts) with advanced, relapsed/refractory MM (ASH 2006 #3582). This phase I/II study sought to determine MTD and evaluate the activity of peri plus Vel +/− dex in pts with relapsed and relapsed/refractory MM, who were either previously treated or refractory to Vel. METHODS: 4 cohorts (at least 3 pts each) were planned, with dosing of peri 50 mg or 100 mg (daily) and Vel 1.0 or 1.3 mg/m2 (d 1, 4, 8, 11) in 21-d cycles. Dex 20mg (on day of and after each Vel dose) could be added in pts with progressive disease (PD). NCI CTCAE v3.0 was used for toxicity assessment; DLT was defined as any grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets 1 occasion despite transfusion. Response was assessed by modified EBMT and Uniform criteria. RESULTS: 18 pts (11 M/ 7 F, median age 64 y, range 42 – 87) have been enrolled; 3 pts in cohort 1 (peri 50mg, Vel 1.0mg/m2), 3 pts in cohort 2 (peri 100mg, Vel 1.0mg/m2), 6 pts in cohort 3 (peri 50mg, Vel 1.3mg/m2) and 6 pts in cohort 4 (peri 100mg, Vel 1.3mg/m2). 14 pts (78%) had relapsed/refractory MM, with a median of 5 lines of prior treatment (range 2–7). Prior therapy included Vel (100%), dex (89%), thalidomide (67%), lenalidomide (33%) and SCT (56%). 16/18 pts were evaluable for toxicity with most common AE’s as follows: Adverse Event (N = 16) Grade 1/2 Grade 3/4 Nausea 31% 0% Vomiting 13% 0% Diarrhea 44% 0% Fatigue 13% 6% Thrombocytopenia 13% 25% Anemia 6% 13% No DVT and no G3 peripheral neuropathy have been reported. 1 pt had peri reduced to 50mg due to persistent G2 nausea and 3 pts had Vel reduced from 1.3 to 1.0mg/m2 secondary to hematologic toxicity (n=2) and rash (n=1). 15/18 pts are evaluable for response, with best response to peri + Vel, or peri + Vel + dex after ≥ 2 cycles as follows: Response (N = 15) N (%) Duration (wks) PR after Peri + Vel 2 (13%) 24, 13+ MR after Peri + Vel 1 (7%) 10+ MR after Peri + Vel + Dex *2 (13%) 38+, 18+ SD after Peri + Vel 3 (20%) 18+, 16+, 13+ SD after Peri + Vel + Dex 3 (20%) 38, 22+, 12+ SD: 〈 25% reduction in M-protein *Pts refractory to prior Vel + Dex Dex was added in 6/18 pts with PD, with 5 pts evaluable for response to date on the dex combination. 10 pts remain on study. CONCLUSIONS: Peri in combination with Vel (+/− dex) was generally well tolerated and active in a heavily pre-treated pt population (78% had relapsed/refractory MM and 100% prior Vel). Responses seen in every cohort with greater toxicity reported in cohorts with 100 mg/d of peri. The phase II portion has now been initiated with peri 50 mg qhs and Vel 1.3mg/m2 days 1, 4, 8 and 11 every 21 days.

Description: BACKGROUND: The phase 2 SUMMIT trial of patients (pts) with relapsed and refractory MM showed that btz (VELCADE®) is active, with a response rate of 27% (CR/PR) as a single agent, median TTP of 7 months, and median OS of 17 months. The phase 3 APEX trial in pts with relapsed MM following 1–3 prior therapies showed btz to be superior to high-dose dexamethasone (dex) in terms of response rate, TTP, and OS. Updated APEX data show a CR/PR rate of 43%, median TTP of 6.2 months, and median OS of 29.8 months. This analysis evaluated the relationship between quality of response to btz (CR/nCR versus PR; PR does not include nCR in this analysis) in these trials and clinical benefit, as defined by treatment-free interval and time-to-alternative-therapy (TFI and TTAT; time from last and first dose of btz, respectively, to first dose of alternative antineoplastic therapy), OS, and TTP. METHODS: In SUMMIT, 202 pts received btz 1.3mg/m2 on days 1, 4, 8, and 11 for up to eight 21-day cycles (median # of cycles: 6). Dex 20mg was added on the day of and day after each btz dose in pts with suboptimal responses to btz alone. In one arm of APEX, 333 pts received btz 1.3mg/m2 on days 1, 4, 8, and 11 for eight 3-week cycles and then on days 1, 8, 15, and 22 for three 5-week maintenance cycles (median # of cycles: 6). Responses in both trials were assessed according to EBMT criteria (modified to include nCR, a CR with positive immunofixation test). RESULTS: Data are shown in the Table. Median TFI appeared longer in pts with CR/nCR vs PR (SUMMIT, 9.8 vs 3.1 months; APEX, 17.5 vs 6.7 months). Similarly, TTAT appeared longer in pts with CR/nCR vs PR (SUMMIT, 15.4 vs 8.5; APEX, 21.2 vs 14.0). Median OS in all response groups has not yet been reached after a median follow-up of 22 months. TTP tended to be longer with CR/nCR vs PR in both studies (SUMMIT, 16.4 vs 9.2; APEX, 12.2 vs 8.3). CONCLUSIONS: Increasing quality of response to btz is associated with greater clinical benefit assessed by extended TFI ,TTAT, and TTP. Long un-maintained remissions can be attained with btz by achieving maximum tumor mass reduction (CR/nCR), even in pts with relapsed/refractory MM. Updated APEX data show that despite rapid initial response, many pts showed continued improvement in terms of M-protein reduction, and an increasing proportion of pts achieved CR with continued therapy. These data, together with the findings of this analysis, support maximizing tumor mass reduction to CR/nCR with btz to achieve greater clinical benefit. Clinical benefit of btz by response Kaplan-Meier median (95% CI) CR/nCR PR* *PR does not include nCR in this analysis; †Includes 8 cycles of protocol-specified therapy plus maintenance cycles SUMMIT, n 19 34 TFI, mo 9.8 (2.7,14.3) 3.1 (2.0,8.7) TTAT, mo 15.4 (7.9,17.6) 8.5 (7.3,14.0) TTP, mo 16.4 (10.6,NE) 9.2 (7.2,NE) Median cycles, n 8 8 APEX, n 48 87 TFI, mo 17.5 (6.7,24.1) 6.7(4.4,10.0) TTAT, mo 21.2 (14.0,27.1) 14.0 (12.6,16.1) TTP, mo 12.2 (8.8,NE) 8.3 (7.6,10.3) Median cycles,† n 9 10

Description: After 3 years of imatinib (IM) therapy, hematologic relapse occurred in 7% of newly diagnosed chronic myeloid leukemia (CML) pts, and 20% of chronic phase (CP)-CML pts after failure to interferon alpha (IFN), which was mostly associated with BCR-ABL mutations and/or clonal evolution. Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases. Dasatinib has been shown to have 325-fold greater potency compared with imatinib in cells transduced with BCR-ABL and is active against 18/19 BCR-ABL mutants tested that confer imatinib resistance. A Phase I dose-escalating study provided early evidence for the safety and efficacy of dasatinib in imatinib-resistant (IM-R) or -intolerant (IM-I) patients in CP-CML, which was followed by ‘START-C’ (CA180013), the first Phase II open-label study in dasatinib in CP IM-R or IM-I CML pts. Between February-May 2005, 186 pts (86 male, median age 60 yrs [range 25–82]) were recruited from 40 institutions. Data from 30 pts accrued prior to March 20, 2005, are available for the initial analysis. The definition of IM-R required a failure of IM doses 〉600 mg/d or the occurrence of BCR-ABL mutations associated with virtual insensitivity to IM. Dasatinib was administered at 70 mg twice daily (BID), based on phase I data and optimal inhibition of BCR-ABL activity from biomarker analysis. Dose escalation to 90 mg BID was permitted in pts lacking response, and dose reductions to 50 and 40 mg BID were allowed in the event of intolerance. Complete blood counts were obtained weekly for the first 12 weeks; bone marrow cytology and cytogenetics every 3 months. In the group of 30 evaluable pts, median age was 59 yrs (range 25–78), 50% were male. Median time from diagnosis of CML was 70.8 months (range 7.9–202.1). Prior therapy included IFN in 77% and stem cell transplantation in 10% of pts. 60% of pts were considered IM-R, with the maximum prior IM dose of 〉600 mg in 60% of pts. 60% of pts received IM for 〉3 yrs. Best response to prior IM therapy was a complete hematologic response in 83%, and complete (CCyR) and partial (PCyR) cytogenetic responses in 17% and 13% of pts, respectively. Median (range) baseline hematologic parameters were: white blood cells 16.1/nl (4.3–84.3); platelets 437/nl (173–960). IM-R BCR-ABL mutations were documented in 6/12 pts with currently available data. Within the first 3 months, 2 pts required dose escalations and 6 had a dose reduction, mostly due to thrombocytopenia. Hematologic responses were documented in 21/24 pts with available data. From 16 pts evaluable for 3-month cytogenetic analysis, 7 cytogenetic responses were observed, including CCyR (n=4) and PCyR (n=1). Analysis of molecular response is in progress. Grade 3/4 neutropenia or thrombocytopenia were reported in 6 pts each. Most common non-hematologic toxicities were diarrhea (6 pts, 1 grade 3), rash (5 pts, all grade 1), edema (3 pts, all grade 1) and pleural effusion (1 pt, grade 2). In conclusion, despite the short follow up, major hematologic and cytogenetic responses were seen in a group of pretreated CP-CML pts, which further supports the activity of dasatinib in this disease. An updated analysis based on 186 pts with 6-month follow up will be presented.

Description: Introduction: Bortezomib (Bz, VELCADE) is a proteasome inhibitor proven safe and effective for patients (pts) with relapsed and/or refractory multiple myeloma (MM). Pts in SUMMIT (NEJM2003;348:2609) and CREST (BJH2004;127:165) underwent rigorous testing (neurologic evaluations, FACT/GOG-Ntx questionnaires, nerve conduction studies) to determine the incidence, characteristics and reversibility of PN. In these phase 2 trials, the PN rate was 31–41% (grade [G] ≥ 3 in 11–12%). Specific dose modification (DM) guidelines for PN were not incorporated into the phase 2 trials but were developed for subsequent studies. The objective of this report was to evaluate the frequency, characteristics and reversibility of PN in an updated analysis of the randomized phase 3 APEX trial (NEJM2005;352:2487), in which specific DM guidelines for PN were implemented. Methods: Pts with relapsed MM were randomized to Bz 1.3 mg/m2 IV on d 1, 4, 8, 11 q3wk for 8 cycles then 3 cycles on d 1, 8, 15, 22 q5wk, or dexamethasone (Dex) 40 mg PO on d 1–4, 9–12, 17–20 q5wk for 4 cycles, then 5 cycles on d 1–4 q4wk. Pts with G ≥ 2 PN were excluded. Data were collected on incidence, severity and reversibility of PN. Results: Of 331 pts safety evaluable enrolled on Bz, 120 (36%) developed PN, including 30 (9%) with G ≥ 3. PN was classified as sensory or not specified in the vast majority of cases; motor neuropathies were rare. Of 91 pts with G ≥ 2 PN, 68 had DM, including 37 with doses reduced, held or schedule modification and 31 with Bz discontinuation (DC); 23 pts not following DM protocol. The majority (58 pts; 64%) of the 91 pts improved (9%) or had complete resolution (55%) of symptoms. Of 37 pts with DM without Bz DC, the majority (26 pts; 70%) had improvement, all with complete resolution of PN to baseline, with a median time to resolution of 78 d. Of 31 pts requiring Bz DC, 2 (6%) improved and 17 (55%) had complete resolution of PN with a median time to improvement/resolution of 121 d. Of 23 pts who did not follow the DM protocol, 12 (52%) had complete resolution with a median time to resolution of 106 d. The rates of PN (any G, G ≥ 3) were similar regardless of pt age or number/type of prior therapies (Table). The median TTP of 91 pts with G ≥ 2 PN, 68 pts with DM, and the Bz arm overall were 6.2, 6.9 and 6.2 months, respectively. Conclusion: The overall rate of PN in APEX was similar to that of SUMMIT and CREST, but the rate of G ≥ 3 PN was lower, perhaps because of specific DM guidelines. PN was reversible in the majority of pts, and DM did not compromise efficacy. Pt age or number/type of prior therapies did not appear to affect the rate or severity of PN. PN Bz Subgroup Any G*, % G ≥3, % *Bz related ge; 65 y 35 9 〈 65 y 37 9 〉 1 prior therapy 36 10 1 prior therapy 37 8 Steroids 38 7 Alkylating agent 35 7 Anthracycline 39 7 Vinca alkaloid 38 8 Thalidomide 44 8 Transplantation 37 7

Description: Introduction: In the international, multicenter phase 3 APEX trial, 669 patients (pts) with multiple myeloma (MM) who had relapsed after 1–3 prior therapies were randomized to receive bortezomib (VELCADE®) 1.3 mg/m2 IV d 1, 4, 8, 11 q3wk for 8 cycles followed by 3 cycles on d 1, 8, 15, 22 q5wk, or dexamethasone (Dex) 40 mg PO d 1–4, 9–12, 17–20 q5wk for 4 cycles followed by 5 cycles on d 1–4 q4wk. Pts refractory to Dex were excluded, and those with progressive disease on Dex were eligible to cross over to bortezomib. Pts receiving bortezomib achieved significant improvement in time to progression (TTP, primary end point), response rate (CR + PR using EBMT criteria), and survival (Richardson. NEJM.2005;352:2487), which resulted in early closure of the trial. The duration of response (DOR) was longer with bortezomib, and infections ≥ grade 3, time to skeletal events, grade 4 adverse events (AE), serious AE, and discontinuations due to AE were similar in the 2 treatment arms. Methods: In this analysis, updated response rates, time to response (TTR), DOR, survival, and TTP are presented after extended follow-up. A matched-pairs analysis comparing survival and TTP of pts on bortezomib in APEX with those in another trial of MM pts who received bortezomib after Dex will also be presented. Results: 669 pts received a median of 7 cycles of therapy. Based on a median follow-up of 15.8 months, the median TTP, 1-year and overall survival (OS), response rates, median TTR, and median DOR for pts receiving bortezomib are shown in the table. Median duration of therapy for responders (CR + PR) was 7.2 months. Improved response with longer therapy (after cycle 6) was observed in 76 pts (56% of responders) in the bortezomib arm (20 pts improved from MR or PR to CR, and 56 pts improved from MR to PR). Furthermore, 28 of 135 responders (21%) achieved first response (CR/PR) after cycle 4, including 18 pts (13%) on or after cycle 6, and 10 pts (7%) on or after cycle 8. OS increased substantially with more follow-up. Median TTR was more rapid, and median DOR was longer in pts achieving CR and near CR than in those with PR. Conclusion: Updated TTP, response rates, survival, TTR, and DOR for the bortezomib group continue to support the findings of the original analysis. Thus, the clinical benefits of single-agent bortezomib in pts with relapsed MM remain robust after extended follow-up, supporting its early use in relapsed MM and its further study in the treatment of newly diagnosed disease. Efficacy Bortezomib (n = 333) Median TTP, mo 6.2 1-year survival, % 80 Median OS, mo 25.4 Response rate, % (n/N) 43 (135/315) CR 9 (27/315) PR 34 (108/315) -near CR 7 (21/315) Median TTR, mo (range) 1.4 (0.5–6.0) CR 0.8 (0.5–4.0) PR 1.4 (0.5–6.0) -near CR 0.8 (0.6–2.4) Median DOR, mo 7.8 CR 9.9 PR 7.6 -near CR 11.5

Description: Introduction/Methods: This international phase 3 study conducted at 93 sites is the largest randomized study to date in relapsed multiple myeloma (MM). Patients (pts) had to have received 1–3 prior therapies and those with dexamethasone (Dex) refractory disease were excluded. Pts were randomized to bortezomib (VELCADE®) 1.3 mg/m2 IV d 1, 4, 8, 11 q3wk for 8 cycles followed by 3 cycles on d 1, 8, 15, 22 q5wk, or Dex 40 mg PO d 1–4, 9–12, 17–20 q5wk for 4 cycles followed by 5 cycles on d 1–4 every 28 d. The 1° endpoint was time to progression (TTP); 2° endpoints included survival, response rate (CR+PR) using EBMT criteria, duration of response, time to response (TTR), time to skeletal events, infections ≥gr 3 and safety; exploratory endpoints included pharmacogenomics and quality of life. Pts with progressive disease on Dex were eligible to crossover to bortezomib in a companion study. Results: 669 pts were randomized and baseline characteristics were balanced in both arms. Based on a median follow-up of 8.3 mo, bortezomib demonstrated a 78% improvement in median TTP (hazard ratio 0.55, P

Description: A high remission rate is achieved with high-dose melphalan (HDM) in multiple myeloma (MM), and autologous transplantation of hematopoietic stem cells allows a prompt hematologic recovery after high-dose therapy. We treated 97 patients with high-risk MM (group 1:44 advanced MM including 14 primary resistances and 30 relapses; group 2: 53 newly diagnosed MM) with a first course of HDM. For responding patients a second course of high-dose therapy with hematopoietic stem cell support was proposed. After the first HDM, the overall response and complete remission rates were 71% and 25% with no significant difference between the two groups. The median durations of neutropenia and thrombocytopenia were significantly longer in group 1 (29.5 days and 32 days, respectively) than in group 2 (23 days and 17 days, respectively). This severe myelosuppression led to eight toxic deaths and the fact that only 38 of the 69 responders could proceed to the second course (three allogenic and 35 autologous transplantations). Among the 35 patients undergoing autologous transplantation (10 in group 1, 25 in group 2), 31 received their marrow unpurged collected after the first HDM, and four received peripheral blood stem cells. The median durations of neutropenia and thrombocytopenia after autologous transplantation were 24 days and 49 days, respectively. Two toxic deaths and nine prolonged thrombocytopenias were observed. The median survival for the 97 patients was 24 months (17 months in group 1, 37 months in group 2) and the median duration of response was 20 months. The only parameters that have a significant impact on the survival are the age (+/- 50 years) and the response to HDM. The median survival of the 35 patients undergoing autologous transplantation is 41 months, but the median duration of remission is 28 months with no plateau of the remission duration curve. Patients responding to HDM may have prolonged survival, but even a second course of high-dose therapy probably cannot eradicate the malignant clone.

Description: Introduction: Bortezomib (Bz, VELCADE®) is a novel proteasome inhibitor that has demonstrated safety and efficacy for patients (pts) with relapsed and/or refractory multiple myeloma (MM) in phase 2 and 3 trials. Bz was associated with transient, cyclical thrombocytopenia in SUMMIT (NEJM.2003;348:2609) and CREST (BJH.2004;127:165). This analysis evaluated the hematologic profiles in pts treated with Bz or high-dose dexamethasone (Dex) in APEX, the largest phase 3 MM trial in relapsed pts. (NEJM.2005;352:2487). Methods:669 pts with relapsed MM were randomized to Bz 1.3 mg/m2 d 1, 4, 8, 11 q3wk for 8 cycles, then 3 cycles on d 1, 8, 15, 22 q5wk, or Dex 40 mg d 1–4, 9–12, 17–20 q5wk for 4 cycles, then 5 cycles on d 1–4 q28d. Data were collected at baseline and regularly through therapy for adverse events, laboratory values, and transfusion (tf) experience. Results:Thrombocytopenia, anemia, and neutropenia reported as adverse events, all grades (G) and those ≥ G3 in pts are shown (Table). Bz-associated thrombocytopenia was cyclical, with recovery toward baseline during the rest period of each cycle. Overall, 15% of pts on Bz and 1% of those on Dex received platelet (plt) tfs and 33% of pts on Bz and 20% of those on Dex received blood tfs. The majority of plt and blood tfs were completed in the first 2 cycles in both treatment arms. Although the number of plt tfs was higher with Bz, the number of clinically significant bleeding events was similar in the 2 arms. Pts on Bz with complete or partial response experienced an increase in mean hemoglobin over time and the requirement for blood tfs decreased from 21% in cycle 1 to 0% after cycle 4. Median duration of therapy for plt transfused pts was 3.8 and 3.4 mo in the Bz and Dex arms, respectively. Bz-associated neutropenia was also transient and cyclical, and febrile neutropenia was rare. Bz was otherwise not associated with severe myelosuppression. Conclusions:Bz is associated with transient, reversible thrombocytopenia and neutropenia—both with a periodicity related to drug administration—but with rapid recovery and few complications compared with Dex. When clinically indicated, plt tf support, rather than dose reduction, particularly in the first 2 cycles, may be warranted to maximize the benefit of Bz therapy. Impact on plts does not appear to be cumulative, and the mechanism of the cyclic variation in neutrophil counts needs further study. Event Bz (n = 331) Dex (n = 332) *Tfs between baseline and last dose of treatment. Thrombocytopenia, n (%) 116 (35) 36 (11) G3/4 98 (30) 22 (7) Neutropenia, n (%) 63 (19) 6 (2) G3/4 49 (15) 5 (2) Anemia, n (%) 92 (28) 77 (23) G3/4 33 (10) 39 (12) Median plt count, x 109/L (range) Baseline count in blood transfused pts 132 146 Baseline count in plt transfused pts 99 74.5 Responders Baseline 205 162.5 First response 195 175 Last assessment 199 198