ALBERT

Description: Risk factors for ONJ in MM pts include dental extraction, bisphosphonates (BP) use, older age and longer survival. There is also an increased risk of skeletal related events (SRE) in ONJ pts (Badros, JCO 2006). The current study provides long term follow-up data for ONJ pts with regard to ONJ recurrence, SRE and MM status. The study included 97 pts: 60 from Greece and 37 from the US. Pts’ characteristics are summarized in the table below. Median follow-up time has not been reached; lower limit of the 95%CI was 3.2 yrs. ONJ resolved in 60 of 97 pts (62%), resolved and recurred in 12 pts (12%), and did not heal over a 9 months period in 25 pts (26%). Dental extraction preceded ONJ in 46 of 97 pts (47%) and was more common in pts with a single episode of ONJ (35 of 60, 58%) than in the recurrent and non-healing pts (11 of 37, 30%) (p-value=0.007). The median number of ONJ episodes in the recurrent group was 3 (range, 2–6); recurrence of ONJ was precipitated by re-initiation of BP and by dental procedures in 5 and 4 pts of 12, respectively. There was a trend toward higher ONJ recurrence rate in the US (8 of 37, 22%) versus the Greek (4 out of 60, 7%) pts (p-value=0.053). Surgery was performed more often in the US than in Greece 17 of 37 (45%) versus 19 of 60 pts (32%). BP reinitiation was more frequent in US 16 of 37 (43%) than in Greece 3 of 60 (5%). Non-healing ONJ lesions were managed with antibiotics; 10 of 25 pts developed fistulas and needed surgery; in 9 pts the lesions remained asymptomatic. Twenty-one ONJ pts had SRE including fractures (ribs, vertebrae and long bones, n=13) and avascular necrosis of the femur (n=8). The rate of MM relapse was higher in pts with recurrent and non-healing ONJ (84%) compared to pts with a single episode (62%) (p-value=0.02). The median OS from diagnosis of MM was 10.8 yrs (95% CI; 9.3 yrs- not reached) and did not differ between pts with single, recurrent/non-healing ONJ (p= 0.2). In summary, pts in whom ONJ followed dental procedures were less likely to have recurrence or non-healing, both, although infrequent, were linked to BP re-challenge, mostly in the setting of relapsed MM. Non-healing ONJ lesions remained stable/asymptomatic without extensive intervention. BP should be discontinuation until ONJ lesions heal. The decision to restart BP should be individualized based on MM-SRE risk. ONJ Pts characteristics and outcome AA, African American; ttt, treatment; CR, complete remission; PR, partial remission; PD, progressive disease; Dex, dexamethasone, thal, thalidomide; Len, lenalidomide; Bort, bortezomib; A, pamidronate; Z zoledronic acid. The Fisher’s Exact test was used, all p-values reported are two-sided. ONJ, n= 97 one episode, n=60 recurrent, n=12 non-healing, n=25 age at MM; median (range) 60 (26–77) 61 (26–77) 55 (43–76) 61 (36–73) Sex; male/female 59/38 38/22 8/4 13/12 Caucasian/AA 87/10 54/6 10/2 23/2 Isotype; IgG, A, D, LCH 60/20/1/16 36/11/1/12 7/2/0/3 17/7/0/1 MM ttt at ONJ (n=93); none/dex/thal/len/bort 22/31/26/6/8 11/25/16/4/2 5/1/3/1/1 6/5/7/1/4 MM status at ONJ diagnosis; CR/PR/PD 7/54/33 4/37/17 3/8/1 0/9/15 BP use; AZ/Z 59/35 34/23 10/2 15/10 Dental extraction 46 35 5 5 Restarted BP 19 11 6 2 bone complciations 21 14 3 4 MM course after ONJ; continous remission/Relapse 29/68 23/37 2/10 4/21 MM status at last follow up; CR/PR/PD (died) 3/59/35(28) 3/35/22(20) 0/10/2(2) 0/14/11(6)

Description: SAHA, vorinostat, an oral, histone deacetylase inhibitor, affects cell growth by modifying the transcription of cellular proteins such as histones, transcription factors, ubiqutin E3 ligases and stress response proteins (e.g. HSP90). In vitro, SAHA showed synergistic cytotoxicity with the proteasome inhibitor Bort in MM cells by disrupting aggregates of the ubiquitin conjugated aggresomes. The aims of the study were to determine the MTD, pharmacokinetics (PK) and pharmacodynamic (PD) effects and activity of SAHA plus Bort in pts with relapsed/refractory MM. Twenty-one Pts have been treated. Median age was 55 yrs (range 38–79). Median time from MM diagnosis to study entry was 5.3 yrs (range: 1.5–15 yrs). Isotypes included IgG (n=10), IgA (n=5), light chain (n=4), and nonsecretory (n=2). Twelve Pts had complex karyotype. Median number of prior regimens was 6 (range 3–10); including tandem SCT (n=11), one SCT (n=8), thalidomide (n=21) and lenalidomide (n=14). Nineteen pts had received a median of 2 (range: 1–5) Bort-based prior regimens, 14 Pts had PD to last Bort therapy. 19 pts had PD to last therapy, with a median of 20 days (15–39) between last therapy and study entry. Only 2 patients were in first relapse on thalidomide maintenance. Five 3-Pt cohorts were evaluated at various dose levels as outlined in the table below.The MTD of SAHA in cycle 1 was 400 mg daily, as 2 DLTs, grade 4 prolonged QT interval and grade 4-fatigue occurred in the 500 mg daily cohort. Several grade 3–4 toxicities were observed after cycle 2, including myelo-suppression requiring transfusional support and growth factors. Non-hematological toxicities grade 2 and higher included fatigue (n=5), diarrhea (n=3), atrial fibrillation (n=1), shingles (n=1), pneumonia (n=2, bacterial and RSV). In 16 pts evaluable for response, there was 1 nCR and 7 PR (overall response rate of 50%), 6 pts had stable disease and 3 had PD. At last follow up, three pts remain in remission off therapy for 3–5 months, 9 had PD and 5 have died. Dexamethasone was added 4 pts in cycle 2; with no upgrade in response. The PK of SAHA after a single oral dose were linear from 100–500 mg with mean AUC (0.7 + 0.45 to 4.4+ 0.07), Cmax (0.3 + 0.14 to 1.2 + 0.06) and Tmax (1.3 + 0.4 to 2.3 + 2.5). Ten pts had CD-138+ cells isolated from bone marrow on day 1 [median, 1.8 × 106, range: 0.2–42.6] and on day 11 of the first cycle [median, 0.9 × 106: range: 0.4–5.4] for PD studies. The MTD for SAHA plus Bort was 400 mg daily × 8 days plus1.3 mg/ m2 days 1, 4, 8 and 11. SAHA administration after Bort does not affect PK. The regimen showed promising responses in Bort-refractory pts and should be evaluated in a phase II trial. Study schedule/response Cohort Bort (mg/m2) SAHA (mg) No. Pts No Cycles Response Bort days 1, 4, 8, 11 of 21-day cycle + SAHA days 4–11. Pts received 8 cycles. Dexamethasone was added for nonresponders, cycle 2. * Of 10 pts to be treated at MTD. PR, partial response; NE, not evaluable; SD/PD, stable/progressive disease. 1 1.0 100 bid 3 5, 7, 5 SD, SD, SD 2 1.3 100 bid 3 5, 6, 3 SD, PR, PD 3 1.3 200 bid 3 8, 3, 8 VGPR, SD, PR 4 1.3 400 daily 3 5, 3, 3 SD, PD, PR 5 1.3 500 daily 3 7, 1, 1 PR, NE, NE MTD 1.3 400 daily 6* 4, 3, 2, “1, 1, 1” PR, PR, PR, “too early for evaluation”

Description: Several studies have established the safety and efficacy of V in various regimens before stem cell mobilization and transplant (SCT). The primary objective of our study was to determine the MTD of V (3 dose levels: 0.7, 1.0, 1.3 mg/m2 days 1, 4, and 8) in combination with DT-PACE (dexamethasone 40 mg/day and thalidomide 200–400 mg/day orally x 4 days, Cisplatinum 10 mg/m2, Adriamycin 10 mg/m2, cyclophosphamide 400 mg/m2 and Etoposide 40 mg/m2 all given by IVCI for 4 days) in newly diagnosed MM. Pts received 2 cycles (C) of VDT-PACE; stem cells were collected after C 1. G-CSF 10-ug/kg/day was given from day 5 until stem cell collection (GCSF was held on day 8 of V). The secondary endpoint was to evaluate the effects of V during mobilization on engraftment. Eleven Pts enrolled, six on dose level I; 3 on dose level II and 2 on dose level III. Median age was 58 yrs (42–70), 9 were males. Four had no prior therapy and 7 had one prior cycle including DT (n=4) and DT-PACE (n=3). Median B2M was 2.9 mg/L (range: 1.9–8.5) and BM plasma cells was 45% (range: 10–80). No DLT was observed. Pts, mostly with cycle 2, had G- 3/4 hematological toxicity requiring transfusiona and neutropenic fever requiring hospitalization. G-3 toxicity included diarrhea (n= 2), (DVT= 3) despite enoxaparin, hypotension (n=3) including syncope (n=2). G-2 included bradycardia (n= 3) and peripheral neuropathy (n= 3). Stem cells were collected at a median of 13 days (range: 12–15). Pts had a median of 20.57 (range: 7.85 – 33.3) x 106 CD 34+/kg in 1 (n=4), 2 (n=6) and 3 days (n=1). Two pts collected additional cells after C 2, both received prior DT-PACE. All 11 Pts responded; CR (n=1), near CR (n=1) and PR (n=9); to date, all pts had received SCT; conditioning regimens were melphalan 200 mg/m2 (n=9) and 140 (n=2), 2 pts had tandem SCTs. Median CFU-C of the infused CD-34 cells was 320.2 (range: 57–1000) x 104/kg. Median time to ANC 〉 1000/mcl was 14 days (range: 13–25), plt 〉 20, 000/mcl was 16 days (range: 10–50) and 〉 50,000 was 25 days (range: 15–57). CMV antigenemia with fever and delayed engraftment was seen in one pt and autologous GVHD (skin and gut), biopsy proven, was seen in one pt. After SCT, pts achieved CR (n=3), nCR (n=4) and PR (n=4). At a median follow up of 252 days (range: 23–467), 1 pt had relapsed at 8 m with high-risk MM, hypodiploid clone. The results were compared to a control group (pts mobilized with DT-PACE; n=14). They had a median of 14.5 days to first day of phoresis (range: 11– 22) with a median 17.8 x 106 CD 34+/kg (range: 9- 35) collected in 1 (n=6), 2 (n=5) and 3 days (n=3). Median CFU-C was 540 (range: 153–1388) x 104/kg. For the control group; ANC 〉 1000 was reached at a median of 12 days (range: 11–20) and plt 〉 20000 at 18 days (range: 13–25) and 〉 50,000 at 19 (range: 15–38). There was no statistically significant correlation between total CD34 count and times to engraftment between both groups. There was a tendency for pts treated with V to have lower CFU-C (p=0.0565), the clinical significance is unclear. In conclusion: the VDT-PACE regimen was associated with expected and acceptable toxicities. There was a rapid response in all pts treated. Adequate numbers of stem cells were collected with prompt engraftment after SCT. VDT-PACE regimen has the advantage of short induction time prior to SCT and should be evaluated in a randomized fashion before SCT against other regimens like DT and VDT with regards to quality of life and long-term toxicities.