- Email: [email protected]
A334 Bortezomib-Based Therapy Following Prior Lenalidomide + Dexamethasone in Relapsed Multiple Myeloma
XII International Myeloma Workshop Table 1
Abstract 333
Dose Level
1
2
3
3 (expanded)
3
3
6
12
Cyclophosphamide Dose (mg/m2)
150
150
300
300
Lenalidomide Dose (mg)
15
25
25
25
Prednisone Dose (mg)
100
100
100
100
Median Number of Cycles Given
12
9
7
3
N
myeloma with a plasmablastic phenotype. He died two weeks after the liver biopsy from sepsis. Conclusion: The liver is a rare site for extramedullary relapse in myeloma but associated with a poor prognosis. MRI appears to be sensitive at detecting hepatic plasmacytomas and should be considered for investigation of myeloma patients with abnormal liver function. In the era of IMiDs, which affect expression of adhesion molecules such as ICAMI and VCAM1, extramedullary relapse at unusual sites such as the liver may become more prevalent.
A333
neutropenia, no other grade 4 AE was observed. The second dose level included 4 patients in panobinostat at 10 mg and unchanged dosing schedules for lenalidomide and dexamethasone. Conclusion: The potential for anti-myeloma activity of this triple combination is strongly supported by preclinical experiments in vitro and in vivo. In this first clinical trial assessing this triple combination, the first dose level of this trial appears very safe. Updated and subsequent dose-level patient data will be presented.”
A330 Hepatic Plasmacytomas as a Manifestation of Extramedullary Relapse in Multiple Myeloma L Fraser, H McCarthy Royal Bournemouth Hospital
Introduction and Aim: Although diffuse hepatic infiltration is common in myeloma at autopsy, case reports of space occupying hepatic plasmacytomas in living patients are rare. On a review of the literature, we found 8 case reports. In a two-year period of 1995-1997 we identified two biopsy-proven cases. The aim of this study was to review the clinical and histologic features of these cases. Methods: Both patients underwent trans-jugular liver biopsies. Clinical and histological features were reviewed from case records. Results: Case 1: A 62-year-old man was treated with 6 courses of CVAD chemotherapy and tandem autologous PBSCT following high-dose melphalan. Seven months post final transplantation he developed hepatomegaly and deranged liver function tests (ALT, 107 IU/L; ALP, 219 IU/L; bil, 37 mmol/L). Multiple space-occupying lesions were identified in the liver on ultrasound and MRI scans. The liver lesions were not visualized by CT which showed a homogeneous appearance. His bone marrow plasma cell infiltrate was < 5% at this time. The liver histology showed a heavy infiltrate of myeloma with a plasmablastic phenotype. Despite sequential treatment with thalidomide, velcade, and lenalidomide in combination with dexamethasone, he died 6 months later. Case 2: A 79-year-old man with multiply relapsed myeloma and end-stage renal failure on hemodialysis presented with hepatomegaly (ALT, 81 IU/L; ALP, 395 IU/L; bil, 220 mmol/L). Liver ultrasound confirmed hepatomegaly but showed no features of focal or diffuse disease. His bone marrow was heavily infiltrated with plasma cells at this time. The liver histology also showed a heavy infiltrate of
Phase I/II Trial of Cyclophosphamide, Prednisone, and Lenalidomide for Relapsed and Refractory MM D Reece, E Masih-Khan, P Anglin, C Chen, V Kukreti, A Khan, J Mikhael, S Trudel University Health Network, Princess Margaret Hospital, Toronto, ON, Canada
We conducted a phase I-II trial of oral lenalidomide (revlimid, [days 1-21]), cyclophosphamide (days 1, 8, and 15), and prednisone 100 mg every 2 days in a 28-day cycle in relapsed/ refractory multiple myeloma (MM) patients. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007-10/2008, 24 patients were treated. Median age, 57 years (range, 40-78 years); 60% were male. Immunoglobulin subtype: IgG K:L in 13:1; IgA K:L in 4:1 and K light chain in 4. Median number of prior regimens was 2 (range, 1-5 regimens), including ASCT. Prior therapy included thalidomide in 7 (29%) and bortezomib in 14 (58%). One patient had FISH 13q deletion. Median B2-microglobulin was 235 nm/L (range, 92-767 nm/L), albumin 38 g/L (range, 32-47 g/L), creatinine 82 μmol/L (range, 50-117 μmol/L), platelet count 230 r 109/L (range, 75-337 r 109/ L) and ANC 2.5 r 109/L (range, 1.1-6.1 r 109/L). The maximum tolerated dose of this regimen was not reached. Grade 3/4 toxicities included thrombocytopenia in 2 patients (1 in cohort 2 and 1 in cohort 3) and neutropenia in 6 patients (1 in cohort 1, 1 in cohort 2, and 4 in cohort 3), managed with dose reduction and/or growth factor support. Other grade 3/4 nonhematologic toxicities were rare. To date, best response includes: dose level 1 (1 nCR, 2 PR); dose level 2 (3 PR); dose level 3 (1 nCR, 4 PR, 1 minimal response [MR]); expanded cohort 3 (3 nCR, 7 PR, 1 MR, and 1 SD). Only 4 patients have progressed. We conclude: (1) full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; (2) the overall response rate (nCR PR MR) in 24 evaluable patients is 96%; (3) longer follow-up is required. Treatment is summarized in Table 1. Median follow-up of patients is 6 months (range, 2-12 months).
A334 Bortezomib-Based Therapy Following Prior Lenalidomide + Dexamethasone in Relapsed Multiple Myeloma Y Trieu,1 W Xu,1 E Masih-Khan,1 S Dean,1 S Trudel,1 V Kukreti,1 P Anglin,1 C Chen,1 J Mikhael,2 D Reece1
Clinical Lymphoma & Myeloma Supplement February 2009
•
S53
Clinical Studies Including Transplantation 1
Princess Margaret Hospital; 2Mayo Clinic Scottsdale
The optimal sequencing of novel agents in multiple myeloma (MM) is not clear. Due to a funding delay for bortezomib (btz) in Canada, patients with relapsed/refractory (rel/ref ) MM preferentially received lenalidomide dexamethasone (len dex) via access programs/clinical trials. These patients later received btz for subsequent relapse. We evaluated the outcome of 35 MM patients treated between 12/2005 and 8/2008, who received len dex for recurrent MM (15 in first, 15 in second, 4 in third, and 1 in fourth relapse after primary therapy), and then btz-based regimens when they progressed again (without any interim therapy). Twentyeight patients (80%) had previously undergone autologous stem cell transplantation as part of initial therapy. Median age was 56 years (range, 31-76 years); 20 were male. The Ig subtype included IgG (16), IgA (8), IgM (1) and light chain only (10). Median b2M was 260 nmol/L, creatinine 81 μmol/L and albumin 40 g/L. FISH cytogenetics available in 14 patients showed 13q del in 5, t(4;14) in 2 and p53 del in 2. The median duration of len + dex was 4 months (range, 1-23 months); best clinical response included nCR in 3 (9%), PR in 19 (54%), MR in 1 (3%), SD in 5 (14%), and progression (prog) in 7 (20%). Subsequent btz-based therapy included btz alone in 12 (34%) patients, btz corticosteroids (CS) in 18 (51%), btz CS oral cyclophosphamide in 3 (9%), and btz other in 2 (6%). The median duration of btz-based therapy was 3 months (range, 0.5-17.2 months). The best clinical response to btz-based therapy was nCR in 1 (3%), VGPR in 5 (14%), PR in 10 (29%), MR in 4 (11%), SD in 6 (17%) and prog in 9 (26%). The 1-year progression-free survival (PFS) was 23% (95% CI, 8%-42%) and overall survival (OS) 31% (95% CI, 11%-54%). The median PFS and OS were 5.6 months (range, 0.7-18.6 months) and 10.1 months (range, 0.8-18.6 months), respectively. Only q PR with btz correlated with PFS (P = .03) and OS (P = .04). We conclude that btz-based therapy (1) is an effective approach in MM patients with advanced rel/ref disease; (2) the efficacy is preserved after prior exposure to the potent len dex combination.
A337 Panobinostat and Bortezomib Phase I Trial in Multiple Myeloma O Sezer,1 D Siegel,1 J San Miguel,2 MV Mateos,2 I Prosser,3 A Guenther,4 J Bladé,5 M Cavo,6 M Jalaluddin,7 K Hazell,7 PM Bourquelot,7 KC Anderson8 1
Hackensack University Medical Center; 2Hospital Universitario de Salamanca; 3The Canberra Hospital; 4University of Kiel; 5Hospital Clinic, IDIBAPS; 6University of Bologna; 7Novartis Pharmaceuticals; 8 Dana-Farber Cancer Institute, Harvard Medical School
Introduction: Panobinostat (LBH589) is a highly potent pandeacetylase inhibitor (pan-DACi), interfering with epigenetic and non-epigenetic pathways implicated in cancer. Panobinostat has demonstrated synergistic cytotoxicity in vitro and in vivo in multiple myeloma (MM) cell lines and patient cells in combination with bortezomib. Methods: This phase Ib trial will determine the maximum tolerated dose (MTD) of panobinostat
S54
•
with bortezomib in patients with relapsed refractory MM. Safety, tolerability, PK/PD, and preliminary efficacy will also be assessed. Results: A total of 21 patients have been enrolled, to date, into three dose level cohorts: (1) 10 mg panobinostat (orally thrice weekly) + 1 mg/m2 bortezomib (I.V., days 1, 4, 8, 11) during a 21-day cycle; (2) 20 mg panobinostat 1 mg/m2 bortezomib; and (3) 20 mg panobinostat 1.3 mg/m2 bortezomib. In cohorts 1-2, the median number of prior therapies was three (range, 1-7), all 14 patients had at least one prior auto-SCT, and 8 patients prior bortezomib. Overall, the combination of panobinostat and bortezomib was safe and well tolerated in cohorts 1 and 2, with no new safety findings. Hematologic AEs have been most frequent, including grade 3/4 anemia (2), thrombocytopenia (11), and neutropenia (3). Nonhematologic AEs included grade 1/2 diarrhea (5), fatigue (7), fever (6), and nausea (4). No DLT was reported in any of the 12 evaluable patients treated in cohorts 1-2. To date in 14 patients, 1 immunofixation negative CR, 1 VGPR, and 3 PR were seen. These responses included patients who were refractory to prior bortezomib treatment which is encouraging. Enrollment into cohort 3 is ending, with 7 patients accrued to date. Conclusion: Preliminary results suggest that the panobinostat/bortezomib combination is safe, well tolerated with no DLT reported to date. Encouraging early activity was seen; updated data will be presented.
A339 The Bone Marker ICTP Adds to the Prognostic Significance of the ISS in Symptomatic Multiple Myeloma C Jakob,1 J Sterz,1 M Mieth,1 U Heider,1 M Kaiser,1 P Liebisch,2 J Rademacher,1 C Müller,3 O Sezer1 1
Department of Hematology and Oncology, Charité, Universitätsmedizin Berlin; 2Department of Hematology and Oncology, University-Hospital Ulm; 3Department of Clinical Chemistry, Charité, Universitätsmedizin Berlin
Introduction: The outcome of patients with newly diagnosed symptomatic multiple myeloma (MM) is highly variable. Several prognostic markers, including parameters of tumor burden and cytogenetics were adopted to identify high-risk patients. Recently the International Staging System (ISS), consisting of B2-microglobulin (B2M) and albumin, was introduced for patients with symptomatic MM. In previous studies the bone resorption marker carboxyterminal telopeptide of type-1 collagen (ICTP) was identified as a sensitive and specific marker of bone resorption and as a prognostic factor for overall survival (OS) in MM. Materials and Methods: We investigated the prognostic impact of the bone marker ICTP in comparison to ISS, B2M, albumin, deletion 13q14 and high-dose therapy (HDT) in 100 patients with newly diagnosed symptomatic MM. Results: B2M alone, albumin alone, ISS, del(13q14) and ICTP were significant prognostic factors for overall survival. In contrast to ICTP, lytic bone lesions were not an independent prognostic factor (P = .289). In a multivariate analysis, ICTP was the most powerful prognostic factor (log rank P < .001, hazardratio: 9.17). Furthermore ICTP (cut off: reference limit) separated a good and a poor prognosis group within each of the ISS stages (ISS I: P = .027; ISS II: P = .022; ISS III: P = .013). A combined ISS-
Clinical Lymphoma & Myeloma Supplement February 2009
Abstract 333
Dose Level
1
2
3
3 (expanded)
3
3
6
12
Cyclophosphamide Dose (mg/m2)
150
150
300
300
Lenalidomide Dose (mg)
15
25
25
25
Prednisone Dose (mg)
100
100
100
100
Median Number of Cycles Given
12
9
7
3
N
myeloma with a plasmablastic phenotype. He died two weeks after the liver biopsy from sepsis. Conclusion: The liver is a rare site for extramedullary relapse in myeloma but associated with a poor prognosis. MRI appears to be sensitive at detecting hepatic plasmacytomas and should be considered for investigation of myeloma patients with abnormal liver function. In the era of IMiDs, which affect expression of adhesion molecules such as ICAMI and VCAM1, extramedullary relapse at unusual sites such as the liver may become more prevalent.
A333
neutropenia, no other grade 4 AE was observed. The second dose level included 4 patients in panobinostat at 10 mg and unchanged dosing schedules for lenalidomide and dexamethasone. Conclusion: The potential for anti-myeloma activity of this triple combination is strongly supported by preclinical experiments in vitro and in vivo. In this first clinical trial assessing this triple combination, the first dose level of this trial appears very safe. Updated and subsequent dose-level patient data will be presented.”
A330 Hepatic Plasmacytomas as a Manifestation of Extramedullary Relapse in Multiple Myeloma L Fraser, H McCarthy Royal Bournemouth Hospital
Introduction and Aim: Although diffuse hepatic infiltration is common in myeloma at autopsy, case reports of space occupying hepatic plasmacytomas in living patients are rare. On a review of the literature, we found 8 case reports. In a two-year period of 1995-1997 we identified two biopsy-proven cases. The aim of this study was to review the clinical and histologic features of these cases. Methods: Both patients underwent trans-jugular liver biopsies. Clinical and histological features were reviewed from case records. Results: Case 1: A 62-year-old man was treated with 6 courses of CVAD chemotherapy and tandem autologous PBSCT following high-dose melphalan. Seven months post final transplantation he developed hepatomegaly and deranged liver function tests (ALT, 107 IU/L; ALP, 219 IU/L; bil, 37 mmol/L). Multiple space-occupying lesions were identified in the liver on ultrasound and MRI scans. The liver lesions were not visualized by CT which showed a homogeneous appearance. His bone marrow plasma cell infiltrate was < 5% at this time. The liver histology showed a heavy infiltrate of myeloma with a plasmablastic phenotype. Despite sequential treatment with thalidomide, velcade, and lenalidomide in combination with dexamethasone, he died 6 months later. Case 2: A 79-year-old man with multiply relapsed myeloma and end-stage renal failure on hemodialysis presented with hepatomegaly (ALT, 81 IU/L; ALP, 395 IU/L; bil, 220 mmol/L). Liver ultrasound confirmed hepatomegaly but showed no features of focal or diffuse disease. His bone marrow was heavily infiltrated with plasma cells at this time. The liver histology also showed a heavy infiltrate of
Phase I/II Trial of Cyclophosphamide, Prednisone, and Lenalidomide for Relapsed and Refractory MM D Reece, E Masih-Khan, P Anglin, C Chen, V Kukreti, A Khan, J Mikhael, S Trudel University Health Network, Princess Margaret Hospital, Toronto, ON, Canada
We conducted a phase I-II trial of oral lenalidomide (revlimid, [days 1-21]), cyclophosphamide (days 1, 8, and 15), and prednisone 100 mg every 2 days in a 28-day cycle in relapsed/ refractory multiple myeloma (MM) patients. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007-10/2008, 24 patients were treated. Median age, 57 years (range, 40-78 years); 60% were male. Immunoglobulin subtype: IgG K:L in 13:1; IgA K:L in 4:1 and K light chain in 4. Median number of prior regimens was 2 (range, 1-5 regimens), including ASCT. Prior therapy included thalidomide in 7 (29%) and bortezomib in 14 (58%). One patient had FISH 13q deletion. Median B2-microglobulin was 235 nm/L (range, 92-767 nm/L), albumin 38 g/L (range, 32-47 g/L), creatinine 82 μmol/L (range, 50-117 μmol/L), platelet count 230 r 109/L (range, 75-337 r 109/ L) and ANC 2.5 r 109/L (range, 1.1-6.1 r 109/L). The maximum tolerated dose of this regimen was not reached. Grade 3/4 toxicities included thrombocytopenia in 2 patients (1 in cohort 2 and 1 in cohort 3) and neutropenia in 6 patients (1 in cohort 1, 1 in cohort 2, and 4 in cohort 3), managed with dose reduction and/or growth factor support. Other grade 3/4 nonhematologic toxicities were rare. To date, best response includes: dose level 1 (1 nCR, 2 PR); dose level 2 (3 PR); dose level 3 (1 nCR, 4 PR, 1 minimal response [MR]); expanded cohort 3 (3 nCR, 7 PR, 1 MR, and 1 SD). Only 4 patients have progressed. We conclude: (1) full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; (2) the overall response rate (nCR PR MR) in 24 evaluable patients is 96%; (3) longer follow-up is required. Treatment is summarized in Table 1. Median follow-up of patients is 6 months (range, 2-12 months).
A334 Bortezomib-Based Therapy Following Prior Lenalidomide + Dexamethasone in Relapsed Multiple Myeloma Y Trieu,1 W Xu,1 E Masih-Khan,1 S Dean,1 S Trudel,1 V Kukreti,1 P Anglin,1 C Chen,1 J Mikhael,2 D Reece1
Clinical Lymphoma & Myeloma Supplement February 2009
•
S53
Clinical Studies Including Transplantation 1
Princess Margaret Hospital; 2Mayo Clinic Scottsdale
The optimal sequencing of novel agents in multiple myeloma (MM) is not clear. Due to a funding delay for bortezomib (btz) in Canada, patients with relapsed/refractory (rel/ref ) MM preferentially received lenalidomide dexamethasone (len dex) via access programs/clinical trials. These patients later received btz for subsequent relapse. We evaluated the outcome of 35 MM patients treated between 12/2005 and 8/2008, who received len dex for recurrent MM (15 in first, 15 in second, 4 in third, and 1 in fourth relapse after primary therapy), and then btz-based regimens when they progressed again (without any interim therapy). Twentyeight patients (80%) had previously undergone autologous stem cell transplantation as part of initial therapy. Median age was 56 years (range, 31-76 years); 20 were male. The Ig subtype included IgG (16), IgA (8), IgM (1) and light chain only (10). Median b2M was 260 nmol/L, creatinine 81 μmol/L and albumin 40 g/L. FISH cytogenetics available in 14 patients showed 13q del in 5, t(4;14) in 2 and p53 del in 2. The median duration of len + dex was 4 months (range, 1-23 months); best clinical response included nCR in 3 (9%), PR in 19 (54%), MR in 1 (3%), SD in 5 (14%), and progression (prog) in 7 (20%). Subsequent btz-based therapy included btz alone in 12 (34%) patients, btz corticosteroids (CS) in 18 (51%), btz CS oral cyclophosphamide in 3 (9%), and btz other in 2 (6%). The median duration of btz-based therapy was 3 months (range, 0.5-17.2 months). The best clinical response to btz-based therapy was nCR in 1 (3%), VGPR in 5 (14%), PR in 10 (29%), MR in 4 (11%), SD in 6 (17%) and prog in 9 (26%). The 1-year progression-free survival (PFS) was 23% (95% CI, 8%-42%) and overall survival (OS) 31% (95% CI, 11%-54%). The median PFS and OS were 5.6 months (range, 0.7-18.6 months) and 10.1 months (range, 0.8-18.6 months), respectively. Only q PR with btz correlated with PFS (P = .03) and OS (P = .04). We conclude that btz-based therapy (1) is an effective approach in MM patients with advanced rel/ref disease; (2) the efficacy is preserved after prior exposure to the potent len dex combination.
A337 Panobinostat and Bortezomib Phase I Trial in Multiple Myeloma O Sezer,1 D Siegel,1 J San Miguel,2 MV Mateos,2 I Prosser,3 A Guenther,4 J Bladé,5 M Cavo,6 M Jalaluddin,7 K Hazell,7 PM Bourquelot,7 KC Anderson8 1
Hackensack University Medical Center; 2Hospital Universitario de Salamanca; 3The Canberra Hospital; 4University of Kiel; 5Hospital Clinic, IDIBAPS; 6University of Bologna; 7Novartis Pharmaceuticals; 8 Dana-Farber Cancer Institute, Harvard Medical School
Introduction: Panobinostat (LBH589) is a highly potent pandeacetylase inhibitor (pan-DACi), interfering with epigenetic and non-epigenetic pathways implicated in cancer. Panobinostat has demonstrated synergistic cytotoxicity in vitro and in vivo in multiple myeloma (MM) cell lines and patient cells in combination with bortezomib. Methods: This phase Ib trial will determine the maximum tolerated dose (MTD) of panobinostat
S54
•
with bortezomib in patients with relapsed refractory MM. Safety, tolerability, PK/PD, and preliminary efficacy will also be assessed. Results: A total of 21 patients have been enrolled, to date, into three dose level cohorts: (1) 10 mg panobinostat (orally thrice weekly) + 1 mg/m2 bortezomib (I.V., days 1, 4, 8, 11) during a 21-day cycle; (2) 20 mg panobinostat 1 mg/m2 bortezomib; and (3) 20 mg panobinostat 1.3 mg/m2 bortezomib. In cohorts 1-2, the median number of prior therapies was three (range, 1-7), all 14 patients had at least one prior auto-SCT, and 8 patients prior bortezomib. Overall, the combination of panobinostat and bortezomib was safe and well tolerated in cohorts 1 and 2, with no new safety findings. Hematologic AEs have been most frequent, including grade 3/4 anemia (2), thrombocytopenia (11), and neutropenia (3). Nonhematologic AEs included grade 1/2 diarrhea (5), fatigue (7), fever (6), and nausea (4). No DLT was reported in any of the 12 evaluable patients treated in cohorts 1-2. To date in 14 patients, 1 immunofixation negative CR, 1 VGPR, and 3 PR were seen. These responses included patients who were refractory to prior bortezomib treatment which is encouraging. Enrollment into cohort 3 is ending, with 7 patients accrued to date. Conclusion: Preliminary results suggest that the panobinostat/bortezomib combination is safe, well tolerated with no DLT reported to date. Encouraging early activity was seen; updated data will be presented.
A339 The Bone Marker ICTP Adds to the Prognostic Significance of the ISS in Symptomatic Multiple Myeloma C Jakob,1 J Sterz,1 M Mieth,1 U Heider,1 M Kaiser,1 P Liebisch,2 J Rademacher,1 C Müller,3 O Sezer1 1
Department of Hematology and Oncology, Charité, Universitätsmedizin Berlin; 2Department of Hematology and Oncology, University-Hospital Ulm; 3Department of Clinical Chemistry, Charité, Universitätsmedizin Berlin
Introduction: The outcome of patients with newly diagnosed symptomatic multiple myeloma (MM) is highly variable. Several prognostic markers, including parameters of tumor burden and cytogenetics were adopted to identify high-risk patients. Recently the International Staging System (ISS), consisting of B2-microglobulin (B2M) and albumin, was introduced for patients with symptomatic MM. In previous studies the bone resorption marker carboxyterminal telopeptide of type-1 collagen (ICTP) was identified as a sensitive and specific marker of bone resorption and as a prognostic factor for overall survival (OS) in MM. Materials and Methods: We investigated the prognostic impact of the bone marker ICTP in comparison to ISS, B2M, albumin, deletion 13q14 and high-dose therapy (HDT) in 100 patients with newly diagnosed symptomatic MM. Results: B2M alone, albumin alone, ISS, del(13q14) and ICTP were significant prognostic factors for overall survival. In contrast to ICTP, lytic bone lesions were not an independent prognostic factor (P = .289). In a multivariate analysis, ICTP was the most powerful prognostic factor (log rank P < .001, hazardratio: 9.17). Furthermore ICTP (cut off: reference limit) separated a good and a poor prognosis group within each of the ISS stages (ISS I: P = .027; ISS II: P = .022; ISS III: P = .013). A combined ISS-
Clinical Lymphoma & Myeloma Supplement February 2009