Abstract 2012
In this trial (DSMM XIII) patients of age 60–75 years with newly diagnosed multiple myeloma having symptomatic and measurable disease were randomly assigned to either (A1) 3 cycles of ...Lenalidomide (25 mg po d1-21/28d) with low-dose Dexamethason (40 mg po d1, d8, d15, d22/28d), followed by stem cell mobilization and then further Len/Dex cycles until progression or (A2) 3 cycles of Len/Dex, followed by stem cell mobilization, tandem high-dose melphalan 140 mg/m2 with autologous blood stem cell transplantation and Len maintenance with 10 mg daily until progression. The maximum time of treatment was defined as 5 years. Antithrombotic prophylaxis consists of LMW heparin for 3 months in both arms. With continued Len/Dex (A1) antithrombotic prophylaxis is also continued after stem cell mobilization with either LMW herparin or aspirin, depending on risk factors. Here we report the severe adverse events (SAEs) after 100 patients who have completed at least 3 cycles induction therapy and the efficacy of stem cell mobilization.
149 patients with a median age of 68 years and a proportion of patients with age ≥70 years of 40%, have been randomized since March 2010. With the first 100 patients having completed 3 cycles of induction Len/Dex, 105 SAEs have been reported in 67 patients. SAEs consisted of infections (36), thromboembolic events (7), fever (6), syncope (5), renal failure (4), fractures (4), dyspnoe (4), heart failure (3), pain (3), hyperglycemia (3), rash (1), plasma cell leukemia (1), second malignancy (1) and others. The second malignancy was a melanoma in situ which was completely surgically removed and reported as a SUSAR. Nine patients have died, 2 during study treatment (progression 1, sepsis 1) and 7 off study (progression 4, heart failure 1, sepsis 1, unknown 1).
For stem cell mobilization, two alternative protocols were allowed. The decision was left open to the investigator. Either G-CSF only (lenograstim 10 μg/kg for 4 days or end of apheresis) or CE chemotherapy with G-CSF (cyclophosphamide 2500 mg/m2, etoposide 300 mg/m2 plus lenograstim 263 μg from day 5 until end of apheresis) were applied. Mobilization data from 75 patients are available. G-CSF only was used in 10 patients (13%) and resulted in a median of 5.3 × 106 CD34 positive cells/kg (range 1.5 – 8.9) collected with a median of 2 leukaphereses (range 1 – 4). CE plus G-CSF was used in 64 patients (85%) and resulted in a median of 7.5 × 106 CD34 positive cells/kg (range 2.0–38.0) collected with a median of 1 leukapheresis (range 1 – 4). In 2 patients (3%) stem cell mobilization failed after CE plus G-CSF.
Len/Dex induction therapy was associated with an acceptable tolerability and feasibility in elderly myeloma patients. Stem cell mobilization was successful in 97% of patients.
Straka:Celgene: Consultancy, Honoraria, Research Funding. Off Label Use: Lenalidomide used for initial therapy in multiple myeloma.
The randomized, open-label, phase III trial HOVON-65/GMMG-HD4 was designed to evaluate the efficacy of bortezomib prior to HDM for response and progression-free survival (PFS) in patients with newly ...diagnosed MM. The trial was performed in 75 referral centers in the Netherlands and Belgium (HOVON group) and Germany (GMMG group). Patients with Salmon & Durie (SD) stage II or III, age 18–65 years inclusive, were randomly assigned to 3 cycles of VAD (vincristine 0.4 mg, adriamycine 9 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, 9–12, and 17–20) or PAD (bortezomib 1.3 mg/m2 days 1,4,8,11, adriamycine 9 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, 9–12, and 17–20). No thrombosis prophylaxis was given. Stem cells were mobilized using the CAD regimen, including cyclophosphamide 1000 mg/m2 iv day 1, and G-CSF. After induction therapy, all patients were to receive 1 or 2 cycles of high-dose melphalan (HDM) 200 mg/m2 with autologous stem cell rescue followed by maintenance with thalidomide 50 mg daily (VAD arm) or bortezomib, 1.3 mg/m2 once every 2 weeks (PAD arm) for 2 years. Between May 4, 2005 and May 16, 2008, 833 patients were randomized. After the trial was closed, we here report the planned interim analysis data on response after induction and HDM-1 of the initial 150 (75 per arm) randomized patients. The data of the initial 300 registered patients (150 per arm) will be available by November 1, 2008 and presented. The 2 randomization arms were equal for SD stage of disease, ISS stage, and distribution of chromosomal abnormalities. 134 patients (89%) completed PAD/VAD and 130 patients (87%) completed HDM-1, with no difference between the treatment arms. Full dose bortezomib could be administered in 95 % (PAD1), 79 % (PAD2) and 85 % (PAD3) of patients. Successful stem cell apheresis was achieved in all 132 patients who received CAD. Adverse events CTC grade 2–4 during PAD vs VAD included neurologic or polyneuropathy (PNP) 38% vs 21 %, constitutional symptoms 30 % vs 24 %. PNP of CTC grade 1–4 was more frequent in the PAD arm (p=0.01), while DVT/pulmonary embolism was diagnosed in 10 % during VAD and 6 % during PAD. Responses were assessed according to EBMT criteria including VGPR after PAD/VAD, after HDM-1 and best response on protocol treatment. Complete Response (CR), Very Good Partial Response (VGPR) and Partial Response (PR) in both arms were compared by logistic regression (table 1)
Response ITT (%)PADVADp-valuePAD+ HDM-1VAD+ HDM-1p-valueCR500.061540.05≥VGPR41170.00159470.14≥PR80640.0392770.01
The (preliminary) overall complete response rate including maintenance was 27 % (PAD arm) and 5% (VAD arm) (p=0.001). Deletion of chromosome 13q did not have a significant impact on response. We conclude that PAD induces significantly more PR+VGPR+CR as compared with VAD, and that this effect is sustained after HDM-1. This trial was supported by the Dutch Cancer Foundation (EudraCT nr 2004-000944-26), the German Federal Ministry of Education and Research and a grant from Johnson and Johnson
We investigated subclonal cytogenetic aberrations (CA) detected by interphase fluorescence in situ hybridization (iFISH) in patients with newly diagnosed multiple myeloma (MM) enrolled in the Haemato ...Oncology Foundation for Adults in the Netherlands (HOVON)-65/German-Speaking MM Group (GMMG)-HD4 phase 3 trial. Patients were either treated with 3 cycles of vincristine, Adriamycin, and dexamethasone or bortezomib, Adriamycin, and dexamethasone and then thalidomide or bortezomib maintenance after tandem autologous transplantation. Subclones were defined either by presence of different copy numbers of the same chromosome loci and/or CA present in at least 30% less and maximally 2/3 of cells compared with the main clone CA. Patients with subclones harbored more frequently high risk (31.0%) or hyperdiploid main clone aberrations (24.8%) than patients with t(11;14) in the main clone (10.1%). Gains and deletions of c-MYC were the only CA that occurred more frequently as subclone (8.1%/20.5%) than main clone (6.2%/3.9%, respectively). Treatment with bortezomib completely overcame the negative prognosis of high-risk CA in patients without subclones, but not in patients with additional subclonal CA. High-risk patients treated without bortezomib showed dismal outcome whether subclones were present or not. Cytogenetic heterogeneity defined by subclonal CA is of major prognostic significance in newly diagnosed MM patients treated with bortezomib within the HOVON-65/GMMG-HD4 trial.
Abstract 332
PURPOSE: In Multiple Myeloma (MM), the combination of serum beta-2-microglobulin level with serum albumin concentration has been proposed as an outcome predictor in the International ...Staging System (ISS). More recently, subgroups of MM defined by genetic and cytogenetic abnormalities have been associated with unique biologic, clinical, and prognostic features.
PATIENTS AND METHODS: We analyzed the prognostic value of 12 chromosomal abnormalities by fluorescent in situ hybridization (FISH) in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Patients with newly diagnosed MM were randomized to receive either three cycles of VAD (arm A; vincristine, adriamycin, dexamethasone) or PAD (arm B; bortezomib, adriamycin, dexamethasone). All patients underwent autologous stem cell transplantation (ASCT) followed by maintenance therapy with thalidomide 50 mg daily (arm A) or bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively. In addition, a second cohort of patients was analyzed as a control group (n=462), undergoing ASCT at the University of Heidelberg between September 1994 and December 2010.
RESULTS: For the entire group of patients treated within the HOVON-65/GMMG-HD4 trial, we identified 233 patients with 2 copies (67.7%), 95 patients with 3 copies (27.6%) and 16 patients (4.7%) with more than three copies of the chromosomal region 1q21. In addition to del(17p13) and t(4;14), we added +1q21 (>3 copies) to the group of high-risk aberrations, since the outcome of these patients was almost as poor as it was observed for patients with del(17p13). Subsequently, we analyzed whether combining the ISS score with information on the presence of high-risk aberrations could improve the prognostic value with regard to patients’ outcome. A combination of the presence or absence of del(17p13), t(4;14), or +1q21 (>3 copies) with the ISS score allowed patients to be stratified into three distinct groups: low-risk absence of del(17p13)/t(4;14)/+1q21 (>3 copies) and ISS I, high-risk presence of del(17p13)/t(4;14)/+1q21 (>3 copies) and ISS II/III, and intermediate-risk (all remaining patients). Most of the patients belonged to the low- (33%) and intermediate-risk (49%) groups, whereas 18% were allocated to the high-risk group. The median PFS times for the low-, intermediate-, and high-risk groups were 41.9 months, 31.1 months (HR=1.7; p=0.0018) and 18.7 months (HR=3.6; p<0.0001), respectively. The 3yr-overall survival (OS) decreased from 94% in the low-risk group to 80% (HR=4.6; p=0.0001) and 43% (HR=12.8; p<0.0001) in the intermediate- and high-risk groups, respectively.
These results were confirmed in the independent cohort of patients: From date of first ASCT, the median PFS times for the low-, intermediate-, and high-risk groups were 43.3 months, 23.0 months (HR=1.5; p=0.015) and 13.8 months (HR=2.4; p=0.0003), respectively. The 4yr-OS decreased from 84% in the low-risk group to 71% (HR=2.1; p=0.0043) and 49% (HR=3.84; p<0.0001) in the intermediate- and high-risk groups, respectively.
CONCLUSION: In our series, the ISS/FISH-based score/algorithm predicted PFS and OS much better than the ISS alone. Our results with molecular cytogenetic techniques may already have implications for the risk-adapted clinical management of patients with MM particularly in younger patients. Display omitted
van de Velde:Ortho Biotech Oncology Research & Development: Employment. Sonneveld:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity’s Board of Directors or advisory committees.
