ALBERT

Description: Abstract 2873 International staging system (ISS) and cytogenetics are the main prognostic factors of Multiple Myeloma (MM) but they reflect biologic characteristics of disease without taking into account individual host features. On the contrary, clinical characteristics of single patient could be substantial as to various points of view. For instance, in elderly MM patients, novel therapies reduction or interruption due to toxicity represent the major cause of unsatisfactory outcome. Therefore, it was empirically suggested different schedule of drugs in these “frail” patients but, how the “frailty” should be assessed in every single patient, is still unsettled. Advanced age, poor performance status (PS) and comorbidities are usually applied to recognize the “frailty” but it is not well known which of them are really prominent and whether these parameters, adjusted for conventional prognostic factors, still affect final outcome. We analyzed a population of symptomatic MM diagnosed from 2007 to 2010 included in the Marche Region MM Registry, to assess the frequency of “frailty” features, such as age, PS, comorbidities, cytopenias, renal insufficiency (RI) and lytic bone lesions, and their role on the overall survival (OS) when adjusted for prognostic factors. Comorbidities were scored according to Charlson Comorbidity Index (CCI) that split patients in 4 categories according to number and type of comorbidity. Patients were treated with transplant or standard therapy according to their eligibility. Overall, 88% of patients were treated with new drug-based therapies and 12% with MP. Median age of the 266 patients analyzed was 73 years (range 38–90). Twenty-four percent of patients had IgA MM, fifty patients (23%) had ISS stage=3 and 29/166 (17.5%) had unfavourable cytogenetics. Regarding “frailty” measures, 38% of patients had 〉 75 years, 39% had PS=2–4, 34% had 1 or more comorbidities. The most frequent comorbidities were hypertension (35%), heart diseases (22%), diabetes (15%), neurological diseases (16%), COBP (8%), secondary malignancies (8%) and chronic renal failure (6%). CCI ≥1 was detected in 51%. Increasing comorbitities number and CCI were associated with increased age although 37% of patients aged less than 65 years had CCI ≥2. Moreover, 35% had at least 2 cytopenias, 76% had bone disease and 14% had RI. Fifty patients (19%) died during follow-up. OS at 3 years was 74%. Univariate analysis performed on the total population determined age 〉 65 years (p=0.065), PS=2–4 (p

Description: Abstract 2828 Poster Board II-804 Studies including thalidomide showed a rate of severe infection that can be life-threatening complication or compromise compliance to therapy ranging from 6% to 22%. Therefore, antibacterial prophylaxis has become a routine clinical practice despite its role in the new-drugs era has to be defined. We performed a post-hoc analysis of patients treated with thalidomide based combinations within controlled trials in order to assess time, type and outcome of infections. We analysed the main demographic and disease related variables to search for factors affecting onset of infections during induction and build a risk model in order to perform targeted prophylaxis. Two hundred and twenty four patients were eligible for this study. Median age was 70 years (range 31-90 years) and 141 patients (63%) had more than 65 years. Fifty three percent of patients had de novo MM whereas the remaining had received thalidomide as second or subsequent lines of therapy. ISS stage 2-3 and renal impairment were present in 156 (69%) and 38 (17%) of patients, respectively. Induction therapy consisted in the following protocols: ThaDD (160 patients: 71.5%), ThaDD-V (42 patients: 19%), VMPT (9 patients: 4%), TD (8 patients: 3.5%) and VTD (5 patients: 2%). Prophylaxis for infections was administered to 168 patients (75%) and consisted of quinolones (72%) or thrimethoprim-sulphamethoxazole (28%). Eighty six patients (38.5%) developed an infection resulting of grade 3-4 in 39 of them (17.5%) (12% grade 3, 5.5% grade 4). Probability of infection at six months was 39% although that of severe infection was 20% (18% at 4 months and just 2% from 4 to 6 months). Among the 39 patients with severe infection, 23 (59%) developed pneumonia, 9 FUO (23%), 6 bacteremia (1 septic shock) and 1 an orbital abscess. Aetiology of severe infection was recognized in 7 patients (4 Gram-negative bacteria, 1 Gram-positive bacteria, 1 CMV and 1 probable fungal infection). Eighty percent of severe infections occurred during the first 3 courses of induction therapy and only 12% during neutropenia. Fifteen percent of patients undergoing antibiotic prophylaxis developed infection vs 25% of patients who did not (p= 0.084). There were no difference between quinolones and thrimethoprim-sulphamethoxazole prophylaxis regarding incidence of infections. The majority of infections were empirically treated and cured with wide spectrum antibiotic therapy except when a specific aetiology was recognized. Only one patient died because of septic shock during neutropenia and 2 patients withdrawn from protocol because of infection. In univariate analysis monoclonal component 〉 2 g (p=0.021), platelets 〈 130.000/ml (p= 0.005), newly diagnosed MM (p=0.083) and antibiotic prophylaxis (p=0.061) were factors predicting severe infection development whereas age, sex, ECOG performance status, MM type, D-S stage, plasmacell infiltration in bone marrow, haemoglobin concentration, serum b2-microglobulin, serum albumin, ISS, serum C-Reactive Protein, serum creatinine, previous stem cell transplantation were not. Cox regression analysis selected monoclonal component 〉 2 g (p=0.015 HR= 1.8) and platelets 〈 130.000/ml (p=0.003 HR= 2.3) as covariates associated to severe infection. The 25 patients without adverse factors, the 125 with 1 and the 74 with 2 adverse factors had a probability of severe infection equal to 4%, 17% and 32 % (p= 0.023), respectively. This model remains useful apart from prophylaxis since the probability of severe infection in patients with at least 1 risk factors receiving prophylaxis is 17% vs 4% in patients without risk factors. Of note, patients developing severe infection had a significantly higher incidence of deep venous thrombosis (DVT) compared with patients who did not (20.5% vs 9%: p= 0.041). DVT occurred after a median time of 0.9 months (range 0.1-5 months; 75% within 2 months) from infection onset. In conclusion, despite antibiotic prophylaxis, patients receiving thalidomide combination therapy can develop severe infections particularly pneumonia. Wide spectrum antibiotic therapy is effective in the majority of cases since viral or fungal infections are very rare. Patients with large size of disease, represented by high MC and low platelets count, are at higher risk of severe infection that in turn significantly increase the risk of DVT. Therefore, these patients at high-risk should receive more suitable antimicrobial prophylaxis. Disclosures: Off Label Use: Thalidomide, Bortezomib and Doxil.

Description: ThaDD regimen has provided significant results in recurrent/relapsed multiple myeloma (MM) patients (Offidani et al, 2006). In order to further improve those results without significantly increasing toxicity, we decided to include Velcade, synergic as per activity but not toxicity with the other drugs of ThaDD regimen. ThaDD-V was scheduled as follows: Thalidomide 100 mg/day, pegylated liposomal Doxorubicin 30 mg/sm iv days 4; Dexamethasone 20 mg days 1–2, 4–5, 8–9, 11–12 and Velcade 1.3 mg/sm iv days 1, 4, 8, 11 every 28 days (induction therapy). Patients received bortezomib for alternate cycles as following: 1 mg/sm day 1, 8, 15 and dexamethasone 20 mg days 1–2, 8–9, 15–16 and thalidomide 100 mg/day and dexamethasone 40 mg/day for 4 days monthly for a total of six cycles as consolidation therapy. Then patients received thalidomide 100 mg/day until relapse (maintenance therapy). Actually 20 patients (7 M, 13 F; median age 62.5 yrs, range 31–75) are assessable for response and toxicity. Five pts (25%) showed WHO performance status (PS) 〉 1, 9 pts (45%) presented refractory disease, 8 pts (40%) were priorily administered ≥ 2 lines of a treatment and 14 patients (70%) were submitted to one previous autologous stem cell procedure. Seven patients (35%) had extramedullary disease and 7 had unfavourable cytogenetics. Twelve patients scored an ISS ≥ 2 and 11 (55%) were in first remission for ≤ 12 months median duration. No patients were previously treated with Velcade, whereas six patients had received short-term Thalidomide treatment. Response was assessed according to IMVG uniform response criteria. Seventeen of 20 patients responded after at least one chemotherapy cycle reporting 5 (25%) sCR, 3 CR (15%), 8 VGPR (40%) and 1 stable disease. Three patients (15%) had extramedullary progressive disease. In a median follow-up of 12 months, 2 (10%) patients progressed and 1 (5%) died from cardiac infarction. Time to progression and overall survival were 73% and 95% at 12 months. We observed 4 grade 3 thrombocytopenia, 2 grade 3 DVT, 1 grade 3 diarrhoea, 1 grade 3 asthenia, 1 grade 4 infection and 1 grade 3 dermatological toxicity. Six patients developed grade 2 peripheral neuropathy and other three grade 3. In conclusion, ThaDD-V is extremely active in advanced MM patients as demonstrated by the elevated precentage of high quality remission. Nevertheless, patients are at substantial risk of developing neurotoxicity so the protocol was amended as per Velcade dose intensity and Thalidomide dose.

Description: Maintenance therapy with Thalidomide in MM offer controversial results. De novo or relapsing MM patients presenting at least a minor response after ThaDD were randomized to receive Interferon 3 MU x 3/week or thalidomide 100 mg /d. Both groups were given also Dexamethasone 20 mg/d x 4 days every month. Actually, we have randomized 50 patients in both treatment arms. The two groups were matched for main prognostic factors and response. During maintenance, both the ID and TD regimens improved response obtained by induction in only 10% and 11% of patients, respectively (p=0.832). After a median 2-years maintenance follow-up for both arms, 30 ID patients (60%) relapsed vs 17 (33%) TD ones (p=0.009). Time-to-progression (TTP) was significantly higher in the TD group vs the ID one (p= 0.024). So that TTP amounted to 23% in the ID group vs the 44% in the TD one. In addition, 3-years overall survival (OS) was significantly better in the TD arm with a value of 67% vs 46% of ID (p = 0.030). Both treatment arms were overall fairly well tolerated: fever, anorexia, weight loss, fatigue, liver and heart function abnormalities and hematologic toxicities were significantly more frequent in the ID cohort whereas neurotoxicity was somewhat more frequent in the TD one. This turned into a rate of therapy dropouts rate significantly higher in the ID group than in the TD one (26% vs 8%; p=0.017). Anyway, estimated risk for treatment interruption due to side effects in a 3-years period with thalidomide was only 21% vs 44% for interferon (p =0.014). We concluded that, in MM patients responding to standard induction therapy, low-dose Thalidomide maintenance therapy is feasible even in the long run and offers a significantly longer control over residual disease when compared to standard maintenance regimen.

Description: Previously we reported the outcome of 50 patients treated with an induction ThaDD regimen followed by a randomized maintenance therapy with a-Interferon or thalidomide and low-dose dexamethasone. At present, 88 patients with newly diagnosed MM have been enrolled in the ThaDD protocol. Here we present the updated results of the first 50 enrolled patients after a 42 months median follow-up (range 27–60). Baseline characteristics of the 50 patients were previously reported. Briefly, median age 72 years (range 65–78; 14% ≥ 75 years), more than three quarter of patients scored ISS 2–3, 60% presented abnormal serum levels of C-reactive protein (sC-RP) and 24% had unfavourable cytogenetics. Post-randomization best response included 34% CR, 14% nCR, 14% VGPR, 28% PR and 6% MR. One patient was diagnosed with progressive disease and two (4%) died early before response assessment. Median and 3-years TTP was 32 months and 40%, respectively. Median and 3-years PPF was 24 months and 38%, respectively. Factors negatively affecting PFS in univariate analysis were age 〉 70 years (p=0.054), abnormal sC-RP level (p=0.023), randomization to Interferon (p=0.046) and response to induction 〈 VGPR (p=0.031) whereas high ISS score, high b2-microglobulin level and unfavourable cytogenetics did not. Multivariate stepwise analysis select abnormal sC-RP (p=0.021; HR=4.1) and response 〈 VGPR (p=0.022; HR=3.8) as adverse features for PFS. Subgroups analysis shows that thalidomide maintenance therapy offered a significantly better PFS (42.5 vs 23.5 months; p=0.015) particularly in non VGPR patients; moreover, consolidation with high-dose therapy and autologous stem cells transplant seems to overcome the adverse impact of abnormal sC-RP albeit it did not significantly prolong PFS in the whole transplanted population vs no-transplant population. First line salvage therapy of relapsed patients was bortezomib-chemotherapy based therapy (Offidani et al, EHA 2008). Three-years OS was 64% and it seems not adversely affected by long-term thalidomide maintenance therapy since response rate and post-relapse PFS were similar between in those patients randomized for Interferon or thalidomide. ThaDD was fairly well tolerated but DVT/PE occurred in 7 patients undergoing prophylaxis with fixed dose warfarin and severe infection in 20% (7% after antibiotic prophylaxis). Grade 3–4 neutropenia occurred in 5 patients whereas no patients presented 〉 grade 2 thrombocytopenia. Only 2 patients dropped out due to toxicity (1 EP, 1 severe infection). During thalidomide maintenance severe peripheral neuropathy was observed in 2 patients and 2 other patients died for myocardial infarction. In conclusion, patients treated with ThaDD showed similar TTP, PFS, OS and non-hematological toxicity but less hematological toxicity and better compliance compared to that reported in patients treated with MPT (Palumbo et al, Blood 2008; Facon et al, Lancet 2006) or VMP (Mateos et al, Haematologica 2008; San Miguel et al, EHA 2008). Patients with normal sC-RP level and achieving at least VGPR after ThaDD gained a very long PFS. However, even patients with abnormal sC-RP level or who didn’t achieve VGPR could have a long-term PFS if transplanted or maintained with thalidomide after induction, respectively. Outcome of salvage therapy with bortezomib, dexamethasone and chemotherapy seems to be not affected by time on thalidomide treatment.

Description: Multiple myeloma represents a typical disease of old age as reported by recent epidemiological data showing that the incidence of MM in persons aged above 75 years is more than 30%. Very elderly MM patients remain very difficult to treat since they more likely have comorbid medical conditions and a poor performance status, limiting the chance of chemotherapy administration. Moreover, this populations is often underrepresented in clinical trials and few studies are specifically designed for patients of old age. Besides these problems, it has to be underlined that not even the introduction of new agents (thalidomide, lenalidomide, bortezomib) has been able to improve survival in patients older than 70 years if compared with younger ones. The aim to this retrospecive study was to assess the safety and efficacy of ThaDD regimen (thalidomide 100 mg/day continously, pegylated liposomal doxorubicin 40 mg/m2 on day 1 for 6 28-day cycles, dexamethasone 40 mg on days 1–4 and 9–12) in 27 newly diagnosed MM patients older than 75 years. In this group of patients median age was 77 years (range 75–91), performance status was poor in one third, 78% had ISS score ≥ 2, 37.5% showed unfavourable cytogenetics abnormalities and 30% impaired renal function. At least a PR and a VGPR were achieved in 85.5% and 52% of patients, respectively, with 15% of them obtaining a CR. After a median follow-up of 25 months (range 7–58), median PFS was 25 months. Two-year PFS and OS resulted 50% and 75%, respectively. More frequent grade 3–4 non hematological side effects were peripheral neuropathy (15%) and constipation (11%). A severe neutropenia was observed only in 4% of patients and in 2 patients (7.5%) occurred a febrile episode requiring antibiotic therapy. On thromboprophylaxis with fixed-dose warfarin, 5 patients (18.5%) developed a deep venous thrombosis and one patients with carotid arteriopathy experienced acute stroke. Two patients died early during treatment, because of acute liver failure and heart attack, respectively. No significant differences in term of toxicity were found between this group of patients and patients younger than 75 years receiving the same regimen although in these latter vascular events were twice as much and early mortality rate higher. Overall, the compliance with therapy was satisfactory and only one patient stopped treatment due to the occurrence of atrial fibrillation and deep venous thrombosis. Pegylated liposomal doxorubicin administration was delayed in one patient who developed fever and mucositis whereas in another patient dexamethasone dose was reduced because of miopathy. Thalidomide discontinuation was necessary in 2 patients due to severe neuropathy and pulmonary embolism, respectively. Our study demonstrate that also MM patients older than 75 are able to derive benefit and to tolerate treatments used for younger patients although in very elderly vascular events seem to be more frequent and requiring maximal care. In patients with poorer performance status drugs adjusted-dose is probably needed to reduce early mortality.

Description: Abstract 3020 Background. In patients with newly diagnosed MM, three/four-drug combinations seem to be more effective compared with two-drug associations in terms of both rate and duration of remission. Moreover, there is an emergent body of evidences that consolidation/maintenance therapy improves quality of response and remission duration. However, the impact of these strategies in relapsed/refractory MM (r-rMM) are still unknown. Methods. This is a multicenter, phase II study including patients with r-rMM having measurable disease, no more than 4 prior lines of therapy, adequate performance status, cardiac and liver function. As induction therapy patients received 6 28-day cycles of oral thalidomide 100 mg/day continuously at bedtime, oral dexamethasone 20 mg on day 1–2, 4–5, 8–9, 11–12, pegylated Liposomal Doxorubicin (pLD) 30 mg/m2 iv on day 4 and bortezomib 1.3 mg/m2 iv on day 1, 4, 8, 11 (ThaDD-V). As consolidation patients underwent 6 28-day cycles of rotating bortezomib 1.3 mg/m2 iv on day 1, 4, 8, 11 plus oral dexamethasone 20 mg on day 1–2, 4–5, 8–9 (3 courses) or thalidomide 100 mg/day continuously at bedtime plus oral dexamethasone 20 mg on day 1–4 (3 courses). Patients eligible and having suitable stem cell storage underwent ASCT instead of standard consolidation at the discretion of attending physician. Maintenance therapy included thalidomide 100 mg/day until relapse or intolerable toxicity. Since in the first 20 patients we recognized an excess of peripheral neuropathy, protocol was amended as follow: bortezomib 1.3 mg/m2 on day 1, 4, 11 and thalidomide 50 mg/day in all therapeutic phases. The primary end-points of this study were best response and toxicity of the planned therapy. Results. Forty-six patients were enrolled. Median age was 63.5 years (range 31–80 years) and the median number of prior regimens was 1 (range 1–4). Twenty-four patients (52%) had undergone autologous stem cell transplantation, 30 (65%) had received anthracyclines, 27 (59%) thalidomide, 8 (17.5%) bortezomib and 16 (35%) were refractory to the last regimen. After induction 16 patients (34.5%) achieved CR (6=13% sCR), 15 (32.5%) VGPR and 4 (8.5%) PR with a ORR of 76.5%. Seven patients (15%) progressed. Out of 46 patients undergone induction, 26 (20 standard, 6 ASCT) received consolidation therapy since 1 patients died during induction, 8 had progressive disease, 1 had second neoplasm, 7 had severe toxicities and 3 undergone allogeneic stem cell transplantation. Excluding 6 patients who have obtained sCR before, 5 (25%) out of 20 patients had further improvement in response. Therefore, best response after induction and consolidation were: 25 CR (54%; 8 sCR=17.5%), 16 VGPR (34.5%) and 2 PR (4.5%). Maintenance therapy did not further improve response. Patients receiving ≤ 2 prior regimens had a CR rate significantly higher than those heavily treated (41% vs 0%; p= 0.010) whereas prior ASCT, thalidomide or bortezomib, refractory disease and bortezomib dose-intensity did not affect quality of response. After a median follow-up of 31 months (range 12–53), 28 patients relapsed and 20 died. Median TTP was 18.5 months, median PFS was 17.5 months and median survival was 40 months. Median TTP of patients achieving PR-VGPR was 16 months (3 years= 10%) whereas in those obtaining CR it was 32.5 months (3 years= 45%; p=0.032) vs not reached (3 years= 85%) in patients achieving sCR (p=0.003). Main toxicity was peripheral neuropathy (PN). Indeed, in the first 20 patients we observed 6 (30%) grade 2 and 3 (15%) grade 3 PN. After amendment, grade 2 and 3 PN occurred in 3 (11.5%) and 2 patients (7.5%), respectively. DVT occurred in 2 patients (4.5%) and severe infection in 7 (15%). Grade 3–4 neutropenia, anemia and thrombocytopenia occurred in 4 (8.5%), 2 (4%) and 7 patients (15%), respectively. Finally, only one patients died of myocardial infarction during induction. During consolidation therapy other 2 patients developed grade 3 peripheral neuropathy. During maintenance with thalidomide no patients developed severe neuropathy requiring discontinuation. Conclusions. Multi-drug combination namely ThaDD-V as induction followed by consolidation-maintenance therapy seems to be very effective in patients with r-rMM provided that this procedure is used early on relapse when very deep responses are still possible. A reduced dose-intensity of bortezomib significantly decreases PN without jeopardizing outcome. Disclosures: Offidani: Celcene, Janssen Cilag: Honoraria. Polloni:Celgene: Honoraria. Corvatta:Celgene: Honoraria. Gentili:Celgene: Honoraria. Brunori:Celgene, Janssen-Cilag: Honoraria. Catarini:Cerlgene, Janssen-Cilag: Honoraria. Malerba:celgene, Janssen-Cilag: Honoraria. Leoni:Celgene, Janssen-Cilag: Honoraria.

Description: Despite the improvements in the treatment of MM patients, they ultimately progress and die of their disease since all attempts to control residual disease with a maintenance therapy have substantially failed in providing significant results. Nevertheless, maintenance therapy may still be an appealing approach. We treated 120 de novo or relapsed/refractory MM patients with Thalidomide, Dexametasone and peghilated liposomal Doxorubicin (ThaDD) as induction treatment of de novo or relapsed/refractory MM. All patients achieving at least minor response were randomized to receive Thalidomide 100 mg continuously or IFN-α 3 MU three times per week subcutaneously until the occurrence of relapse or major toxicities. Both drugs were combined with oral 20 mg Dexamethasone for 4 days monthly. In the original protocol an interim analysis was planned after a median follow-up of two years in order to assess a unacceptable imbalance between the two treatment arms leading to a premature interruption of protocol. At this moment, 74 patients are evaluable for maintenance therapy, 36 in the Thal-dex arm and 38 in the IFN-dex arm. The two groups of patients were matched on the basis of the main prognostic factors as age, serum β2-microglobulin, serum albumin, ISS score, CRP, cytogenetics and response to therapy. IFN-dex and Thal-dex improved response in 13% and 17% of patients, respectively (p=0.532) whereas rate of progression (58% vs 36%; p=0.0061) and mortality (42% vs 19.5%; p=0.035) were significantly higher in the IFN-dex arm. After a median 24 months follow-up, median TTP was 21 months and 2 years TTP was 45% in the IFN-dex arm vs Thal-dex arm whereas median was not reached and 2 years TTP was 59% (p=0.0139). A clear better OS trend was observed in the Thal-dex arm when compared with IFN-dex arm (2-yrs OS 84% vs 71%; p=0.0821). Multivariate analysis found serum CRP ≤ 3 mg/l, not unfavourable cytogenetics, response to induction ≥ VGPR and maintenance with Thal-dex significantly associated with better TTP. Both treatment arms were overall well tolerated: fever, anorexia, weight loss, fatigue, liver and heart function abnormalities and hematologic toxicities were significantly more frequent in the IFN-dex arm whereas neurotocity (somnolence, constipation and peripheral neurophaty) were somewhat more frequent in the Thal-dex arm. This turned into a rate of therapy reduction and interruption significantly higher in the IFN-dex arm than in the Thal-dex one (23% vs 5%; p=0.0231). In conclusion, our data show that in MM patients the combination Thal-dex administered as maintenance therapy after thalidomide, dexamethasone and chemotherapy combination, although it does not significantly improve the quality of response obtained after induction therapy, is significantly better in controlling residual disease than the IFN-dex combination which, on the other hand, leads more frequently either to systemic side effects or organ toxicity.