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: Introduction. Multiple myeloma (MM) represents a population with an increased risk of developing infection up to 10-fold if compared with controls. Moreover, patients treated with new-drugs are at higher risk of infections compared with those treated previously (Blimark C. et al. Haematologica 2015). Grade 3-4 non-hematological toxicity, particularly cardiac and infection complications, are associated with shorter OS in patients with MM (Bringhen S. et al. Haematologica 2013) whereas thrombosis did not. Anyway, guidelines to prevent thrombosis are available but there are not as regard infections although they would be advisable since infections still represent one of leading non-hematological adverse event in any protocols. Methods. Newly diagnosed MM patients included in 2 prospective trials (VMP vs VMPT, Palumbo et al. JCO 2014; MPR vs MEL-200, Palumbo et al. NEJM 2014) were studied with the aim to assess probability, type, severity, timing and factors predictive of grade 3-5 infectious complications (according to CTCAE version 4.03) occurred during the first years of treatment with these bortezomib or lenalidomide combinations. Patients who underwent autologous transplantation were censored at the time of transplant. Infections were classified according to Immunocompromised Host Society criteria (J Infect Dis, 1990). All patients received thrimethoprim-sulphamethoxazole prophylaxis and patients treated with bortezomib received anti-viral prophylaxis, yet. Results. Four-hundred and seventy-six patients were analyzed. Median age was 66 years (range 36-85). Karnofsky performance status (KPS) was 〈 70 in 115 patients (24%), 106 (22%) had IgA heavy chain myeloma, 106 (22%) had ISS stage 3, 14 (3%) had renal insufficiency and 103/343 evaluated (30%) had unfavorable cytogenetic. Bortezomib combinations was administered to 257 patients (54%; 152 VMP, 105 VMPT) whilst 219 received lenalidomide combinations as induction-consolidation therapy (46%; 132 Rd, 87 MPR). One-hundred and fifty-eight febrile episodes (33.2%) were identified within the study population. Grade (G) 3-5 infections occurred in 53 patients (11%; G3=45, G4=7, G5=2). Out of these latter, 29 (55%) infections were clinically documented (pneumonia=22, soft tissue=5, gastrointestinal=2), 8 (15%) were microbiologically document (bacterial=7, viral=1) and 17(30%) were FUO (febrile neutropenia=11, sepsis=6). Pneumonia was the prevalent type of infection during treatment with Rd, VMP or VMPT whilst most febrile neutropenia or sepsis occurred during MPR treatment. Overall, probability of grade 3-5 infection was 13% at 12 months. However, the probability of infection reaching a plateau at 10-11% at 4 months in patients treated with Rd, VMP or VMPT whereas there was a second peak of infection at 35% probability at 12 months in patients treated with Rd followed by MPR consolidation (Fig. 1). Stepwise Cox regression analysis showed that KPS 65 years, male sex, IgA myeloma type, renal failure, presence of plasmocytoma, unfavorable cytogenetic, bone marrow plasma cells 〉 60% and new agent used in induction (bortezomib or lenalidomide) were not. No significant difference in OS was found between patients who have had or not an infection (59 vs 71 months; p=0.333). Conclusions. This study suggests that, in patients with newly diagnosed MM treated with bortezomib or lenalidomide combinations, infections are a frequent cause of morbidity but not of mortality. Infections, mainly pneumonia, usually occurred in the first 4 months; however, when MPR was used as consolidation after Rd, the risk of unusual and severe infections continues all time long. Besides anti-PJ and anti-VZV prophylaxis, patients with poor KPS, with high tumor burden and who underwent MPR regimen, should receive antibiotic prophylaxis and they may be the ideal candidates to be included in a prospective, randomized study regarding antibiotic prophylaxis to prevent severe bacterial infections. Figure 1. Figure 1. Disclosures Offidani: Celgene, Janssen: Honoraria. Off Label Use: Lenalidomide. Corvatta:Celgene, Janssen: Honoraria. Bringhen:Onyx: Consultancy; Janssen-Cilag, Celgene, Novartis: Honoraria; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees. Gentili:Celgene, Janssen: Honoraria. Gay:Celgene, Janssen: Honoraria. Boccadoro:Celgene, Janssen: Consultancy, Honoraria. Palumbo:Celgene, Janssen: Consultancy, Honoraria, Research Funding.

Description: Introduction: Multiple Myeloma (MM) is a heterogeneous disease with a very wide range of progression free survival (PFS) and overall survival (OS) duration. At now, Revised- International Staging System (R-ISS), that classifies patients as low- (LR), intermediate- (IR) and high-risk (HR) according to ISS, cytogenetic and lactate dehydrogenase (LDH), is the most powerful tool to stratify patients with different outcome. Nevertheless, there is still too much variability in outcome in each risk group, particularly in the IR risk group, that deserves further dissection. However, this variability, behind initial prognostic factors, may be still dependent on dynamic features that are unpredictable at diagnosis and that could provide information during the course of the disease. The aim of this study is to evaluate how much dynamic aspects, such as therapy strategy and response to the therapy, could explain the variability in the R-ISS risk groups and how these information during the course of the disease could be helpful to tailor disease management. Methods: We analyzed 192 patients recorded in our data-base from 2005 to 2015. All patients received new-drugs (immunomodulatory drugs and proteasome inhibitors) as induction therapy. We classified patients according to R-ISS staging system and analyzed their outcome, in terms of PFS and OS, according to Kaplan-Meier method. Moreover, we analyzed the effect of dynamic variables, such as initial therapy, response to therapy and subsequent therapy, on the outcome of each R-ISS subgroup by stepwise Cox regression method. Results: Median age of the 192 analyzed patients was 67 years (range 37-93); 27% of patients had 〉 75 years. Forty-three patients (22%) had stage III ISS and 25% had high-risk cytogenetics. Thalidomide-, proteasome inhibitors- and lenalidomide-based induction therapy was used in 16%, 62% and 22%, respectively. Forty-five percent of patients underwent transplant and 40% received maintenance therapy (54% lenalidomide, 38% bortezomib). According to R-ISS staging system, LR group (63 patients, 33%), IR group (108 patients, 56%) and HR group (21 patients, 11%) had a median PFS and OS of 58.5 and 124.6 months, of 42.5 and 78.5 months and of 20 and 41.3 months, respectively. Analyzing separately the three R-ISS risk-groups according to the abovementioned dynamic variables, we found that, into the LR population, patients who received maintenance therapy had a significantly longer PFS compared to those who did not (87 vs 40 months; HR=0.36, 95%CI=0.15-0.84; p=0.019) whereas initial therapy and response to therapy were not significantly related. In the IR population, patients who did not achieve a CR had a significantly shorter PFS compared to the patients who did (31 vs 63.5 months; HR=2.5, 95%CI=1.4-4.3; p=0.002); moreover, patients receiving maintenance therapy had a significantly longer PFS compared to those who did not (55 vs 34 months; HR=0.55, 95%CI=0.33-0.94; p=0.028). Finally, in the small HR population we found that patients treated with immunomodulatory drugs tend to have a shorter PFS compared to those treated with proteasome inhibitors (20 vs 34.5 months; HR=2.7, 95%CI=1.0-9.2; p=0.106). No dynamic variables were significantly related to OS in the LR and HR groups whereas in the IR population, patients not achieving CR had a significantly shorter OS (67 months vs not reached, HR=2.6, 95%CI=1.2-5.5; p=0.012). Conclusions: These results suggest that therapeutic strategy and response to therapy, could modify a priori prognostication given by R-ISS. Patients allocated in IR group achieving CR and that received maintenance therapy have a PFS and OS similar to those patients who were classify as LR (63 vs 58 months and NR vs 124 months, respectively). Moreover, in the LR group, maintenance therapy is proved to maximize PFS. In the HR group, R-ISS seems to be almost predictive for the outcome. These patients seem to benefit from proteasome inhibitor based-therapy although none of the available therapies seem to be really effective. These data could be used to plan studies, testing different therapeutic strategies, with the aim to personalize therapeutic approach according to risk-group assigned at diagnosis. Disclosures Offidani: Celgene: Honoraria, Research Funding; Janssen: Honoraria.

Description: Abstract 4769 From 1980 to 2005 in our institution we've diagnosed and treated 361 patients (pts) affected by Hodgkin's disease. At the moment of diagnosis the median age of the patients was 29 years (range 13-69).About 72% of patients were in the stage I-II and 28% were in the stage III-IV. More than 54% of all patients received ABVD, 17% received MOOP, 10% MOOP/ABVD, 3% VBM and 1% received Stanford V scheme. Over 70% of all patients received radiotherapy (RT) with median dose of 4500 cGy (range 1000-16210). Over 94% of all patients obtained a Complete remission, however 11% relapsed. 130 patients among 361 are at this moment evaluable for late effects of chemo-radiotherapy.26 pts were treated in the period 1980-84 (25%) ; 6 pts treated 1985-89 (4,6%);21 pts treated in 1990-94 (16,1%); 24 pts treated in 1995-99 (19%) and 35 pts in the period 2000-2005 (27%). 50 pts among 130 (38,5%) present late effects related to the therapy. 24 pts (48%) present heart disease: 13 pts (40%) Valvulopathy,8 pts (25%) Ischemic heart disease, 7 pts (21%) Congestive heart failure, 4 pts (14%) Pericardic disease. Therapies of these patients were performed : In 1980-89 (11 pts), 6 pts (25%) received MOOP + RT,2 pts (8,3%) received M/A and 3 pts only RT. In 1990-99 (7 pts), 3 pts(12,5%) received ABVD +RT, 2 pts(8,3%) received MA+RT, 1 pt(4,1%) received ABVD and 1 pt(4,1%) received M/A. In 2000-05 (6 pts), 2 pts (8,3%) received ABVD+RT and 4pts(16,6%) received only ABVD. 18 pts present Endocrinological-disease, in all cases, represented by hypothyroidism; 16 pts among 18 had done Chemoteraphy and Radiotheraphy, while 2 pts received only Chemotheraphy. Besides 8 pts show both endocrinological and cardiological disease; in these cases 3 pts (37,5) had done ABVD+RT, 4 pts (50%) MOOP+RT and 1 patient (12,5%) only RT. Furthermore 26/130 (20%) developed a second neoplasm. Conclusions In our population 38% of patients had developed secondary late effects and we assess that about 15% of our Hodgkin's population die for a secondary late effect of therapies Although there are many variables for the development of a late effect we think that this analysis could lead to try to reduce the late toxicities of treatments. Disclosures: Offidani: Celgene: Honoraria; Janssen Cilag: Honoraria.

Description: New drugs such as thalidomide, bortezomib and lenalidomide have expanded the therapeutic options for MM while improving outcome in both young and elderly patients. However, the best novel agents sequence in the therapeutic strategy for MM is still not definitely delineated as relapsed MM right after first line thalidomide therapy seems to be more resistant jeopardizing final outcome as per overall survival while still making questionable when to administer it, either at the beginning or later during the course of the disease. We analyzed 72 relapsed MM patients who were enrolled in two salvage study protocols which included bortezomib, dexamethasone and chemotherapy (Offidani et al, ASH 2007 and EHA 2008) and who had been treated with thalidomide first (18 patients) or subsequently (30 patients) or not treated at all with thalidomide (24 patients). We compared these three groups of patients in terms of response rate, post-relapse PFS and post-relapse OS with the aim to assess the role of previous administration of thalidomide on final outcome in this patient population. Median age for the 72 patients was 65 years (range 31–82); ISS stage 2–3 assessed in 51% of patients and unfavourable cytogenetics in 42%. Thirty four patients had been rescued in first relapse, 19 in second and 19 in third or subsequent relapse. Median disease history was 34 months (range 8–173). Forty four patients relapsed after high-dose therapy and autologous stem cell transplantation. The 48 patients were previously treated with thalidomide a median time of 8 months (range 4–48 months). VGPR or better response rate in the groups of patients treated with thalidomide in first line, second or subsequent line or never treated with thalidomide were 44%, 42% (p=0.795) and 79% (p=0.003; p=0.002), respectively.. Multivariate stepwise regression analysis selected only previous thalidomide treatment (OR=1.9; 95%CI=1.5–2.4; p=0.024) as factors affecting response whereas age, previous therapy lines, previous remission duration, previous transplant, previous disease history, sCRP, ISS stage and cytogenetics were not significantly associated to response. In the same groups post-relapse PFS was 9 months, 14 months (p=0.308) and not reached (p=0.018; p=0.055) while post-relapse 2 years OS was 51%, 50% (p=0.564) and 72% (p=0.074; p=0.135). Cox regression analysis showed that the presence of ISS 2–3 (p=0.010), previous thalidomide administration (p=0.052), and response 〈 VGPR (p

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.