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Astolf et al provide the first report of acute promyelocytic leukemia driven by viral insertion into the RARA locus. This represents a clear demonstration of a pathology driven by the member of the anelloviruses, a group of viruses otherwise thought to have minimal or no pathogenic potential.

We present the results of a phase 2 study using thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) in the treatment of 50 patients older than 65 years with newly diagnosed multiple myeloma. Thalidomide 100 mg was administered orally at bedtime continuously, dexamethasone 40 mg was administered orally on days 1 to 4 and 9 to 12, and pegylated liposomal doxorubicin 40 mg/m2 was administered intravenously on day 1 over the 28-day cycle. Response was assessed according to the EBMT criteria. Seventeen (34%) patients achieved CR, 7 (14%) nCR, 5 (10%) VGPR, 15 (30%) PR, and 5 (10%) MR, resulting in an ORR of 98%. Only 1 patient (2%) presented progressive disease. Time to progression (TTP), event-free survival (EFS), and overall survival (OS) projected at 3 years were 60%, 57%, and 74%, respectively, and these parameters were significantly higher in those patients achieving a response of at least VGPR versus those who did not. Grade 3 and 4 nonhematologic adverse events were constipation (10%), fatigue (6%), tremors (4%), mucositis (4%), and palmar-plantar erythrodysesthesia (2%). Grade 3 and 4 neutropenia occurred in 12% of patients. Grade 3 and 4 infections and thromboembolic accidents were observed in 22% and 14% of patients, respectively. In the treatment of elderly patients with newly diagnosed multiple myeloma, ThaDD is a very effective regimen with manageable toxicity.

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.

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.

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.

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.

No standard therapy is still available for older patients with multiple myeloma (MM) despite two third of patients aged over 65 years.The combination melphalan-prednisone yields unsatisfactory results and high-dose therapy can be too toxic or unfeasible.Thalidomide has opened up new horizons also for the treatment of older patients with MM.This multicenter study included patients with de novo symptomatic MM older than 65 years regardless of comorbidities, performance status and renal function. All patients received thalidomide 100 mg continuously, pegylated-liposomal doxorubicin (Caelyx®) 40 mg/m2 on day 1 every 28 days, dexamethasone 40 mg on days 1–4 and 9–12.They also were given warfarin 1.25 mg/day for prophylaxis of thromboembolic disease and ciprofloxacin 250 mg twice daily after a high incidence of infections was recognized. Forty-one patients are valuable for response and toxicity so far.Median age was 72 years (range 64–78) and 63% were older than 70 years. Baseline characteristics are the following: clinical stage III in 30 patients (70%), PS>2 in 7(18%), ISS≥2 in 73%, creatinine≥2 mg/dl in 15%, unfavourable cytogenetics in 33% of patients with a valuable test. Fifteen patients (37%) achieved CR according to the EBMT criteria, 4 (10%) nCR, 4(10%) VGPR, 15(32%) PR, 4(10%) MR and one patient progressed resulting an ORR of 98%.The majority of the best responses were achieved within the first 3 cycles of therapy. Eight patients underwent autologous stem cell transplantation.Side effects were mild or moderate according to NCI scale.Severe non-hematological toxicity consisted of constipation (7%), fatigue (5%), tremors (2%), mucositis (4%).No patients had peripheral neuropathy or PPE more than grade 2. Grade 3–4 neutropenia was seen in 4(10%) of patients but severe infections occurred in 7(17%) without related deaths. DVT occurred in 5 patients (12%) with one case of pulmonary embolism; all cases resolved with common anticoagulant therapies.No patients discontinued the protocol because of toxicity although two patients refused to continue it after the occurrence of pulmonary embolism and septic shock.With a median follow-up of 15 months, EFS and OS at two years were 65% and 70%, respectively.Our study demonstrated that low-dose thalidomide in combination with pegylated-liposomal doxorubicin and high-dose dexamethasone is very effective inducing an ORR and particularly a CR rate higher than those reported with all other treatments, including high-dose therapy.High quality of response positively impacts on EFS and OS. This combination results well tolerated also by older-frail patients but infections and thromboembolic disease require adequate prophylaxis and therapy. An update of these data will be presented.