Thalidomide-dexamethasone versus interferon-alpha-dexamethasone as maintenance treatment after ThaDD induction for multiple myeloma: a prospective, multicentre, randomised study.

Maintenance therapy was explored in multiple myeloma (MM) patients after conventional thalidomide, dexamethasone and pegylated liposomal doxorubicin (ThaDD). Patients with newly or relapsed MM obtaining at least minor response after 6 ThaDD courses, were randomised to receive alpha-interferon (IFN) 3 MU 3 times a week or thalidomide 100 mg daily until relapse. Both groups also received pulsed dexamethasone 20 mg 4 d a month. Fifty-one patients were randomized in the IFN-dexamethasone (ID) arm and 52 in the thalidomide-dexamethasone (TD) arm. The characteristics of two groups were similar. A significantly better 2-years progression-free survival (PFS; 63% vs. 32%; P = 0.024) and overall survival (84% vs. 68%; P = 0.030) was observed in the thalidomide arm. In high-risk patients and in those achieving less than very good partial response after induction, TD fared better in term of PFS. Main side effects were peripheral neuropathy and constipation in TD group, fatigue, anorexia and haematological toxicity in ID arm. There was a 21% probability of discontinuation at 3 years in the thalidomide arm and 44% in the IFN arm (P = 0.014). Low-dose thalidomide plus pulsed low-dose dexamethasone after conventional thalidomide combination-based therapy was also feasible in the long term, enabling significantly better residual disease control if compared with a standard maintenance therapy.

Serum C-reactive protein at diagnosis and response to therapy is the most powerful factor predicting outcome of multiple myeloma treated with thalidomide/ anthracycline-based therapy.

BACKGROUND: Few studies have focused on factors affecting outcome in patients with multiple myeloma (MM) treated with thalidomide-based therapy. We investigated factors affecting response, progression-free survival (PFS), and overall survival (OS) in patients with MM treated with the thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) regimen with the aim to select patients benefiting more from this therapy. PATIENTS AND METHODS: Sixty-six patients with MM were treated first line with the ThaDD regimen. We analyzed demographics and disease-related characteristics to search for factors affecting response (> or = very good partial remission [VGPR] vs. < VGPR], PFS, and OS. RESULTS: Overall, 45 patients (68%) showed response > or = VGPR; median TTP and OS were 23.5 months and 35.5 months, respectively. Multivariate analysis selected only serum C-reactive protein (sCRP) as a predictive factor for response (P < .0001). By multivariate analysis, normal sCRP level (P = .001) and response to treatment > or = VGPR (P = .007) were found to be associated with longer PFS. The factors that remained significantly associated with a longer OS when assessed by multivariate analysis were normal sCRP level (P = .005) and response to therapy > or = VGPR (P = .019). CONCLUSION: Serum C-reactive protein before therapy and response after therapy are the only factors useful in identifying patients benefiting from anthracycline/thalidomide-based therapy.

Thalidomide-dexamethasone plus pegylated liposomal doxorubicin vs. thalidomide-dexamethasone: a case-matched study in advanced multiple myeloma.

OBJECTIVES: Nearly all patients with multiple myeloma (MM) relapse or become refractory to front-line therapy. Several salvage therapies have been explored, but the optimal combination regimen has not been defined. We performed a case-matched study comparing patients with relapsed/refractory MM receiving thalidomide-dexamethasone alone or the combination thalidomide-dexamethasone-liposomal pegylated doxorubicin. METHODS: Forty-seven patients received thalidomide (100 mg/d), dexamethasone (40 mg p.o. on days 1-4 and 9-12), and pegylated liposomal doxorubicin (40 mg/m(2) on day 1 every 28 d) (ThaDD). Their clinical outcome was compared with that of 47 pair mates selected from patients treated at relapse with thalidomide (100 mg/d) and dexamethasone (40 mg p.o. on days 1-4) (Thal-Dex) and matched for age, beta2-microglobulin and previous therapy. RESULTS AND CONCLUSIONS: Overall response rate was significantly higher in ThaDD group (92% vs. 63.5%; P < 0.0001) as partial response rate (> or =PR) (75.5% vs. 59.5%; P = 0.077), very good partial response rate (> or =VGPR) (36% vs. 15%; P = 0.018) and near complete remission rate (> or =nCR) (30% vs. 10.5%; P = 0.002). Non-hematologic toxicity was similar in the two groups of patients whereas hematologic toxicity and infections were significantly higher in ThaDD patients. Median progression-free survival, event-free survival, and overall survival were significantly longer in patients receiving ThaDD than in those treated with Thal-Dex. ThaDD regimen significantly improved response rate and overall survival in comparison with Thal-Dex. Although the frequency of hematologic toxicity and infections resulted higher in ThaDD group compared with control group, they were not particularly frequent after adequate prophylaxis was added and were easily managed when occurred.

Technetium-99m sestamibi scintigraphy is sensitive and specific for the staging and the follow-up of patients with multiple myeloma: a multicentre study on 397 scans.

We evaluated the additional benefit of Technetium(99)-sestamibi (99mTc-MIBI) scanning in comparison with standard X-ray techniques for multiple myeloma patients either at diagnosis or during follow-up. Between February 2001 and January 2005, 397 whole body scans were acquired. On 229 scans performed at diagnosis, 146 (64%) were positive and 81 cases have discordant X-ray results. The sensitivity of 99mTc-MIBI and X-ray were 77% and 45% respectively. As a result of 99mTc-MIBI, 40% of asymptomatic myeloma patients were up-staged. The positivity of 99mTc-MIBI correlated significantly with all of the most relevant clinical and biological parameters. Multivariate analysis selected only high reactive C protein (P = 0.0005), bone marrow infiltration (P = 0.02) and bone pain (P = 0.002) as factors affecting 99mTc-MIBI pattern. In 22 patients with solitary myeloma, 99mTc-MIBI was positive in 86% of cases and detected more disease sites than X-ray. Among 168 scans performed during follow-up, 99mTc-MIBI presented high specificity in patients showing a complete response (CR; 86%), and correlated with myeloma activity and with response to therapy. At multivariate analysis, a positive pattern correlated with bone marrow infiltration (P = 0.002) and disease status other than CR (P = 0.03). We conclude that 99mTc-MIBI scanning is an additional diagnostic tool with a high specificity for the staging and the follow-up of multiple myeloma patients.

Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma.

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.

Low-dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/refractory multiple myeloma: a prospective, multicenter, phase II study.

The aim of this prospective, multicenter, phase II study was to investigate the combination of pegylated liposomal doxorubicin (Caelyx) 40 mg/m2 on day 1 every 28 days, dexamethasone 40 mg p.o. on days 1-4 and 9-12 and thalidomide 100 mg daily in 50 patients with advanced multiple myeloma. Twenty-six percent of patients achieved a complete response, 6% a near complete response, 6% a very good partial response, 38% a partial response, 16% a minor response and 8% progressed, for an overall response rate of 92%. The median event-free survival was 17 months and the median overall survival was not reached. Grade 3 non-hematologic toxicity occurred in 12% of patients, thromboembolic disease in 12% and severe infection in 16%. The combination of pegylated liposomal doxorubicin, dexamethasone an thalidomide is safe and very effective in advanced multiple myeloma.

Comparison of two regimens for the treatment of elderly patients with acute lymphoblastic leukaemia (ALL).

Acute lymphoblastic leukemia (ALL) represents a rare malignancy in the elderly and few authors have specifically focused on the treatment of ALL in this setting. We recently published the results of a prospective phase II study comprising an induction therapy with vincristine, Daunoxome and dexamethasone (VDXD) given to 15 patients aged 60 years. Here, we update the results after enrolling 17 patients, and we compare these with the results obtained in 17 elderly patients treated according to the GIMEMA ALL 0288 protocol. With the VDXD combination, elderly ALL had a higher CR rate (76.5%) than with the 0288 protocol (41%), and it was likely due to both lower induction mortality (17.5% vs. 35%) and a less resistant disease (6% vs. 24%). Infectious complications were more frequent with the VDXD combination whereas non-hematological side effects were comparable. Despite the similar DFS obtained with the two induction treatments, median EFS (3.9 months with 0288 vs. 12.8 with VDXD; p = 0.0486) and OS (4.5 vs. 21 months; p = 0.0239) were significantly higher with the VDXD regimen. In elderly ALL patients the administration of high-dose daunorubicin as a liposomal compound is feasible and seems able to improve CR rate, EFS and OS without increase in toxicity.

Thalidomide plus oral melphalan compared with thalidomide alone for advanced multiple myeloma.

Thalidomide, the prototype of a new class of agents active against multiple myeloma (MM), exerts synergistic/additive effects when combined with other drugs. The aim of this study was to compare the toxicity and efficacy of thalidomide alone and in combination with oral melphalan. Patients with advanced MM received 100 mg/day oral thalidomide escalated weekly up to 600 mg/day (n=23; T group), alone or with 0.20 oral mg/kg/die melphalan administered monthly for four consecutive days (n=27; TM group). A>/=50% paraprotein reduction was observed in 59% of TM compared with 26% of T patients (P=0.009); three TM patients were found to have an absence of paraprotein by immunofixation. After a median follow-up of 13 months (range 6-32), progression-free survival (PFS) at 2 years was significantly longer in the TM group (61 versus 45%; P=0.0376), whereas overall survival did not differ significantly. Toxicity was not significantly greater with the combination therapy; although DVT was more frequent (11 versus 4%), as was grade 3 leukopenia (30 versus 13%; P=0.073), there were no cases of severe infection. Thalidomide administered with oral melphalan improved response rates and PFS in patients with advanced MM without significantly increasing severe toxicity.

Risk assessment of patients with hematologic malignancies who develop fever accompanied by pulmonary infiltrates: a historical cohort study.

BACKGROUND: The mortality rate associated with fever accompanied by pulmonary infiltrates after chemotherapy for hematologic malignancies remains higher than the corresponding rate associated with febrile neutropenia without pulmonary infiltrates. Nonetheless, few studies have focused on the factors that predict outcome for patients with lung infiltrates. The purpose of the current study was to construct a risk model for clinical use by assessing the factors that affect outcome for patients with fever and pulmonary infiltrates. METHODS: A historical cohort of 110 patients with hematologic malignancies who developed fever and pulmonary infiltrates was examined. Using parameters for which data were available at the onset of lung infiltrates, univariate and multivariate analyses were performed to assess factors affecting outcome. After a value of one point was assigned to each significant variable, a prediction score was calculated for each patient; scores were used to generate a system for identifying patients with a low risk of death due to fever accompanied by pulmonary infiltrates. RESULTS: The crude mortality rate associated with pulmonary infiltrates was 23%; factors associated with cure included a favorable change in white blood cell counts (odds ratio [OR], 5.6; 95% confidence interval [CI], 1.7-18.9; P = 0.001), C-reactive protein levels < 10 mg/dL (OR, 4.6; 95% CI, 1.6-13.8; P = 0.001), and serum albumin levels > or = 3 g/dL (OR, 3.2; 95% CI, 1.4-7.3; P = 0.004). Low-risk patients (risk score, 2-3) and high-risk patients (risk score, 0-1) had survival rates of 95% and 46%, respectively (P < 0.0001). The risk model had a specificity of 88% and a positive predictive value of 95%. CONCLUSIONS: The risk model tested in the current study accurately predicted the survival of patients with hematologic malignancies who developed fever with pulmonary infiltrates. Once prospectively validated, the model could be used to select patients for trials involving novel diagnostic and therapeutic strategies.

Common and rare side-effects of low-dose thalidomide in multiple myeloma: focus on the dose-minimizing peripheral neuropathy.

OBJECTIVES: Thalidomide has demonstrated a remarkable efficacy in the treatment of multiple myeloma but its use may cause several toxicities. We have investigated the common and rare side-effects, especially analysing peripheral neuropathy, in order to optimise the thalidomide dose for minimizing this harmful side-effect. METHODS: Fifty-nine patients were treated with thalidomide alone or combined with oral melphalan. The median age was 69 yr. The initial dose of thalidomide was 100 mg/day increasing weekly by 100 mg increments until a maximum dose of 400 mg was attained. Melphalan was administered at a dose of 0.20 mg/kg/d for 4 d every 28 d. RESULTS AND CONCLUSIONS: Nearly one-fourth of patients discontinued thalidomide because of toxicity. Constipation (71%), somnolence (36%) and fatigue (20%) were the most common side-effects and they were not dose dependent. Peripheral neuropathy occurred in 39% of patients and a thalidomide median daily dose of more than 150 mg was significantly associated with higher frequency and actuarial risk of peripheral neuropathy without improving the response rate. Deep venous thrombosis was observed in 7% of patients and other side-effects were rare. In patients with advanced multiple myeloma we found that a thalidomide daily dose of 150 mg minimizes peripheral neuropathy without jeopardizing response and survival.

High-dose daunorubicin as liposomal compound (Daunoxome) in elderly patients with acute lymphoblastic leukemia.

Elderly acute lymphoblastic leukemia (ALL) is a rare condition associated with low complete remission (CR) rate and short survival. In order to improve these results, we evaluate the efficacy and toxicity of Daunoxome, a liposomal daunorubicin, exhibiting toxicity profile and pharmacokinetic indices better than standard daunorubicin. In total, 15 consecutive patients with nonmature ALL were enrolled on a prospective phase II study. No exclusion was made because of older age, poor performance status and organ dysfunctions. Median age was 69 years; performance status resulted >/=2 in nine patients (60%), six patients (40%) were bcr-abl positive and two-thirds of the patients had comorbidities. Induction therapy consisted of vincristine, Daunoxome and dexamethasone. Patients in CR received one or two consolidation cycles of cyclophosphamide, cytarabine and topotecan followed, in patients achieving CR, by a two-year rotating maintenance course including vincristine, Daunoxome, cyclophosphamide and prednisone. In all, 11 patients (73%) achieved CR, three patients (20%) died early during the induction phase and one patient (7%) had resistant disease. Five patients (33%) relapsed after 5-21 months. With a median follow-up of 20 months, disease free survival (DFS) and overall survival (OS) at 2 years were 36 and 38%, respectively. Major toxicity included myelosuppression and infection. Our experience demonstrates that a high dose of daunorubicin as liposomal compound can be safely administered in elderly ALL, exhibiting high antitumor activity. Our therapeutic program shows evidence of benefit in DFS and OS.