Thalidomide, dexamethasone, Doxil and Velcade (ThaDD-V) followed by consolidation/maintenance therapy in patients with relapsed-refractory multiple myeloma.

In newly diagnosed multiple myeloma (MM), three/four-drug combinations as induction therapy seem to be more effective compared with two-drug associations in terms of response rate and duration of remission. Moreover, there is an emergent body of evidences that consolidation/maintenance therapy improves the quality of response and remission duration. However, the impact of these strategies in relapsed/refractory MM (r-rMM) is still unknown. This phase II study explored the four-drug combination of thalidomide, dexamethasone, pegylated liposomal doxorubicin (pLD), and bortezomib (ThaDD-V) as induction followed by consolidation therapy based on bortezomib-dexamethasone and thalidomide-dexamethasone and maintenance therapy with thalidomide in r-rMM patients. The primary end points of this study were best response and toxicity of the planned therapy. Forty-six patients were enrolled. At the end of therapy, the best response was as follows: 37% complete response (CR), 34.5% VGPR, and 4.5% PR with an ORR of 76%. Patients receiving ≤ 2 prior regimens had a CR rate significantly higher than those heavily treated (41% vs 0%; p=0.010). With a median follow-up of 31 months, median time to progression (TTP) and OS were 18.5 months and 40 months, respectively. By a 6-month landmark analysis, patients who completed the protocol had a significantly longer TTP compared with those who did not because of toxicity (not reached vs 7 months; p<0.0001). After the dose intensity of bortezomib was reduced due to an excess of peripheral neuropathy (PN), grade 3 PN occurred in 7.5% of patients. ThaDD-V 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 seem to be the rule.

ThaDD plus high dose therapy and autologous stem cell transplantation does not appear superior to ThaDD plus maintenance in elderly patients with de novo multiple myeloma.

OBJECTIVES: With the aim to address the issue whether high-dose therapy (HDT) is required after new drugs combinations to improve outcome of elderly newly diagnosed multiple myeloma (MM) patients, we compared the toxicity and the outcome of ThaDD plus maintenance to those of ThaDD plus HDT-autologous stem cell transplantation (ASCT). METHODS: Sixty-two patients not eligible for HDT receiving six courses of ThaDD regimen plus maintenance with thalidomide were compared to 26 patients eligible for HDT treated with four courses of ThaDD followed by melphalan 100-200 mg/m(2) and ASCT. The two groups were matched for the main characteristics except for age favouring the HDT group. RESULTS AND CONCLUSIONS: Complete remission (CR) obtained with ThaDD plus maintenance was 24% whereas it was 57% after ThaDD plus HDT-ASCT (P = 0.0232). However, after a median follow-up of 36 months, median time to progression (TTP) and progression free survival (PFS) of the group of patients undergone HDT were not significantly different to those of patients receiving ThaDD plus maintenance (32 vs. 31 months: P = 0.962; 32 vs. 29 months: P = 0.726, respectively). Five-year overall survival (OS) was 49% in the first group and 46% in the latter one (P = 0.404). As expected, a significantly higher incidence of grade 3-4 neutropenia, thrombocytopenia, infections, mucositis and alopecia were observed in the ThaDD plus HDT group. Our results suggest that in elderly MM patients ThaDD plus HDT, albeit significantly increases CR rate, seems to be equivalent to ThaDD plus maintenance in terms of TTP, PFS and OS. These results challenge the requirement for HDT consolidation in this subset of patients.

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.

Phase II study of melphalan, thalidomide and prednisone combined with oral panobinostat in patients with relapsed/refractory multiple myeloma.

The combination of melphalan, prednisone and thalidomide (MPT) has demonstrated efficacy and acceptable toxicity in newly diagnosed and relapsed/refractory patients with multiple myeloma (MM). Panobinostat is a potent oral pan-deacetylase inhibitor (pan-DACi). In preclinical and clinical studies, panobinostat showed good anti-myeloma activity in combination with several agents. This phase II study evaluated the combination of a fixed dose of MPT with escalating doses of panobinostat (three times weekly for 3 weeks, followed by a 9-day rest period) in relapsed/refractory MM. We used a two-stage design to determine whether the combination was safe and effective. At least a partial response was observed in 38.5% of patients. The maximum tolerated dose of panobinostat in combination with MPT could not be determined due to the high rate of dose-limiting toxicities experienced with panobinostat at doses of 10 and 15 mg. The most common grade 3/4 adverse events were neutropenia (71%) and thrombocytopenia (35.5%). In conclusion, MPT in combination with panobinostat three times weekly for 3 weeks followed by a 9-day rest period is not well tolerated in patients with relapsed/refractory MM. Future studies should evaluate alternative dose schedules of panobinostat.

Assessment of vulnerability measures and their effect on survival in a real-life population of multiple myeloma patients registered at Marche Region Multiple Myeloma Registry.

UNLABELLED: Multiple myeloma (MM) therapy should be tailored according to patient characteristics although we do not know which ones to use. By studying the characteristics of 266 real-life patients, we found performance status (PS) and Charlson Comorbidity Index (CCI) as factors affecting survival of MM patients regardless of their disease characteristics. This study might help to select patients for tailoring therapy in clinical practice. BACKGROUND: Multiple myeloma is a typical disease of the elderly but how many and which patients can be considered 'vulnerable' and how this may affect patient outcome remain unsolved issues. PATIENTS AND METHODS: Data from 266 symptomatic MM patients registered at Marche MM registry from 2007 to 2010 were evaluated retrospectively. Vulnerability was defined as age > 75 years, PS (World Health Organization) ≥ 2, renal insufficiency (RI), bone fracture, cytopenias, and CCI score ≥ 1. Kaplan-Meier method and Cox regression were used to assess survival and associated factors. A vulnerability score (VS) incorporating significant vulnerability features was pursued to predict survival. RESULTS: Thirty-eight percent of patients were older than 75 years, 39% had PS = 2-4, 35% had at least 2 cytopenias, 40% had bone fracture, 14% RI, and 51% had CCI score ≥ 1. Cox regression selected international staging system (ISS) = III (hazard ratio [HR] = 1.6; P = .033), PS = 2-4 (HR = 2.5; P = .007), and CCI = 1-3 (HR = 2.1; P = .028) as factors associated with a worse overall survival. A VS including PS and CCI predicted median survival of 27 months in the 63 patients having a VS = 2 (both PS = 2-4 and CCI = 1-3) versus not reached (NR) in the 203 patients with VS = 0-1 (HR = 4.0; P < .0001). In younger patients multivariate analysis selected ISS = III (HR = 5.2; P = .006) and VS = 2 (HR = 5.5; P = .024) as factors associated with shorter survival whereas only VS = 2 (HR = 3.5; P = .002) affected worse survival in elderly. CONCLUSION: Such VS proved to be a powerful prognostic factor for survival of MM patients and it might be useful to identify true vulnerable patients regardless of age.

Infectious complications in patients with multiple myeloma treated with new drug combinations containing thalidomide.

The literature provides scant data concerning infectious complications and their effect on the outcome of patients with multiple myeloma (MM) treated with new drug combinations. Despite no substantial myelotoxic effect, thalidomide increases the risk of severe infections in patients with MM. We studied 202 patients who received regimens containing thalidomide in order to assess the time, type, outcome, and factors affecting development of severe infections, role of antibiotic prophylaxis, and effect of severe infections on final outcome. Thirty-eight patients (19%) developed a severe infection early during induction therapy and most infections were pneumonia. Only one patient died due to septic shock during neutropenia. No significant differences were reported in terms of progression-free survival (PFS) and overall survival (OS) between patients developing a severe infection and those who did not. Multivariate analysis determined a monoclonal component >3 g/dL and platelets <130 ,000/µL as factors associated with increased risk of severe infection. Primary antibiotic prophylaxis significantly decreased the probability of severe infection only in patients having both the above risk factors. Patients with MM receiving thalidomide combinations with high tumor burden are at high risk of developing severe infections and require primary antibiotic prophylaxis, whereas in other patients it is questionable. However, patient final outcome was not affected by infection development.

Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial.

PURPOSE: In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens. PATIENTS AND METHODS: A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment. RESULTS: Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, -3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, -1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded. CONCLUSION: In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH.

Outcome and toxicity in the modern era of new drugs for multiple myeloma: a reappraisal for comparison with future investigational trials.

The introduction of new drugs such as thalidomide, lenalidomide, and bortezomib has led to novel treatment strategies and significantly improved the outcome of patients with multiple myeloma (MM). The enhanced knowledge of myeloma pathogenesis has allowed the identification of new therapeutic targets and many clinical trials are either planned or in progress to evaluate these more selective drugs in the near future. The results of these studies, however, will have to be compared with the results of existing novel therapies for the treatment of MM in order to define whether new protocols do not duplicate current new standards and constitute a real improvement. We reviewed the results of a series of phase I, II, III studies with thalidomide, lenalidomide, and bortezomib combinations for newly diagnosed MM in order to define a reasonable standard in terms of activity, efficacy, and toxicity and to have a potentially useful starting point for comparisons with future investigational trials. Three-drug regimens appear to double the complete remission (CR) rate (20%), though regimens containing 4 drugs triple the CR rate (30%), compared with those containing only 2 agents (10%). These improvements in the depth and quality of response translate into a progressive increase in the progression-free survival rate at 2 years (from approximately 54%-62% to 75%, respectively). Conversely, by using additional agents, a marked increase in hematologic toxicity has been described (8%, 28%, and 28% respectively), whereas nonhematologic toxicity appears to be similar (26%, 24%, and 27%, respectively). These results suggest that new trials in the future will constitute significant progress if they can improve on the current relatively favorable efficacy/toxicity ratio. Nonetheless, exciting new combinations in development do hold promise and results from these studies are eagerly awaited.

Melphalan, prednisone, and thalidomide versus thalidomide, dexamethasone, and pegylated liposomal doxorubicin regimen in very elderly patients with multiple myeloma: a case-match study.

The outcome of patients with multiple myeloma (MM) aged over 75 years remains poor, and the best therapeutic approach has still to be defined. We compared the response, toxicity, and outcome of 34 very elderly patients with MM receiving thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) to those of 34 patients matched for age, International Staging System (ISS), and creatinine who received melphalan, prednisone, thalidomide (MPT). ThaDD resulted in a significantly higher response: > or =PR (87.5% vs. 61.5%, p = 0.009) and > or =VGPR (55.5% vs. 29.5%; p = 0.03). No statistical differences were detected in terms of median probability of progression-free survival (PFS) and overall survival (OS) between the two treatments. Patients treated with MPT had more neutropenia, neuropathy, and heart toxicity, whereas thromboembolism resulted more frequently in patients receiving ThaDD. Therapy discontinuation occurred in 9% and 14.5% of patients treated with ThaDD and MPT, respectively. ThaDD can be considered a therapeutic option in very elderly patients with MM since it induces a faster and deeper response than that obtained with MPT, having similar safety profile.

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.

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.