You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.



Title 1:
Thalidomide and dexamethasone combination for refractory multiple myeloma.
Abstract 1:
BACKGROUND Thalidomide is effective in approximately 30 % of patients with refractory multiple myeloma .  Dexamethasone is active in 25 % of patients with disease resistant to alkylating agents . We investigated the combination of thalidomide with dexamethasone as salvage treatment for heavily pretreated patients with multiple myeloma , in order to assess its efficacy and toxicity . PATIENTS AND METHODS Forty-four patients with refractory myeloma were treated with thalidomide , 200 mg p.o . daily at bedtime , with dose escalation to 400 mg after 14 days , and dexamethasone , which was administered intermittently at a dose of 20 mg/m2 p.o . daily for four days on day 1 - 4 , 9 - 12 , 17 - 20 , followed by monthly dexamethasone for four days . Patients ' median age was 67 years . All patients were resistant to st and ard chemotherapy , 77 % were resistant to dexamethasone-based regimens and 32 % had previously received high-dose therapy . RESULTS On an intention-to-treat basis twenty-four patients ( 55 % ) achieved a partial response with a median time to response of 1.3 months . The thalidomide and dexamethasone combination was equally effective in patients with or without prior resistance to dexamethasone-based regimens and in patients with or without prior high-dose therapy . Toxicities were mild or moderate and consisted primarily of constipation , morning somnolence , tremor , xerostomia and peripheral neuropathy . The median time to progression for responding patients is expected to exceed 10 months and the median survival for all patients is 12.6 months . CONCLUSION The combination of thalidomide with dexamethasone appears active in patients with refractory multiple myeloma . If this activity is confirmed , further studies of this combination as second-line treatment for patients resistant to conventional chemotherapy , and as primary treatment for patients with active myeloma , should be considered


Title 2:
Low‐dose thalidomide plus low‐dose dexamethasone therapy in patients with refractory multiple myeloma
Abstract 2:
We report the results of a non‐r and omized phase II study of low‐dose thalidomide plus low‐dose dexamethasone therapy in 66 patients with refractory multiple myeloma .  The overall response rate ( near complete , partial and minimal response ) was 63.6 % , and progression‐free and overall survival periods were 6.2 and 25.4 months . In adverse events , the incidence of peripheral neuropathy and deep vein thrombosis was lower than the data reported in USA and Europe . On the other h and , leukopenia was observed in 41 % of patients , including 11 % of those with Grade 3 . Leukopenia was closely related to pretreatment pancytopenia , especially thrombocytopenia . The incidence of adverse events related to dexamethasone was low . In conclusion , low‐dose thalidomide plus low‐dose dexamethasone therapy was as effective as high‐dose thalidomide plus high‐dose dexamethasone therapy in patients with refractory multiple myeloma . Leukopenia is one of the most serious adverse events in Japanese patients , especially in patients with pretreatment pancytopenia


Title 3:
Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma.
Abstract 3:
PURPOSE The efficacy of low-dose thalidomide ( THAL ) plus dexamethasone ( DEX ) has been evaluated in myeloma . The clinical outcome of patients treated with THAL-DEX  was compared with that of a control group treated with conventional chemotherapy ( CC ) . EXPERIMENTAL DESIGN A total of 120 relapsed/refractory patients to one ( 52 % ) , or two or more(48 % ) lines of chemotherapy were treated with THAL 100mg/day ( continuous ) and DEX 40 mg ( days 1 - 4 of each month ) . Their clinical outcome was compared to a control group of 120 patients frequency matched for serum beta2-microglobulin levels and Durie and Salmon clinical stage . Clinical characteristics were homogeneous in the two groups . RESULTS In patients treated after one line of chemotherapy , THAL-DEX significantly improved outcome . Median progression-free survival ( PFS ) was superior in THAL-DEX group versus CC group ( 17 months versus 11 months , P = 0.0024 ) . The median survival for THAL-DEX patients has not to been reached , but the probabilities of survival at 3 years were 60 % after THAL-DEX and 26 % after CC ( P = 0.0016 ) . The clinical outcome of patients receiving THAL-DEX or CC after two or more lines of chemotherapy , was similar . In the THAL-DEX group , the medianPFS was 11 months compared to 9 months in the CC group ( P = NS ) . No differences in overall survival ( OS ) were observed ( median OS 19 months for both THAL-DEX and CC ) . CONCLUSIONS As first salvage regimen , THAL-DEX was superior to CC , as second or third salvage regimen , it was equivalent to CC . THAL-DEX is not myelotoxic . It postpones the delivery of effective salvage chemotherapy . This might explain the survival benefit


Title 4:
The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio
Abstract 4:
The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone ( Thal/Dex ) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy .  We studied 35 patients , who received thalidomide at a dose of 200 mg/daily . We measured , pre- , 3 and 6 months post-treatment soluble receptor activator of nuclear factor-κB lig and ( sRANKL ) , osteoprotegerin ( OPG ) , osteopontin ( OPN ) , markers of bone resorption and formation . Before treatment , patients had increased levels of sRANKL/OPG ratio , bone resorption markers and OPN , while they had suppressed bone formation . The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease . Thal/Dex administration result ed in a significant reduction of sRANKL/OPG ratio , and bone resorption . Bone formation , OPG and OPN did not show any alteration . Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers . Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months . The response rate was 65.7 % . The median survival was 19.5 months . β2-microglobulin , type of response and International Staging System predicted for survival . These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio


Title 5:
Thalidomide in combination with dexamethasone for pretreated patients with multiple myeloma: serum level of soluble interleukin-2 receptor as a predictive factor for response rate and for survival
Abstract 5:
The aim of this study was to assess the side effects and the efficacy of thalidomide alone or in combination with dexamethasone in relapsed multiple myeloma ( MM ) and to evaluate possible predictive factors for response rate and survival . Twenty-nine pretreated patients were enrolled , including 13 patients with a relapse after high-dose chemotherapy . The median number of relapses was 3 ( range : 1–7 ) . Twenty-two patients received thalidomide in combination with dexamethasone and seven patients thalidomide alone . The dosage of thalidomide was 400 mg/day and the dosage of dexamethasone 20 mg/m2 daily for 4 consecutive days every 3 weeks . Cycles of dexamethasone were given until maximal decline of myeloma protein was achieved , whereas therapy with thalidomide was maintained until disease progression . Responses occurred in 62 % of patients , including 5 ( 17 % ) complete remissions and 13 ( 45 % ) partial remissions . The median event-free survival ( EFS ) was 7.2 months and the median overall survival ( OS ) 26.1 months . In multivariate analysis , pretreatment serum levels of soluble interleukin-2 receptor ( sIL-2R ) were a significant prognostic factor for EFS , and those of β2-microglobulin ( β2 M ) and sIL-2R for OS . Serum levels of sIL-2R significantly increased after 3 weeks of treatment in 89 % of patients , possibly representing lymphocyte activation induced by thalidomide . Two patients died of septic complications within 3 months after starting treatment with thalidomide and dexamethasone and one patient of herpes encephalitis after 26 months of treatment with thalidomide alone . Also , one case of pneumonia and one case of deep venous thrombosis of the lower limb occurred . Other side effects were somnolence , peripheral neuropathy , and bradycardia occurring in 35 , 55 , 38 and 55 % of patients , respectively . The combination of thalidomide and dexamethasone is an effective therapy in heavily pretreated myeloma patients with a high response rate and acceptable toxicities . A powerful predictive factor both for EFS and OS was the pretreatment serum level of sIL-2R


Title 6:
Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma.
Abstract 6:
PURPOSE Although thalidomide ( Thal ) was introduced successfully in the treatment of multiple myeloma ( MM ) , the optimal Thal dosage and schedule are still controversial . The aim of this study was to analyze whether the effect of Thal in MM is dose dependent and whether the outcome might be improved when the Thal dosage is adjusted to parameters reflecting body size . EXPERIMENTAL DESIGN From December 1998 to March 2001 , 83 patients with relapsed MM were enrolled in a clinical Phase II trial and treated with a maximum Thal dosage of 400 mg daily . We performed a retrospective analysis and studied the effect of the cumulative 3-month Thal dosage on progression-free survival and overall survival ( OS ) together with age and the pretreatment levels of beta2-microglobulin , C-reactive protein , albumin , and hemoglobin in a Cox regression model . RESULTS After a median follow-up time of 17 months ( range , 1 - 30 months ) , the estimated 12-month progression-free survival and OS were 45 % ( SE = 6 % ) and 86 % ( SE = 4 % ) for the whole patient group . After backward selection , hemoglobin ( P = 0.002 ) and the cumulative 3-month Thal dosage ( P = 0.002 ) were the remaining factors for OS . The effect on OS could not be improved when the cumulative 3-month Thal dosage was adjusted to parameters reflecting body size such as height , weight , body surface area , or body mass index in comparison with Thal alone . CONCLUSIONS Our retrospective analysis demonstrates that the cumulative 3-month Thal dosage is one of the major prognostic factors for OS , supporting the hypothesis of a dose-dependent effect of Thal in relapsed MM
Thus , using Thal/Dex results in an improved response rate in relapsed/refractory MM , with a toxicity rate comparable to thalidomide monotherapy