Magnitude of response with myeloma frontline therapy does not predict outcome: importance of time to progression in Southwest Oncology Group Chemotherapy Trials

University of Arkansas at Little Rock, Little Rock, Arkansas, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 05/2004; 22(10):1857-63. DOI: 10.1200/JCO.2004.05.111
Source: PubMed


Four Southwest Oncology Group (SWOG) standard-dose chemotherapy protocols for multiple myeloma (MM) initiated between 1982 and 1992 were evaluated. The purpose was to clarify the predictive value of specific levels of myeloma-associated monoclonal protein reduction and time to first progression using mature data sets.
Study data on 1,555 eligible previously untreated patients with MM enrolled onto SWOG phase III trials 8229, 8624, 9028, and 9210 were used in these analyses. Six-month and 12-month landmark analyses were performed to evaluate the outcome for patients in each response category.
The overall and event-free survivals for the four protocols combined were 33 months and 18 months, respectively. Using 6- and 12-month landmarks, the median survivals of 30 to 35 months were not different for responders (> or = 50% and > or = 75% regression) versus nonresponders in patients without disease progression before the landmarks. Conversely, at the 6- and 12-month landmarks, the median survivals for patients who had experienced disease progression were 13 and 15 months, respectively, versus a 34-month median for patients who did not experience progression. Using the Cox survival model, with response and progression considered as time-dependent covariates, survival duration was influenced more by the occurrence of progression than by the occurrence of response.
The magnitude of response, as a single variable, does not predict survival duration. Patients with response and stable disease have equivalent outcome. Only patients with progressive disease have a poorer outcome. The best indicator of survival is time to first progression.

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    • "Certainly, the attainment of CR is associated with a better survival but randomised clinical trials need to address the issue of whether treatment should be altered in this setting in order maximise responses in order to reach CR. In patients not achieving CR, the depth of the initial response may be a poor predictor of outcome (Durie et al, 2004) although controversial (Schaar et al, 2004) and it is the achievement of plateau which may be more relevant, particularly in the non-intensive treatment setting. Retrospective analysis of the MRC UK trials identified a significant proportion of longer term survivors as having a poor response to initial treatment (Drayson et al, 2007), reflecting the biological and clinical heterogeneity of myeloma. "
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    ABSTRACT: Over the last few years new immunoassays have emerged that allow the measurement of free immunoglobulin light chains (FLCs) in serum to a level of 2-4 mg/l and provide a much greater sensitivity than older methods, such as immunofixation, which is able to detect FLCs at a minimum concentration of 100-150 mg/l. The new FLC assay has enabled the detection of monoclonal protein in some patients with non-secretory myeloma and amyloidosis that were previously undetectable. FLC measurements are quantitative, correlating with disease activity, and are an advance in monitoring light chain only multiple myeloma, AL amyloidosis, non-secretory and oligo-secretory multiple myeloma. Serum FLC concentrations also reflect the disease course in the majority of myeloma patients producing intact monoclonal immunoglobulin proteins and have been incorporated into the new response criteria. The rapid half life of lambda and kappa free light chains means that FLC assays may provide a more rapid indication of the response to treatment but their clinical utility in this setting needs further study. An abnormal FLC ratio has been shown to be a risk factor for progression of monoclonal gammopathy of undetermined significance, smouldering myeloma and solitary plasmacytoma of bone and is prognostic in multiple myeloma.
    British Journal of Haematology 06/2008; 141(4):413-22. DOI:10.1111/j.1365-2141.2008.07079.x · 4.71 Impact Factor
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    • "Likewise, analysis of a prospective randomized multicentre study of the Italian Cooperative Group of Study Treatment of Multiple Myeloma found that the median survival did not differ between patients who had CR, PR, or SD to initial therapy (Riccardi et al, 2003). The predictive value of initial chemotherapy response at 6 and 12 months landmarks was also examined in four South West Oncology Group standard dose chemotherapy protocols (Durie et al, 2004), and patients with CRs, PRs or SD were found to have equivalent median survival. Only patients with POD at 6–12 months had a shorter median survival. "
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    ABSTRACT: Among the drug combinations designed for the initial treatment of multiple myeloma, none has been unequivocally shown to be superior. However, a regimen leading to a high response rate and a low incidence of adverse events is highly desirable. We report the results of a phase II clinical trial involving 45 patients with Durie-Salmon stage II and III multiple myeloma. Doxorubicin and dexamethasone were given for 2 or 3 months followed by thalidomide and dexamethasone for 2 months (AD-TD regimen) with prophylactic antibiotics and daily aspirin (81 mg/d). Among the 42 patients whose response could be assessed, 38 responded to therapy (90.5%). The intent-to-treat response rate was 84.4% with seven complete responses (CR 15.5%), nine near complete responses (nCR 20.0%), and 22 partial responses (PR 48.9%). Two patients had stable disease (4.4%), and two progression of disease (4.4%). Normalization of the free light chain ratio after one or two cycles of treatment was highly predictive of achievement of CR or nCR. Patients tolerated the treatment well although five patients developed thromboembolic complications (11%). AD-TD administered with low dose aspirin for deep vein thrombosis prophylaxis was well tolerated and yielded a high response rate with minimal treatment-related morbidity.
    British Journal of Haematology 02/2006; 132(2):155-61. DOI:10.1111/j.1365-2141.2005.05848.x · 4.71 Impact Factor
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    • "A previous meta-analysis on 14 prospective randomised studies showed a 6% higher response rate with IFNchemotherapy regimens combined with chemotherapy without IFN (Fritz & Ludwig, 2000). An increase in response rate does not necessarily translate into increased survival (Durie et al, 2004). Nevertheless, patients with responding tumour usually enjoy – at least temporarily – a better quality of life, unless compromised by increased treatment-related toxicity. "
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    ABSTRACT: We report on a randomised trial that aimed to compare the efficacy of continued daily prednisolone treatment during the entire induction phase, with prednisolone given for 2 weeks of each cycle in combination with VMCP (vincristine, melphalan, cyclophosphamide, prednisolone)-interferon-alpha 2b (IFN-alpha 2b) treatment in 299 previously untreated elderly patients (median age: 67 years) with multiple myeloma. After completion of induction treatment patients were randomised to IFN-alpha 2b with or without prednisolone, thrice weekly. Response rate was 62% in the continuous and 60% in the control arm (intent to treat analysis, P=0.81). Progression-free survival [median: 20 months vs. 19 months; hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.74-1.33, P=0.97] and overall survival (median: 34 months vs. 37 months; HR: 1.16, 95% CI: 0.85-1.59, P=0.35) were similar in both groups. Reduced performance status (Eastern Cooperative Oncology Group, grades 2-4) was the predominant risk factor for poor survival followed by age >65 years, high beta2-microglobulin, and impaired renal function. There was more grades 3-4 dyspnoea and cardiac impairment and grades 1-2 hyperglycaemia, but less nausea, emesis and anaemia in patients on continuous prednisolone therapy. In conclusion, continuing prednisolone treatment during the entire duration of the induction phase with VMCP-IFN-alpha 2b did not improve outcome.
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