Trial efficacy vs real world effectiveness in first line treatment of multiple myeloma

Background: Large randomized clinical trials (RCT) are the foundation of the registration of newly developed drugs. A potential problem with RCTs is that the inclusion/exclusion criteria will make the population different from the actual population treated in real life. Hence, it is important to understand how the results from the RCT can be generalized to a general population. Aims: The primary aim of the present study was to assess the generalizability of the large 1st line RCTs in Multiple Myeloma (MM) to the Nordic setting and to understand potential difference and magnitude in outcomes between RCTs and patients treated in standard care in the Nordics. Methods: A retrospective analysis was performed on an incident cohort of 2960 MM-patients from 24 hospitals in Denmark, Finland, Norway and Sweden. The database contained information on patient baseline characteristics, treatments and outcomes. Data from relevant 1st line MM RCTs was selected from the treatment MP (Waage, A., et al., Blood. 2010], MPT (Waage, A., et al., Blood. 2010) and VMP (San Miguel, J.F., et al., N Engl J Med, 2008) and baseline characteristics were compared to newly diagnosed Nordic MM treated patients. Potential difference in response and overall survival (OS) was estimated by adjusting the RWE population to the RCT population using matching adjusted indirect comparisons. Patients were matched on age (median approximated to mean), gender, calcium, beta2-microglobulin and ISS score 3. These variables were selected because they were reported in all trials and have previously been identified as having prognostic value. Results: Patients in the Nordic database treated with MP (n=880) had a response rate of (PD, NR, PR, VGPR, ≥nCR) of (13%, 39%, 38%, 6%, 4%). After matching (n=347), the response rate was slightly worse (12%, 43%, 36%, 6%, 3%). This can be compared to the response rate from the RCT of (7%, 53%, 33%, 3%, 4%). OS for Nordic MP treated patients was 2.67 years (2.25-3.17). After matching the OS was 3.37 years (2.86-3.96) and this can be compared to the trial with OS 2.40 years (2.23-2.66). Patients treated with MPT (n=283) in the Nordic countries had a response rate of (5%, 14%, 52%, 20%, 9%). After matching (n=179) the response rate was slightly changed to (6%, 20%, 50%, 13% 11%). The corresponding RCT response results were 14%, 29%, 34%, 10%, and 13% respectively. OS for Nordic MPT treated patients was 4.15 years (3.73- 4.74). After matching the OS was 4.28 years (3.98-NA) years and compared to 2.42 years (2.08-3.17) OS observed in the corresponding trial. Patients treated with VMP (n=59) in the Nordic countries had a response rate of (4%, 5%, 40%, 18%, 33%). After matching (n=31) the response rate was improved to (8%, 11%, 28%, 8%, 45%). This corresponding response rates shown in the trial are 1%, 23%, 33%, 8%, and 33% respectively. OS for Nordic MP treated patients was 4.86 years (3.79-NA). After matching the OS was 4.86 years (4.86-NA) and this can be compared to the trial with OS 4.70 years. Summary and Conclusions: Surprisingly Nordic treated MM patients do very well compared to, and even better than, patients treated in RCTs. Since the OS for all tested treatments improves after matching to the RCT baseline characteristics, patients recruited to the RCTs seems to be a bit better than ordinary Nordic patents. The database used in the present study, and the used method, can be valuable for generalizing the results to the Nordic setting and estimating potential difference for future RCTs and Nordic MM treated patients. Future research should include different data cuts to see whether the analyses are biased by differences subsequent treatments applied in RCTs and clinical practice

Is a deep response the key to successful treatment of multiple myeloma?

Background: Several authors have highlighted the importance of a deep response to chemotherapy in multiple myeloma (MM), especially in first line. Aims: The objective was to assess which patient/treatment/disease characteristics are prognostic for a deep response. Also, to assess whether the deep response is prognostic for overall survival (OS) independent of treatment, treatment line and patient/disease characteristics. Methods: A retrospective analysis was performed on 2960 MM-patients from 24 hospitals in Denmark, Finland, Norway and Sweden. The database contained information on patient baseline characteristics such as age, gender, ISS stage, albumin, creatine, and MM type, which were recorded at start of first line therapy. The following outcomes were considered; response, time to next line of treatment (TTNT) and OS. The following categories of response were differentiated: progressive disease (PD), no response (NR), partial response (PR), very good PR (VGPR) and equal or better than near complete response (>=nCR). To identify prognostic factors for response, univariate and multivariate multinomial regression were conducted with response as dependent and patient baseline characteristics and type of treatment as independent variables. To assess whether response is an independent predictor of OS, multivariate cox-proportional hazard models were run for the first four lines of treatment. Results: Patients in the dataset were on average 67 years old, 48% were male, 28%, 41% and 31% in ISS stages I, II and III, respectively. Multinomial regression showed that type of treatment, age, ISS type and MM type were significant prognostic factors for response in first line. In second line, first line response, type of treatment and age were significant prognostic factors for response in second line. Multivariate cox-regression showed that in first line patients with NR, PR, VGPR and >=nCR had significant lower hazard ratio's (HRs) 0.61 (0.43-0.85), 0.56 (0.41-0.78), 0.34 (0.22-0.51) and 0.36 (0.24-0.54) respectively compared to PD. Age, Albumin, Calcium and Beta-2-microglobulin levels were also significant prognostic factors for OS with HRs of 1.03 (1.01- 1.04), 0.98 (0.96-0.99), 1.41 (1.11-1.79) and 1.02 (1.01-1.03) respectively. The following categorical variables also were significant prognostic factors for first line OS; type of treatment, ISS-stage and MM type. For second line OS multivariate cox-regression showed that patients with PR, VGPR and >=nCR had significant lower HR's 0.58 (0.46-0.73), 0.42 (0.3-0.58), 0.4 (0.27-0.6) compared to PD respectively. Age also had a significant HR of 1.02 (1.01-1.03). For third line OS multivariate cox-regression showed that patients with NR, PR, VGPR and >=nCR had significant lower HR's 0.67 (0.5-0.89), 0.37 (0.27-0.51), 0.32 (0.21-0.5), 0.18 (0.1-0.34) compared to PD respectively. Age also had a significant HR of 1.01 (1.00-1.02). For fourth line OS multivariate cox-regression showed that patients with PR, VGPR and >=nCR had significant lower HR's 0.45 (0.31-0.64), 0.31 (0.19-0.52) and 0.39 (0.21-0.73) compared to PD respectively. Age was also identified as a significant prognostic factor. Summary and Conclusions: Type of treatment, age, ISS type and MM type were significant prognostic factors for response in first line. For second line response, the significant prognostic factors were response in first line, type of treatment and age. Moreover, multivariate cox-regressions shows that in the first four lines of treatment, response is an independent prognostic factor for OS. Future research should include genetic prognostic factors, which were not collected in our dataset and could therefore not be assessed