Alexander J. Szubert

The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis

Thalidomide maintenance has the potential to modulate residual multiple myeloma (MM) after an initial response. This trial compared the effect of thalidomide maintenance and no maintenance on progression-free survival (PFS) and overall survival (OS) in MM patients. After intensive or nonintensive induction therapy, 820 newly diagnosed MM patients were randomized to open-label thalidomide maintenance until progression, or no maintenance. Interphase FISH (iFISH) analysis was performed at study entry. Median PFS was significantly longer with thalidomide maintenance (log-rank P < .001). Median OS was similar between regimens (log-rank P = .40). Patients with favorable iFISH showed improved PFS (P = .004) and a trend toward a late survival benefit. Patients with adverse iFISH receiving thalidomide showed no significant PFS benefit and worse OS (P = .009). Effective relapse therapy enhanced survival after progression, translating into a significant OS benefit. Meta-analysis of this and other studies show a significant late OS benefit (P < .001, 7-year difference hazard ratio = 12.3; 95% confidence interval, 5.5-19.0). Thalidomide maintenance significantly improves PFS and can be associated with improved OS. iFISH testing is important in assessing the clinical impact of maintenance therapy. Overview analysis demonstrated that thalidomide maintenance was associated with a significant late OS benefit. This trial was registered at www.isrctn.org as #ISRCTN68454111.

Minimal Residual Disease Assessed by Multiparameter Flow Cytometry in Multiple Myeloma: Impact on Outcome in the Medical Research Council Myeloma IX Study

PURPOSE To investigate the prognostic value of minimal residual disease (MRD) assessment in patients with multiple myeloma treated in the MRC (Medical Research Council) Myeloma IX trial. PATIENTS AND METHODS Multiparameter flow cytometry (MFC) was used to assess MRD after induction therapy (n = 378) and at day 100 after autologous stem-cell transplantation (ASCT; n = 397) in intensive-pathway patients and at the end of induction therapy in non-intensive-pathway patients (n = 245). RESULTS In intensive-pathway patients, absence of MRD at day 100 after ASCT was highly predictive of a favorable outcome (PFS, P < .001; OS, P = .0183). This outcome advantage was demonstrable in patients with favorable and adverse cytogenetics (PFS, P = .014 and P < .001, respectively) and in patients achieving immunofixation-negative complete response (CR; PFS, P = .0068). The effect of maintenance thalidomide was assessed, with the shortest PFS demonstrable in those MRD-positive patients who did not receive maintenance and longest in those who were MRD negative and did receive thalidomide (P < .001). Further analysis demonstrated that 28% of MRD-positive patients who received maintenance thalidomide became MRD negative. MRD assessment after induction therapy in the non-intensive-pathway patients did not seem to be predictive of outcome (PFS, P = .1). CONCLUSION MRD assessment by MFC was predictive of overall outcome in patients with myeloma undergoing ASCT. This predictive value was seen in patients achieving conventional CR as well as patients with favorable and adverse cytogenetics. The effects of maintenance strategies can also be evaluated, and our data suggest that maintenance thalidomide can eradicate MRD in some patients.

A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial.

The association of genetic lesions detected by fluorescence in situ hybridization (FISH) with survival was analyzed in 1069 patients with newly presenting myeloma treated in the Medical Research Council Myeloma IX trial, with the aim of identifying patients associated with the worst prognosis. A comprehensive FISH panel was performed, and the lesions associated with short progression-free survival and overall survival (OS) in multivariate analysis were +1q21, del(17p13) and an adverse immunoglobulin heavy chain gene (IGH) translocation group incorporating t(4;14), t(14;16) and t(14;20). These lesions frequently co-segregated, and there was an association between the accumulation of these adverse FISH lesions and a progressive impairment of survival. This observation was used to define a series of risk groups based on number of adverse lesions. Taking this approach, we defined a favorable risk group by the absence of adverse genetic lesions, an intermediate group with one adverse lesion and a high-risk group defined by the co-segregation of >1 adverse lesion. This genetic grouping was independent of the International Staging System (ISS) and so was integrated with the ISS to identify an ultra-high-risk group defined by ISS II or III and >1 adverse lesion. This group constituted 13.8% of patients and was associated with a median OS of 19.4 months.

Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation

As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.

Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results

Background Thalidomide is active in multiple myeloma and is associated with minimal myelosuppression, making it a good candidate for induction therapy prior to high-dose therapy with autologous stem-cell transplantation. Design and Methods Oral cyclophosphamide, thalidomide, and dexamethasone was compared with infusional cyclophosphamide, vincristine, doxorubicin, and dexamethasone in patients with newly diagnosed multiple myeloma. Results The post-induction overall response rate (≥ partial response) for the intent-to-treat population was significantly higher with cyclophosphamide-thalidomide-dexamethasone (n=555) versus cyclophosphamide-vincristine-doxorubicin-dexamethasone (n=556); 82.5% versus 71.2%; odds ratio 1.91; 95% confidence interval 1.44–2.55; P<0.0001. The complete response rates were 13.0% with cyclophosphamide-thalidomide-dexamethasone and 8.1% with cyclophos-phamide-vincristine-doxorubicin-dexamethasone (P=0.0083), with this differential response being maintained in patients who received autologous stem-cell transplantation (post-transplant complete response 50.0% versus 37.2%, respectively; P=0.00052). Cyclophosphamide-thalidomide-dexamethasone was non-inferior to cyclophosphamide-vincristine-doxorubicin-dexamethasone for progression-free and overall survival, and there was a trend toward a late survival benefit with cyclophosphamide-thalidomide-dexamethasone in responders. A trend toward an overall survival advantage for cyclophosphamide-thalidomide-dexamethasone over cyclophosphamide-vincristine-doxorubicin-dexamethasone was also observed in a subgroup of patients with favorable interphase fluorescence in situ hybridization. Compared with cyclophosphamide-vincristine-doxorubicin-dexamethasone, cyclophosphamide-thalidomide-dexamethasone was associated with more constipation and somnolence, but a lower incidence of cytopenias. Conclusions The cyclophosphamide-thalidomide-dexamethasone regimen showed improved response rates and was not inferior in terms of survival outcomes to the standard infusional regimen of cyclophosphamide-vincristine-doxorubicin-dexamethasone. Based on its oral administration and the reduced incidence of infection and cytopenia, cyclophosphamide-thalidomide-dexa-methasone may be considered an effective induction therapy option for patients with newly diagnosed multiple myeloma. (ISRCTN: 68454111)

Long-term Follow-up of MRC Myeloma IX Trial: Survival Outcomes with Bisphosphonate and Thalidomide Treatment

Purpose: Medical Research Council (MRC) Myeloma IX was a phase III trial evaluating bisphosphonate and thalidomide-based therapy for newly diagnosed multiple myeloma. Results were reported previously after a median follow-up of 3.7 years (current controlled trials number: ISRCTN68454111). Survival outcomes were reanalyzed after an extended follow-up (median, 5.9 years). Experimental Design: At first randomization, patients (N = 1,970) were assigned to bisphosphonate (clodronic acid or zoledronic acid) and induction therapies [cyclophosphamide–vincristine–doxorubicin–dexamethasone (CVAD) or cyclophosphamide–thalidomide–dexamethasone (CTD) followed by high-dose therapy plus autologous stem cell transplantation for younger/fitter patients (intensive pathway), and melphalan–prednisone (MP) or attenuated CTD (CTDa) for older/less fit patients (nonintensive pathway)]. At second randomization, patients were assigned to thalidomide maintenance therapy or no maintenance. Interphase FISH (iFISH) was used to analyze cytogenics. Results: Zoledronic acid significantly improved progression-free survival (PFS; HR, 0.89; P = 0.02) and overall survival (OS; HR, 0.86; P = 0.01) compared with clodronic acid. In the intensive pathway, CTD showed noninferior PFS and OS compared with CVAD, with a trend toward improved OS in patients with favorable cytogenics (P = 0.068). In the nonintensive pathway, CTDa significantly improved PFS (HR, 0.81; P = 0.007) compared with MP and there was an emergent survival benefit after 18 to 24 months. Thalidomide maintenance improved PFS (HR, 1.44; P < 0.0001) but not OS (HR, 0.96; P = 0.70), and was associated with shorter OS in patients with adverse cytogenics (P = 0.01). Conclusions: Long-term follow-up is essential to identify clinically meaningful treatment effects in myeloma subgroups based on cytogenetics. Clin Cancer Res; 19(21); 6030–8. ©2013 AACR.

Osteonecrosis of the jaw and renal safety in patients with newly diagnosed multiple myeloma: Medical Research Council Myeloma IX Study results

Bisphosphonates are recommended in patients with osteolytic lesions secondary to multiple myeloma. We report on the safety of bisphosphonate therapy with long‐term follow‐up in the Medical Research Council Myeloma IX study. Patients with newly diagnosed multiple myeloma were randomised to zoledronic acid (ZOL; 4 mg intravenously every 21–28 d) or clodronate (CLO; 1600 mg/d orally) plus chemotherapy. Among 1960 patients (5·9‐year median follow‐up), both bisphosphonates were well tolerated. Acute renal failure events were similar between groups (ZOL 5·2% vs. CLO 5·8% at 2 years; incidence plateaued thereafter). The overall incidence of confirmed osteonecrosis of the jaw (ONJ) was low, but higher with ZOL (ZOL 3·7% vs. CLO 0·5%; P < 0·0001). ONJ events were generally low grade and most occurred between 8 and 30 months (median time to ONJ, 23·7 months). Among 10 patients with ONJ recovery data, four patients in the ZOL group completely recovered, two patients improved, and three patients experienced no improvement; one CLO patient experienced no improvement. Dental surgery or trauma preceded ONJ in six ZOL patients. The incidence of renal adverse events was similar for ZOL and CLO. ONJ incidence remained low and was lower with CLO compared to ZOL. We have seen no further ONJ cases to date.

Minimal residual disease following autologous stem cell transplant in myeloma: impact on outcome is independent of induction regimen

Minimal residual disease (MRD) is a powerful determinant of overall outcome in multiple myeloma (MM). Previous studies have demonstrated that the presence of MRD at the traditional day 100 assessment point following autologous stem cell transplant (ASCT) independently predicts for both progression-free (PFS) and overall survival (OS). This effect on outcome is demonstrable in patients achieving a complete response (CR) and in those with both high-risk and standard-risk cytogenetics.1–4 As a consequence, MRD assessment is currently being considered as a surrogate end point for survival in academic clinical trials and for regulatory drug approval.5,6 Surrogate end points are clearly desirable in MM given the increasing complexity of treatment schedules and continually improving complete response rates and survival, such that trials of up-front therapy require 5–10 years of follow up in order to demonstrate survival differences. Acceptance of MRD as an appropriate end point would also ideally require the demonstration that this effect was independent of the treatment received. We have, therefore, assessed the impact of induction regimen and MRD on outcome in the context of the Medical Research Council (MRC) Myeloma IX trial (ISRCTN68454111). MRC Myeloma IX was a multi-center, randomized phase III trial with protocol and clinical results previously reported.7,8 All patients provided written informed consent. This analysis involves 397 patients randomly assigned to CTD (cyclophosphamide, thalidomide, and dexamethasone; n=189) or CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone; n=208) for 4–6 cycles, then high-dose melphalan (HDM, 200 mg/m2) and ASCT. Bone marrow (BM) aspirates for MRD assessment were obtained at the end of induction (n=252) and at day 100 post ASCT (n=397). Patients were then randomly assigned to maintenance thalidomide (50–100 mg daily) or no further therapy. Flow cytometry for MRD detection was performed as reported previously. Briefly, we assessed 500,000 cells incubated with 6-color antibody combinations including CD138/CD38/CD45/CD19 with CD56/CD27 in all cases and CD81/CD117 in some cases as required.3 Statistical analyses were landmarked from date of MRD assessment, with a median follow up of 71 months. Fisher’s exact test was used to perform between-group comparisons and survival (OS and PFS) was analyzed using Kaplan-Meier and the log rank tests with a 5% significance level. We have previously reported that the CTD regimen showed superior categorical response rates to CVAD. Overall response rate was 82.5%: CTD versus 71.2% with CVAD (P<0.0001). Similarly, the CR rate was 13.0% versus 8.1% when assessed at the end of induction and 50.0% versus 37.2% post ASCT (P=0.008 and 0.0005, respectively).7 MRD analysis was performed in a subset of 397 patients and a greater proportion of patients became MRD-negative with CTD than with CVAD both at the end of induction (25% vs. 13%; P=0.0039) and post ASCT (71% vs. 54%; P<0.001).3 When outcome is assessed according to MRD status post ASCT, there is a highly significant outcome advantage for those who are MRD negative (median PFS 28.6 vs. 15.9 months, P<0.001; median OS 80.6 vs. 59.0 months, P=0.018).3 When this effect is also assessed according to the induction therapy received, it is clear that the prognostic effect of MRD negativity is identical in those who received CTD and those who received CVAD. For MRD-negative patients, the median PFS was 28.9 months with CTD versus 28.7 months with CVAD (P=0.54) (Figure 1A) while the median OS was 80.6 months versus not reached (P=0.81) (Figure 1B). Similarly, in MRD-positive patients, outcome was identical with each induction regimen, with a median PFS of 14.9 months with CTD versus 15.9 months for CVAD (P=0.96) (Figure 1A) and median OS 58.7 versus 61.9 months (P=0.91) (Figure 1B). This pattern was also demonstrable when the PFS analysis was restricted to patients achieving a conventional immunofixation-negative complete response (Figure 1C). Figure 1. Outcome following autologous stem cell transplant (ASCT) according to day 100 minimal residual disease (MRD) and induction therapy received. The impact of MRD on outcome did not differ according to induction therapy received. For MRD-negative patients ... We and others have previously demonstrated that the outcome of patients is also impacted by MRD at the end of induction as well as following ASCT, such that the outcome is best in those MRD-negative at both time points, and worst in those with detectable disease at both time points.1,3 We have also assessed this according to induction regimen and found no significant differences. In those patients who were MRD-negative at both time points, the median PFS was 44.2 months for those receiving CTD and 40.7 months for those receiving CVAD (P=0.84). Similarly, outcomes were identical in those who were MRD-positive post induction and MRD-negative post ASCT (median PFS 25.0 months, CTD; 24.2 months, CVAD; P=0.56) and in those who were positive at both time points (median PFS 13.3 months, CTD; 14.0 months, CVAD; P=0.79) (Figure 2). Figure 2. Induction regimens do not impact outcome when considered according to MRD assessed both at the end of induction and following ASCT. The outcome of patients who are MRD-negative at both time points (A), MRD-positive post induction and MRD-negative post ... The majority of studies of MRD in myeloma have assessed the value of achieving MRD-negativity, typically with a 10−4 threshold, on outcome. Flow cytometry can also provide a quantitative assessment of residual tumor in those with detectable disease. In a recent analysis, we demonstrated that the level of residual disease is also highly informative, such that an approximate 1-year OS benefit is demonstrable for each log of tumor depletion.4 We have also assessed this effect according to induction regimen and note that a greater proportion of patients receiving CVAD had high levels of MRD ( 0.1%; CVAD n= 68, CTD n=33; P=0.0005) but no difference in PFS was demonstrable across several logs of detectable disease. For those with MRD more than 1% median, PFS was 9.5 months with CTD and 6.5 months with CVAD (P=0.49). A similar pattern was also demonstrable in MRD-positive patients with lower levels of disease (0.1% – <1% median PFS 13.7 months CTD vs. 13.6 months CVAD, P=0.9; 0.01% – <0.1% median PFS 22.1 months CTD vs. 23.6 months CVAD, P=0.84) (Figure 3). Figure 3. Impact of quantitative level of MRD on outcome. The outcome of MRD-positive patients with MRD levels of 0.01% – <0.1% (A), 0.1% – <1% (B) and greater than 1% (C) did not differ with induction regimen (P=0.84, 0.9 and 0.49, ... We would conclude that these data demonstrate that the prognostic impact of MRD is independent of the induction therapy received. The proportion of patients who become MRD-negative (at the 10−4 level) can vary significantly between regimens, but the impact of MRD-negativity is similar regardless of the induction therapy received. It is possible that differences may emerge with more effective induction regimens as levels of disease may then vary over several logs in those patients who are MRD-negative. However, data from those with quantifiable residual disease suggest that outcome is determined by the level of disease rather than the regimen received. This phenomenon has also been clearly demonstrated in B-cell chronic lymphocytic leukemia (CLL) in the German CLL Study Group CLL8 trial.9 In this study, patients were treated with fludarabine-cyclophosphamide (FC) with/without rituximab (R). MRD-negativity was associated with improved PFS and OS, and although a greater proportion of patients became MRD-negative with FCR, there was no difference between the treatment arms when outcome was assessed according to levels of disease. These data provide further evidence to support the role of MRD as a surrogate end point for survival in clinical trials.

Gender Disparities in the Tumor Genetics and Clinical Outcome of Multiple Myeloma

Background: Several cancer types have differences in incidence and clinical outcome dependent on gender, but these are not well described in myeloma. The aim of this study was to characterize gender disparities in myeloma. Methods: We investigated the association of gender with the prevalence of tumor genetic lesions and the clinical outcome of 1,960 patients enrolled in the phase III clinical trial MRC Myeloma IX. Genetic lesions were characterized by FISH. Results: Disparities were found in the prevalence of primary genetic lesions with immunoglobulin heavy chain gene (IGH) translocations being more common in women (50% of female patients vs. 38% of male patients, P < 0.001) and hyperdiploidy being more common in men (50% female vs. 62% male, P < 0.001). There were also differences in secondary genetic events with del(13q) (52% female vs. 41% male, P < 0.001) and +1q (43% female vs. 36% male, P = 0.042) being found more frequently in female myeloma patients. Female gender was associated with inferior overall survival (median: 44.8 months female vs. 49.9 months male, P = 0.020). Conclusions: We found gender-dependent differences in the prevalence of the primary genetic events of myeloma, with IGH translocations being more common in women and hyperdiploidy more common in men. This genetic background may impact subsequent genetic events such as +1q and del(13q), which were both more frequent in women. The higher prevalence of lesions associated with poor prognosis in the female myeloma population, such as t(4;14), t(14;16) and +1q, may adversely affect clinical outcome. Impact: These differences suggest that gender influences the primary genetic events of myeloma. Cancer Epidemiol Biomarkers Prev; 20(8); 1703–7. ©2011 AACR.

A multi-centre phase 2 study of azacitidine in chronic myelomonocytic leukaemia.

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