Steve Schey

Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial

BACKGROUNDnFew effective treatments exist for patients with refractory or relapsed and refractory multiple myeloma not responding to treatment with bortezomib and lenalidomide. Pomalidomide alone has shown limited efficacy in patients with relapsed multiple myeloma, but synergistic effects have been noted when combined with dexamethasone. We compared the efficacy and safety of pomalidomide plus low-dose dexamethasone with high-dose dexamethasone alone in these patients.nnnMETHODSnThis multicentre, open-label, randomised phase 3 trial was undertaken in Australia, Canada, Europe, Russia, and the USA. Patients were eligible if they had been diagnosed with refractory or relapsed and refractory multiple myeloma, and had failed at least two previous treatments of bortezomib and lenalidomide. They were assigned in a 2:1 ratio with a validated interactive voice and internet response system to either 28 day cycles of pomalidomide (4 mg/day on days 1-21, orally) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally) or high-dose dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20, orally) until disease progression or unacceptable toxicity. Stratification factors were age (≤75 years vs >75 years), disease population (refractory vs relapsed and refractory vs bortezomib intolerant), and number of previous treatments (two vs more than two). The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01311687, and with EudraCT, number 2010-019820-30.nnnFINDINGSnThe accrual for the study has been completed and the analyses are presented. 302 patients were randomly assigned to receive pomalidomide plus low-dose dexamethasone and 153 high-dose dexamethasone. After a median follow-up of 10·0 months (IQR 7·2-13·2), median PFS with pomalidomide plus low-dose dexamethasone was 4·0 months (95% CI 3·6-4·7) versus 1·9 months (1·9-2·2) with high-dose dexamethasone (hazard ratio 0·48 [95% CI 0·39-0·60]; p<0·0001). The most common grade 3-4 haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups were neutropenia (143 [48%] of 300 vs 24 [16%] of 150, respectively), anaemia (99 [33%] vs 55 [37%], respectively), and thrombocytopenia (67 [22%] vs 39 [26%], respectively). Grade 3-4 non-haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups included pneumonia (38 [13%] vs 12 [8%], respectively), bone pain (21 [7%] vs seven [5%], respectively), and fatigue (16 [5%] vs nine [6%], respectively). There were 11 (4%) treatment-related adverse events leading to death in the pomalidomide plus low-dose dexamethasone group and seven (5%) in the high-dose dexamethasone group.nnnINTERPRETATIONnPomalidomide plus low-dose dexamethasone, an oral regimen, could be considered a new treatment option in patients with refractory or relapsed and refractory multiple myeloma.nnnFUNDINGnCelgene Corporation.

Treatment of relapsed and refractory multiple myeloma in the era of novel agents

The introduction of the Immunomodulatory drugs (IMiDs) and proteasome inhibitors, used either as a single-agent or combined with classic anti-myeloma therapies, has improved the outcome for patients with relapsed myeloma. However, there is currently no generally accepted standard treatment for relapsed/refractory myeloma patients, partly because of the absence of trials comparing the efficacy of the novel agents in relapsed/refractory myeloma. Choice of a new treatment regimen depends on both patient and disease-specific characteristics. A lenalidomide-based regimen is the first choice in patients with neuropathy, while bortezomib has the highest efficacy in patients with renal insufficiency and is not associated with increased risk of thromboembolism. A second autologous stem cell transplantation (auto-SCT) can be applied in patients with a progression-free period of ≥ 18-24 months after the first auto-SCT. In high-risk relapse such as occurring early after auto-SCT consolidation with allogeneic SCT can be considered. In this review we provide an overview of the various salvage regimens and give recommendations for treatment of patients with relapsed/refractory myeloma in different clinical settings.

Cost-effectiveness of lenalidomide in multiple myeloma.

Lenalidomide represents the first drug in a novel class of agents known as IMiDs. It has both direct antimyeloma activity and an indirect effect acting through the microenvironment. In the relapsed/refractory setting, lenalidomide has been demonstrated to be highly active, producing partial and complete responses that translate into improved survival. Generally, the drug is well tolerated and more recently this agent has been used in combination with steroids, chemotherapy agents and other novel agents that have further enhanced its efficacy in clinical trials. However, the cost of this and other novel agents is significantly greater than previously used chemotherapy protocols, which in turn means that they have fallen under the scrutiny of regulatory bodies such as NICE. It is important that researchers understand the instruments used by these bodies to come to decisions regarding cost–effectiveness if patients are not to be disadvantaged by not being given access to these active new agents. This article outlines the models used by health economists and assesses their potential shortcomings. It also suggests alternative methods and identifies areas of research where improvements might be achieved.

Bendamustine, thalidomide and dexamethasone combination therapy for relapsed/refractory myeloma patients: results of the MUKone randomized dose selection trial

There is a significant unmet need in effective therapy for relapsed myeloma patients once they become refractory to bortezomib and lenalidomide. While data from the front line setting suggest bendamustine is superior to melphalan, there is no information defining optimal bendamustine dose in multiply‐treated patients. We report a multi‐centre randomized two‐stage phase 2 trial simultaneously assessing deliverability and activity of two doses of bendamustine (60 mg/m2 vs. 100 mg/m2) days 1 and 8, thalidomide (100 mg) days 1–21 and low dose dexamethasone (20 mg) days 1, 8, 15 and 22 of a 28‐d cycle. Ninety‐four relapsing patients were treated on trial, with a median three prior treatment lines. A pre‐planned interim deliverability and activity assessment led to closure of the 100 mg/m2 arm due to excess cytopenias, and led to amendment of entry criteria for cytopenias. Non‐haematological toxicities including thromboembolism and neurotoxicity were infrequent. In the 60 mg/m2 arm, treatment was deliverable in 61·1% subjects and the partial response rate was 46·3% in the study eligible population, with 7·5 months progression‐free survival. This study demonstrates bendamustine at 60 mg/m2 twice per month with thalidomide and dexamethasone is deliverable for repeated cycles in heavily pre‐treated myeloma patients and has substantial clinical activity.

Real‐world use of pomalidomide and dexamethasone in double refractory multiple myeloma suggests benefit in renal impairment and adverse genetics: a multi‐centre UK experience

Myeloma patients who become refractory to immunomodulatory agents (IMiDs) and bortezomib have poor survival, with limited therapeutic options. Pomalidomide has shown improved survival and good tolerability in this patient cohort in clinical trials, but real world data are scarce. We retrospectively analysed all patients treated with pomalidomide at five UK centres between 2013 and 2016. Of 85 patients identified, 70 had sufficient information for response assessments. Median age was 66 years [40–89], 96·5% were refractory to IMiDs, 72·9% were refractory to both an IMiD and bortezomib and 92·9% were refractory to their last treatment. Of 45 patients with fluorescence in situ hybridization results 64% had adverse risk, 19 patients (22·4%) had an estimated glomerular filtration rate <45 ml/min. Grade ≥3 non‐haematological toxicities occurred in 42·4%, and grade ≥3 neutropenia and thrombocytopenia in 38% and 24% respectively, but only 18·8% had dose reductions. The overall response rate was 52·9%. At a median follow‐up of 13·2 months, median progression‐free survival was 5·2 months [95% confidence interval (CI) 4·150–6·238], and median overall survival was 13·7 months (95% CI 11·775–15·707). No significant difference was seen in response, survival or tolerability by renal function, age or cytogenetic risk. This real‐world data support the results seen in published clinical trials.

Stem cell harvesting after bortezomib-based re-induction for myeloma relapsing after autologous transplant: results from the BSBMT/UKMF Myeloma X (Intensive) trial.

The phase III British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X trial (MMX) demonstrated prospectively, for the first time, superiority of salvage autologous stem cell transplantation over chemotherapy maintenance for multiple myeloma (MM) in first relapse after previous ASCT. However, many patients have stored insufficient stem cells (PBSC) for second ASCT and robust evidence for remobilization after first ASCT is lacking. We report the feasibility, safety, and efficacy of remobilization after bortezomib-doxorubicin-dexamethasone reinduction in MMX and outcomes of second ASCT with these cells. One hundred ten patients underwent ≥1 remobilization with 32 and 4, undergoing second and third attempts, respectively. Toxicities of remobilization were similar to those seen in first-line mobilization. After all attempts, 52% of those with insufficient previously stored PBSC had harvested a sufficient quantity to proceed to second ASCT. Median PBSC doses infused, neutrophil engraftment, and time to discharge after second ASCT were similar regardless of stem cell source, as were the toxicities of second ASCT. No significant differences between PBSC sources were noted in depth of response to ASCT or time to progression. Harvesting after bortezomib-doxorubicin-dexamethasone reinduction for MM at first relapse is safe and feasible and yields a reliable cell product for second ASCT. The study is registered with ClinicalTrials.gov (NCT00747877) and EudraCT (2006-005890-24).

Stem Cell Harvesting after Bortezomib-Based Reinduction for Myeloma Relapsing after Autologous Transplantation: Results from the British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X (Intensive) Trial

The phase III British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X trial (MMX) demonstrated prospectively, for the first time, superiority of salvage autologous stem cell transplantation over chemotherapy maintenance for multiple myeloma (MM) in first relapse after previous ASCT. However, many patients have stored insufficient stem cells (PBSC) for second ASCT and robust evidence for remobilization after first ASCT is lacking. We report the feasibility, safety, and efficacy of remobilization after bortezomib-doxorubicin-dexamethasone reinduction in MMX and outcomes of second ASCT with these cells. One hundred ten patients underwent ≥1 remobilization with 32 and 4, undergoing second and third attempts, respectively. Toxicities of remobilization were similar to those seen in first-line mobilization. After all attempts, 52% of those with insufficient previously stored PBSC had harvested a sufficient quantity to proceed to second ASCT. Median PBSC doses infused, neutrophil engraftment, and time to discharge after second ASCT were similar regardless of stem cell source, as were the toxicities of second ASCT. No significant differences between PBSC sources were noted in depth of response to ASCT or time to progression. Harvesting after bortezomib-doxorubicin-dexamethasone reinduction for MM at first relapse is safe and feasible and yields a reliable cell product for second ASCT. The study is registered with ClinicalTrials.gov (NCT00747877) and EudraCT (2006-005890-24).

Is the revised International staging system for myeloma valid in a real world population

Larson, R.A. & Bloomfield, C.D. (2005) Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B Study. Journal of Clinical Oncology, 23, 5705–5717. Qin, Y.Z., Xu, L.P., Chen, H., Jiang, Q., Wang, Y., Jiang, H., Zhang, X.H., Han, W., Chen, Y.H., Wang, F.R., Wang, J.Z., Zhu, H.H., Liu, Y.R., Jiang, B., Liu, K.Y. & Huang, X.J. (2015) Allogeneic stem cell transplant may improve the outcome of adult patients with inv(16) acute myeloid leukemia in first complete remission with poor molecular responses to chemotherapy. Leukemia & Lymphoma, 56, 3116–3123. Schlenk, R.F., Benner, A., Krauter, J., B€ uchner, T., Sauerland, C., Ehninger, G., Schaich, M., Mohr, B., Niederwieser, D., Krahl, R., Pasold, R., D€ ohner, K., Ganser, A., D€ ohner, H. & Heil, G. (2004) Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. Journal of Clinical Oncology, 22, 3741– 3750. Wang, Y., Liu, Q.F., Xu, L.P., Liu, K.Y., Zhang, X.H., Ma, X., Fan, Z.P., Wu, D.P. & Huang, X.J. (2015) Haploidentical vs. identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood, 125, 3956–3962. Yoon, J.H., Kim, H.J., Kim, J.W., Jeon, Y.W., Shin, S.H., Lee, S.E., Cho, B.S., Eom, K.S., Kim, Y.J., Lee, S., Min, C.K., Cho, S.G., Lee, J.W., Min, W.S. & Park, C.W. (2014) Identification of molecular and cytogenetic risk factors for unfavorable core-binding factor-positive adult AML with post-remission treatment outcome analysis including transplantation. Bone Marrow Transplantation, 49, 1466–1474.

The Cost Impact of Lenalidomide for Newly Diagnosed Multiple Myeloma in the EU5

IntroductionLenalidomide is an active agent that was approved for use in the EU in 2015 as a first-line therapy for previously untreated, non-transplant eligible multiple myeloma patients. Our objective was to assess the cost impact of lenalidomide when selected as a first-line treatment for transplant-ineligible patients in France, Germany, Italy, Spain, and the United Kingdom (EU5).MethodsWe developed a cost-impact model of the total costs associated with newly diagnosed multiple myeloma over 5xa0years in the EU5 based on treatment duration and time to progression (TTP) (taken from trial data). We compared a baseline scenario (of current lenalidomide uptake) with two alternative future scenarios. Future Scenario A used an increased uptake of first-line lenalidomide: up to 50% in Year 5. Future Scenario B was similar to the baseline, but included a 20% increased uptake of the triple therapy regimen, carfilzomib, lenalidomide, and dexamethasone (KRd) at second line.ResultsCompared to alternative first-line care pathways, lenalidomide provides a time to progression advantage of up to 5.1xa0months. In the baseline scenario, the costs per patient were €40,692 in Year 1. Future Scenario A showed an additional expenditure of €867 per patient in Year 1, increasing to €3358 per patient by Year 5, a 2.1% and 8.2% increase from baseline, respectively. However, lenalidomide use was associated with a lower monthly hospitalisation per-patient cost (€813) compared with bortezomib (€1173) and thalidomide (€1532). Future Scenario B was associated with a 29% increase in cost.ConclusionsCompared to other first line therapies, lenalidomide delays time to progression resulting in associated savings across a patient’s treatment pathway and overall is likely to result in a limited impact on budget. Lenalidomide should, therefore, be considered as a first treatment option for multiple myeloma patients ineligible for transplant.FundingCelgene Ltd.

Longitudinal validity and reliability of the Myeloma Patient Outcome Scale (MyPOS) was established using traditional, generalizability and Rasch psychometric methods

PurposeThe Myeloma Patient Outcome Scale (MyPOS) was developed to measure quality of life in routine clinical care. The aim of this study was to determine its longitudinal validity, reliability, responsiveness to change and its acceptability.MethodsThis 14-centre study recruited patients with multiple myeloma. At baseline and then every two months for 5 assessments, patients completed the MyPOS. Psychometric properties evaluated were as follows: (a) confirmatory factor analysis and scaling assumptions (b) reliability: Generalizability theory and Rasch analysis, (c) responsiveness and minimally important difference (MID) relating changes in scores between baseline and subsequent assessments to an external criterion, (d) determining the acceptability of self-monitoring.Results238 patients with multiple myeloma were recruited. Confirmatory factor analysis found three subscales; criteria for scaling assumptions were satisfied except for gastrointestinal items and the Healthcare support scale. Rasch analysis identified limitations of suboptimal scale-to-sample targeting, resulting in floor effects. Test–retest reliability indices were good (Rxa0=xa0>xa00.97). Responsiveness analysis yielded an MID of +2.5 for improvement and -4.5 for deterioration.ConclusionsThe MyPOS demonstrated good longitudinal measurement properties, with potential areas for revision being the Healthcare Support subscale and the rating scale. The new psychometric approaches should be used for testing validity of monitoring in clinical settings.