Insufficient evidence exists to use histopathologic subtype to guide treatment of idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular [HyperV] more recently), plasmacytic, or "mixed." Though the etiology is unknown, a pro-inflammatory cytokine storm, often involving interleukin-6 (IL-6), contributes to pathogenesis. Anti-IL-6 therapy with siltuximab is the only FDA- or EMA-approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first-line for iMCD, except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real-world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18 of 79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real-world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype.

Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial.

BACKGROUND: As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. METHODS: We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of ß2 microglobulin at screening. Bortezomib (1·3 mg/m2) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. FINDINGS: Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9-21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66-13·73] vs 7·10 months [5·88-8·48]; hazard ratio 0·61, 95% CI 0·49-0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had febrile neutropenia), infections (86 [31%] vs 48 [18%]), and thrombocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]). INTERPRETATION: Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. FUNDING: Celgene.

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.

The Myeloma Patient Outcome Scale is the first quality of life tool developed for clinical use and validated in patients with follicular lymphoma.

OBJECTIVES: The development of novel agents and an ageing population has led to an increasing number of patients with follicular lymphoma (FL) living longer with their disease. Health-related quality of life (HRQOL) is a priority for patients and should guide clinical decisions. The Myeloma Patient Outcome Scale (MyPOS), originally developed for myeloma, was validated in a cross-sectional survey recruiting 124 FL patients. METHODS: Content and construct validity, structural validity using confirmatory factor analyses, reliability and acceptability were evaluated. RESULTS: Three subscales were indicated: symptoms and function, emotional response, and healthcare support. MyPOS symptom and function scores were higher (worse) in participants with poorer ECOG performance status (F=26.2, P<.000) and discriminated between patients on and off treatment. Good convergent and discriminant validity in comparison to the EORTC-QLQ-C30 and FACT-Lym were demonstrated. Internal consistency was good; α coefficient 0.70-0.95 for the total MyPOS score and subscales. CONCLUSION: The MyPOS is valid, reliable and acceptable, and can be used to support clinical care of FL patients. This is the first measurement tool developed specially for use in clinical practice that has been validated for use in people with FL. Further longitudinal validation is now required to support its use in outcome measurement.

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

PURPOSE: The 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. METHODS: This 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. RESULTS: 238 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 (R = > 0.97). Responsiveness analysis yielded an MID of +2.5 for improvement and -4.5 for deterioration. CONCLUSIONS: The 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.

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).

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.

Weekly intravenous bortezomib is effective and well tolerated in relapsed/refractory myeloma.

OBJECTIVES: Bortezomib is an effective antimyeloma therapy, but clinical benefits can be limited by neurotoxicity. In newly diagnosed, older patients, modification of the biweekly dosing schedule to weekly regimens improves tolerability whilst maintaining efficacy. There is less information on the efficacy and tolerability of weekly bortezomib regimens in the relapsed/refractory setting. Here, we report our experience of weekly intravenous bortezomib in clinical practice in relapsed/refractory patients. METHODS: We analysed fifty-two patients who received weekly bortezomib for relapsed/refractory MM. RESULTS: Thirty-one per cent of patients received bortezomib beyond first relapse. Almost all (94%) also received steroids and 48% also received an alkylator. The median cumulative dose was 22.6 mg/m(2) , and median length of treatment was 164 d. Three patients reported grade 2 sensory neuropathy, and one reported grade 3 motor neuropathy. There were no grade 4 neurotoxicities. Eighty-three per cent achieved a PR or greater, and the median PFS for the whole group was 13 months. One-year PFS and OS were 53% (95% CI 39-66.6%) and 78% (95% CI 66.7-89.6%), respectively. CONCLUSIONS: Weekly intravenous bortezomib when used in combination with steroids ± alkylator is effective in relapsed/refractory MM, producing outcomes comparable with biweekly regimens and with lower rates of peripheral neuropathy.

Inhibition of PI3K Class IA Kinases Using GDC-0941 Overcomes Cytoprotection of Multiple Myeloma Cells in the Osteoclastic Bone Marrow Microenvironment Enhancing the Efficacy of Current Clinical Therapeutics.

Osteoclasts contribute to bone marrow (BM)-mediated drug resistance in multiple myeloma (MM) by providing cytoprotective cues. Additionally, 80% of patients develop osteolytic lesions, which is a major cause of morbidity in MM. Although targeting osteoclast function is critical to improve MM therapies, pre-clinical studies rarely consider overcoming osteoclast-mediated cytoprotection within the selection criteria of drug candidates. We have performed a drug screening and identified PI3K as a key regulator of a signalling node associated with resistance to dexamethasone lenalidomide, pomalidomide, and bortezomib mediated by osteoclasts and BM fibroblastic stromal cells, which was blocked by the pan-PI3K Class IA inhibitor GDC-0941. Additionally, GDC-0941 repressed the maturation of osteoclasts derived from MM patients and disrupted the organisation of the F-actin cytoskeleton in sealing zones required for bone degradation, correlating with decreased bone resorption by osteoclasts. In vivo, GDC-0941 improved the efficacy of dexamethasone against MM in the syngeneic GFP-5T33/C57-Rawji mouse model. Taken together, our results indicate that GDC-0941 in combination with currently used therapeutic agents could effectively kill MM cells in the presence of the cytoprotective BM microenvironment while inhibiting bone resorption by osteoclasts. These data support investigating GDC-0941 in combination with currently used therapeutic drugs for MM patients with active bone disease.

GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death.

GCS-100 is a galectin-3 antagonist with an acceptable human safety profile that has been demonstrated to have an antimyeloma effect in the context of bortezomib resistance. In the present study, the mechanisms of action of GCS-100 are elucidated in myeloma cell lines and primary tumor cells. GCS-100 induced inhibition of proliferation, accumulation of cells in sub-G(1) and G(1) phases, and apoptosis with activation of both caspase-8 and -9 pathways. Dose- and time-dependent decreases in MCL-1 and BCL-X(L) levels also occurred, accompanied by a rapid induction of NOXA protein, whereas BCL-2, BAX, BAK, BIM, BAD, BID, and PUMA remained unchanged. The cell-cycle inhibitor p21(Cip1) was up-regulated by GCS-100, whereas the procycling proteins CYCLIN E2, CYCLIN D2, and CDK6 were all reduced. Reduction in signal transduction was associated with lower levels of activated IkappaBalpha, IkappaB kinase, and AKT as well as lack of IkappaBalpha and AKT activation after appropriate cytokine stimulation (insulin-like growth factor-1, tumor necrosis factor-alpha). Primary myeloma cells showed a direct reduction in proliferation and viability. These data demonstrate that the novel therapeutic molecule, GCS-100, is a potent modifier of myeloma cell biology targeting apoptosis, cell cycle, and intracellular signaling and has potential for myeloma therapy.

Risk of relapse of multiple myeloma following kidney transplantation.

BACKGROUND: Autologous stem cell transplantation (ASCT) and novel therapies have improved the prognosis for patients with multiple myeloma (MM). For those who undergo ASCT while on dialysis, a similar survival compared with the overall MM population has been reported. Therefore, for patients achieving remission following ASCT, kidney transplantation is an attractive option, offering an improved quality of life and significant economic advantage. METHOD: This case series investigates the outcome of five patients who underwent an ASCT for MM with subsequent kidney transplantation between 2006 and 2012. RESULTS: Four patients presented with end-stage renal disease (ESRD) and one progressed to ESRD shortly after diagnosis. Induction chemotherapy regimens with novel agents including thalidomide and bortezomib were utilized. Following attainment of very good partial remission or complete remission, high-dose melphalan ASCTs were performed after a median of 10 months. Kidney transplantation (living donor n = 3, deceased donor n = 2) with tacrolimus-based immunosuppression regimens was completed at a median of 27 months after ASCT. Patients 1 and 3 experienced relapse of myeloma at 6 and 16 months after kidney transplantation. Patients 2, 4 and 5 remain alive at 55 months (median) after kidney transplantation with no evidence of relapse. CONCLUSION: Forty percent of our cohort experienced a relapse in MM within 2 years of kidney transplantation. Death-censored graft survival and patient survival were 80% at 4 years. Our study adds to the growing literature supporting kidney transplantation following successful ASCT for MM and is useful when counselling patients regarding renal and haematological outcomes.

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

INTRODUCTION: Lenalidomide 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). METHODS: We developed a cost-impact model of the total costs associated with newly diagnosed multiple myeloma over 5 years 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. RESULTS: Compared to alternative first-line care pathways, lenalidomide provides a time to progression advantage of up to 5.1 months. 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. CONCLUSIONS: Compared 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. FUNDING: Celgene Ltd.

Life-threatening motor neurotoxicity in association with bortezomib.

Bortezomib has been licensed to be used in relapsed and refractory multiple myeloma. It is a promising agent for this incurable condition but our effort is to caution hematologists about the life-threatening neurotoxicity (grade 4) which was seen in two of six patients treated with this agent although the complication cannot definitely be attributed to bortezomib.

The incidence and outcome of myeloid malignancies in 2,112 adult patients in southeast England.

There is a paucity of epidemiological data on chronic myeloproliferative disorders and myelodysplastic syndromes (MDS), while subtypes of acute myeloid leukemia (AML) are rarely defined. We identified 2,112 adult myeloid malignancies in the South Thames area between 1999 and 2000. The incidence (European standard population) of AML was 3.00/100,000, that of MDS 3.47/100,000, chronic myelomonocytic leukemia (CMML) 0.46/100,000, idiopathic myelofibrosis (IMF) 0.37/100,000, polycythemia vera (PV) 1.08/100,000, primary thrombocythemia (PT) 1.65/100,000 and chronic myeloid leukemia (CML) 1.09/100,000. The 3-year survival for AML was 15%, MDS 45%, CMML 29%, IMF 48%, PV 80%, PT 81% and CML 50% We believe this study reflects the true incidence and outcome of myeloid malignancies in South East England.

The prognostic value of interim positron emission tomography scans combined with immunohistochemical data in diffuse large B-cell lymphoma.

The treatment of hematologic malignancies is moving towards risk-stratified directed therapy, whereby treatment is based on the disease's biological characteristics and response to treatment. We investigated whether BCL2 and BCL6 status could add to the prognostic information yielded by an interim positron emission tomography (PET) scan in the ability to predict outcome. Negative interim scans and BCL2-negative status correlated with continuing remission (p<0.005) at a median follow up of 24 months.

Lenalidomide for multiple myeloma: cost-effectiveness in patients with one prior therapy in England and Wales.

PURPOSE: To determine the cost effectiveness of lenalidomide plus dexamethasone (LEN/DEX) versus DEX alone in managing multiple myeloma (MM) patients who have failed one prior therapy. MATERIALS AND METHODS: An individual simulation model was designed to capture the costs and outcomes of LEN/DEX versus DEX therapy in relapsed refractory MM patients. MM009/010 efficacy data were adjusted for treatment cross-over and extrapolated to patient lifetime. Resource use for MM disease progression and adverse events were obtained from expert physicians and costed from the perspective of the National Health Service (England and UK) and included a patient access scheme for LEN. Utility values were obtained from published literature. RESULTS: The simulation model estimated an incremental improvement in time to progression of 9.5 months, an additional 3.2 life-years, and 2.2 quality adjusted life years (QALY) for LEN/DEX compared to DEX alone. Including the costs of therapy with the patient access scheme, adverse events, and disease follow-up, the incremental cost effectiveness ratio was £30,153/QALY for LEN/DEX compared to DEX alone in MM patients who have failed one prior therapy. CONCLUSION: LEN/DEX is a cost effective oncology therapy from the perspective of the NHS for MM patients with one prior treatment.

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.