RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature.

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.

International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

Symptoms and anxiety predict declining health-related quality of life in multiple myeloma: A prospective, multi-centre longitudinal study.

BACKGROUND: Patients with multiple myeloma, an incurable haematological cancer, often receive palliative care only late in their trajectory. Criteria for early referral are lacking. AIM: To identify which patients might benefit from early integration, by identifying trajectories of health-related quality of life and the determinants for declining or poor Health related quality of life . DESIGN: Prospective, longitudinal cohort study. PARTICIPANTS: Multiple myeloma patients at all stages (newly diagnosed, first-line or second-line treatment, early or later treatment-free interval, refractory disease) from in- and outpatient units at 14 hospitals in England were recruited. In addition to clinical information and standardised Health related quality of life and psychological aspects, the Myeloma Patient Outcome Scale (MyPOS) measured palliative care concerns. RESULTS: A total of 238 patients were recruited, on average 3.5 years ( SD: 3.4) post-diagnosis. Latent mixture growth models identified four Health related quality of life trajectories. Classes 3 and 4 represent trajectories of stable poor Health related quality of life or declining Health related quality of life over an 8-month period. The strongest predictors of poor outcome at the end of follow-up were general symptom level (odds ratio (OR): 1.3, 95% CI: 1.0-1.6, p = 0.028), presence of clinically relevant anxiety (OR: 1.2, 95% confidence interval (CI): 1.0-1.4, p = 0.019), and presence of pain (OR: 1.02, 95% CI: 1.0-1.1, p = 0.018), all being more predictive than demographic or clinical characteristics. CONCLUSION: General symptom level, pain and presence of anxiety predict declining Health related quality of life in multiple myeloma. Identification of patients with palliative care needs should focus on assessing patient-reported symptoms and psychosocial well-being for identifying those at risk of deterioration.

The impact of disease-related symptoms and palliative care concerns on health-related quality of life in multiple myeloma: a multi-centre study.

BACKGROUND: Multiple myeloma, the second most common haematological cancer, remains incurable. Its incidence is rising due to population ageing. Despite the impact of the disease and its treatment, not much is known on who is most in need of supportive and palliative care. This study aimed to (a) assess symptom severity, palliative care concerns and health-related quality of life (HRQOL) in patients with multiple myeloma, and (b) to determine which factors are associated with a lower quality of life. We further wanted to know (c) whether general symptom level has a stronger influence on HRQOL than disease characteristics. METHODS: This multi-centre cross-sectional study sampled two cohorts of patients with multiple myeloma from 18 haematological cancer centres in the UK. The Myeloma Patient Outcome Scale (MyPOS) was used to measure symptoms and concerns. Measures of quality of life included the EORTC QLQ-C30, its myeloma module and the EuroQoL EQ-5D. Data were collected on socio-demographic, disease and treatment characteristics and phase of illness. Point prevalence of symptoms and concerns was determined. Multiple regression models quantified relationships between independent factors and the MyPOS, EORTC global quality of life item and EQ5D Index. RESULTS: Five-hundred-fifty-seven patients, on average 3.5 years (SD: 3.4) post-diagnosis, were recruited. 18.2 % had newly diagnosed disease, 47.9 % were in a treatment-free interval and 32.7 % had relapsed/progressive disease phase. Patients reported a mean of 7.2 symptoms (SD: 3.3) out of 15 potential symptoms. The most common symptoms were pain (72 %), fatigue (88 %) and breathlessness (61 %). Those with relapsed/progressive disease reported the highest mean number of symptoms and the highest overall palliative care concerns (F = 9.56, p < 0.001). Factors associated with high palliative care concerns were a general high symptom level, presence of pain, anxiety, low physical function, younger age, and being in the advanced stages of disease. CONCLUSION: Patients with multiple myeloma have a high symptom burden and low HRQOL, in the advanced and the earlier stages of disease. Identification of patients in need of supportive care should focus on assessing patient-reported outcomes such as symptoms and functioning regularly in clinical practice, complementary to traditional biomedical markers.

Prevalence of symptoms in patients with multiple myeloma: a systematic review and meta-analysis.

OBJECTIVES: Multiple myeloma (MM) is an incurable haematological disease. Due to novel agents, overall survival has improved in this group, yet there are no systematic reviews to understand the symptom profiles resulting from disease and treatment-related toxicities. We aimed to synthesise data on the prevalence of symptoms in patients with MM. METHODS: A systematic database and grey literature search were conducted in six databases. Random-effects meta-analysis with inverse variance weighting to pool prevalence data was performed. RESULTS: Thirty-six studies were included of which 34 studies (N = 3023) provided data for meta-analysis. Twenty-seven distinct symptoms were reported, with the majority of studies focusing on pain (n = 27), fatigue (n = 19) and problems with functioning (n = 15). The most prevalent symptoms were fatigue (98.8%, 95% CI 98.1-99.2%), pain (73%, 39.9-91.7), constipation (65.2%, 22.9-92.2) and tingling in the hands/feet with 53.4% (0.4-99.7). The most common problems were decreased physical functioning (98.9%, 98.2-99.3), decreased cognitive functioning (80.2%, 40-96.1) and financial difficulties (78.4%, 39.1-95.4). These problems were present in newly diagnosed to advanced disease stage. CONCLUSIONS: Optimal quality of life and good symptom management in this incurable disease can only be achieved by routinely assessing symptoms throughout the disease trajectory.

Improving the assessment of quality of life in the clinical care of myeloma patients: the development and validation of the Myeloma Patient Outcome Scale (MyPOS).

BACKGROUND: Multiple myeloma is an incurable cancer with a rising incidence globally. Less toxic treatments are increasingly available, so patients are living longer and treatment decisions are increasingly guided by QOL concerns. There is no QOL assessment tool designed specifically for use in the clinical care of people with myeloma. This study aimed to develop and test the psychometric properties of a new myeloma-specific QOL questionnaire designed specifically for use in the clinical setting - the MyPOS. METHODS: The MyPOS was developed using findings from a previously reported literature review and qualitative study. The prototype MyPOS was pretested using cognitive interviews in a purposive sample of myeloma patients and refined prior to field testing. The psychometric properties of the MyPOS were evaluated in a multi-centre, cross sectional survey of myeloma patients recruited from 14 hospital trusts across England. RESULTS: The prototype MyPOS contained 33 structured and open questions. These were refined using cognitive interviews with 12 patients, and the final MyPOS contained 30 items taken forward for field-testing. The cross-sectional survey recruited 380 patients for the MyPOS validation. Mean time to complete was 7 minutes 19 seconds with 0.58% missing MyPOS items overall. Internal consistency was high (α = 0.89). Factor analysis confirmed three subscales: Symptoms & Function; Emotional Response and Healthcare Support. MyPOS total scores were higher (worse QOL) in those with active disease compared to those in the stable or plateau phase (F = 11.89, p < 0.001) and were worse in those currently receiving chemotherapy (t = 3.42, p = 0.001). Scores in the Symptoms & Function subscale were higher (worse QOL) in those with worse ECOG performance status (F = 31.33, p < 0.001). Good convergent and discriminant validity were demonstrated. CONCLUSIONS: The MyPOS is the first myeloma-specific QOL questionnaire designed specifically for use in the clinical setting. The MyPOS is based on qualitative enquiry and the issues most important to patients. It is a brief, comprehensive and acceptable tool that is reliable and valid on psychometric testing. The MyPOS can now be used to support clinical decision making in the routine care of myeloma patients.

Understanding what matters most to people with multiple myeloma: a qualitative study of views on quality of life.

BACKGROUND: Multiple myeloma is an incurable haematological cancer that affects physical, psychological and social domains of quality of life (QOL). Treatment decisions are increasingly guided by QOL issues, creating a need to monitor QOL within clinical practice. The development of myeloma-specific QOL questionnaires has been limited by a paucity of research to fully characterise QOL in this group. Aims of the present study are to (1) explore the issues important to QOL from the perspective of people with multiple myeloma, and (2) explore the views of patients and clinical staff on existing QOL questionnaires and their use in clinical practice. METHODS: The 'Issues Interviews' were semi-structured qualitative interviews to explore the issues important to QOL in a purposive sample of myeloma patients (n = 20). The 'Questionnaire Interviews' were semi-structured qualitative interviews in a separate purposive sample of myeloma patients (n = 20) to explore views on existing QOL questionnaires and their clinical use. Two patient focus groups (n = 7, n = 4) and a focus group of clinical staff (n = 6) complemented the semi-structured interviews. Thematic content analysis resulted in the development of a theoretical model of QOL in myeloma. RESULTS: Main themes important to QOL were Biological Status, Treatment Factors, Symptoms Status, Activity & Participation, Emotional Status, Support Factors, Expectations, Adaptation & Coping and Spirituality. Symptoms had an indirect effect on QOL, only affecting overall QOL if they impacted upon Activity & Participation, Emotional Status or Support Factors. This indirect relationship has implications for the design of QOL questionnaires, which often focus on symptom status. Health-service factors emerged as important but are often absent from QOL questionnaires. Sexual function was important to patients and difficult for clinicians to discuss, so inclusion in clinical QOL tools may flag hidden problems and facilitate better care. Patients and staff expressed preferences for questionnaires to be no more than 2 pages long and to include a mixture of structured and open questions to focus the goals of care on what is most important to patients. CONCLUSION: Existing QOL questionnaires developed and validated for use in myeloma do not capture all that is important to patients and may not be well suited to clinical use.

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.

BACKGROUND: Few 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. METHODS: This 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. FINDINGS: The 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. INTERPRETATION: Pomalidomide plus low-dose dexamethasone, an oral regimen, could be considered a new treatment option in patients with refractory or relapsed and refractory multiple myeloma. FUNDING: Celgene Corporation.