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All patients who had had a previous infection had a robust antibody response to the first dose of COVID-19 vaccine and 60% of patients had an optimal immune response to the first dose of COVID-19 vaccination. COVID symptoms, testing, shielding impact on patient-reported outcomes and early vaccine responses in individuals with multiple myeloma Keywords: myeloma; COVID-19; vaccination; wellbeing; shielding EN myeloma COVID-19 vaccination wellbeing shielding 95 98 4 12/27/21 20220101 NES 220101 Patients with myeloma have been shielded and self-isolated since the start of the COVID-19 pandemic, due to the concern for and subsequent reports of higher risk of severe COVID-19 disease and mortality.1 In addition, guidelines have encouraged attenuation of myeloma therapeutics or a switch to oral therapies, ostensibly to reduce hospital foot-fall, facilitate shielding and potentially to limit further treatment-related immune suppression.2 Myeloma requires ongoing immune-suppressive chemotherapy, frequent medical visits and has previously demonstrated universally poor response to vaccinations.3 The protective titre of antibodies required to prevent re-infection is unclear, as is the ability to protect patients from SARS-CoV-2 virus variants of concern (VoC). [Extracted from the article]

Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1–7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3–4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population. [ABSTRACT FROM AUTHOR]

This article provides information on the diagnosis and management of smouldering myeloma, a precursor condition to multiple myeloma. It discusses various diagnostic tests and imaging techniques used to identify smouldering myeloma and emphasizes the importance of restaging if there is evidence of progression. The article also provides recommendations for screening and initial investigations for suspected myeloma. Additionally, it discusses risk stratification models and treatment options for smouldering myeloma, including the use of lenalidomide. The article concludes by highlighting ongoing clinical trials and the need for further research in the treatment of smouldering myeloma. [Extracted from the article]

The article discusses clinical management and diagnosis of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) that manifest with osteoporosis and fragility fractures. Topics explored include the increasing prevalence of osteoporosis and fractures in the elderly, the standardized incidence ratio of osteoporotic fracture in patients with MGUS, and the screening guidelines for myeloma bone disease and MGUS.

The response of the tumour microenvironment to anti-cancer drugs can influence treatment efficacy. Current drug-screening methodologies fail to distinguish and quantify simultaneously the concomitant effect of drugs on the tumour stroma and cancer cells. To overcome this limitation we have developed a fluorescence-based experimental model that employs m Cherry-labelled stromal cells (e.g. bone marrow fibroblastic stromal cells) co-cultured in direct contact with enhanced green fluorescent protein-labelled tumour cell lines for accurate assessment of proliferation and viability in both cell compartments and adhesion of tumour cells. Additionally, we used fluorescence-based image analysis to determine morphological changes that correlate with cell function (e.g. morphology of the actin cytoskeleton and nuclearity of osteoclasts to predict their bone resorption activity). Using this platform we have revealed that dexamethasone induces HS5 fibroblast proliferation and contact with multiple myeloma cells via a process involving Src/c- Abl kinases. Osteoclasts also inhibited dexamethasone-induced apoptosis in myeloma cells while retaining their normal morphology and functionality in bone resorption. Myeloma resistance to dexamethasone mediated by HS5 cells and osteoclasts was reversed by treatment with the Src/c- Abl inhibitor dasatinib but not with bortezomib. This new experimental platform provides a more precise screening of new therapeutics for improved efficacy of tumour cell killing within the bone marrow microenvironment. [ABSTRACT FROM AUTHOR]

Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1-7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3-4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population. [ABSTRACT FROM AUTHOR]

Daratumumab is the first anti-CD38 targeting monoclonal antibody approved as monotherapy in multiply relapsed myeloma patients who progressed following prior treatment with proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs). We present real world data on the efficacy of single agent daratumumab in a cohort of 55 multiply relapsed patients treated in the UK. The median age was 72 years, the majority (96%) received ≥ 3 previous lines of treatment; 54.5% were PI-refractory, 76.4% were IMiD-refractory and 47.2% were double refractory; 20% of patients had high-risk (HR) disease. The overall response rate was 49%. After a median follow up of 9.2 months, the median progression-free survival (PFS) for the total cohort was 5.1 months. Patients who achieved a partial response or better (≥PR) demonstrated a significantly longer PFS compared to those with

Simple Summary: The activation of osteoclasts occurs in up to 80% of myeloma patients. Osteoclasts promote myeloma resistance to therapeutic treatments and the formation of bone lytic lesions, resulting in bone pain and fractures in patients. However, the role of osteoclasts in drug resistance is generally overseen when performing preclinical screenings to identify new therapeutics for multiple myeloma. We propose in our study a new methodology, scalable to high throughput for the analysis of drug efficacy to better predict efficacy in myeloma patients that develop bone disease. We have identified GDC-0941 as a drug candidate that, used in combination treatments, could enhance the efficacy of currently used therapeutic drugs for myeloma by overcoming resistance mediated by osteoclasts, as well as bone marrow mesenchymal/fibroblastic stromal cells. Our work supports exploring GDC-0941 in combination with current clinical drugs for myeloma patients with active bone disease. 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. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) remains an incurable malignancy. Approximately 37% of patients with plasma cell myeloma are over the age of 75 and the median age of diagnosis is 70. The management approach to over 70s differs from younger patients, as treatment goals may vary and underlying co-morbidities and expected treatment related toxicities have to be taken into account. Individualisation of management is important, aiming to achieve the best response whilst minimising adverse events. A proportion of patients will be unable to tolerate any treatment with palliation being appropriate. Age alone should not be a barrier to treatment however, with some fit patients over the age of 70 potentially benefitting from intensive treatment options including high dose chemotherapy with autologous stem cell rescue. Comprehensive geriatric assessment is indicated in the over 70s; this should be employable in a clinic outpatient setting to make it feasible. Outcomes of this assessment potentially help physicians’ choice of therapy. For decades the combination of Melphalan and prednisolone was the standard of care for older MM patients. Over the last ten years, newer drugs and combinations have improved therapeutic options for patients but are yet to demonstrate vast improvement in overall survival in this cohort. [ABSTRACT FROM AUTHOR]

Summary: Proteasome inhibitors have been associated with thrombotic microangiopathy (TMA) — a group of disorders characterised by occlusive microvascular thrombosis causing microangiopathic haemolytic anaemia, thrombocytopenia and end‐organ damage. To date, carfilzomib‐associated TMA has predominantly been described in relapsed/refractory myeloma patients. We report eight patients with newly diagnosed myeloma who experienced TMA events while receiving carfilzomib on the phase II CARDAMON trial. The first three occurred during maintenance single‐agent carfilzomib, two occurred at induction with carfilzomib given with cyclophosphamide and dexamethasone (KCd) and three occurred during KCd consolidation. At TMA presentation 6/8 were hypertensive; 7/8 had acute kidney injury and in three, renal impairment persisted after resolution of TMA in other respects. The mechanism of carfilzomib‐associated TMA remains unclear, though patients with known hypertension seem particularly susceptible. Given the first three cases occurred during maintenance after a longer than five‐week treatment break, a protocol amendment was instituted with: aggressive hypertension management, carfilzomib step‐up dosing (20 mg/m2 on day 1) at start of maintenance before dose escalation to 56 mg/m2 maximum, and adding 10 mg dexamethasone as premedication to maintenance carfilzomib infusions. No further TMA events occurred during maintenance following this amendment and the TMA incidence reduced from 4·2 to 1·6 per 1 000 patient cycles. [ABSTRACT FROM AUTHOR]

Objective: There are limited data on the efficacy and tolerability of VCD chemotherapy in transplant‐non‐eligible (TNE) newly diagnosed myeloma (NDMM) patients. In this retrospective study, we set out to evaluate this triplet combination in this setting across Thames Valley Cancer Network (UK). Methods: The primary end point was overall response rate (ORR). Secondary outcomes included event‐free survival (EFS), overall survival (OS) and adverse events (AEs). Results: In a total cohort of 158 patients, ORR for total cohort was 72.1%. Median EFS was 10.5 months, and for subgroups by age (<75:11.7 vs ≥75:10.3 months, P =.124), by Charlson Co‐morbidity Index (CCI) (<5:11.1 vs ≥5:8.2 months, P =.345). The 4‐month landmark analysis showed the following median EFS results: by cumulative bortezomib dose (≥26 mg/m2: 9.0 months vs <26 mg/m2: 6.4, P =.13), by cumulative cyclophosphamide dose (≥7000 mg: 9.2 vs <7000 mg: 7.0 months, P =.02) and by cumulative dexamethasone dose (>600 mg: 7.8 vs ≤600 mg: 8.3 months, P =.665). Median OS was 46.9 months. The incidence rate of AE was as follows: any grade (76.8%), ≥G3 (27.1%), ≥G3 haematological AEs (7.9%), any grade infections (31.1%) and ≥G3 infections (11.9%). Conclusion: This study demonstrated a good ORR achieved from fixed duration VCD, which was reasonably well tolerated. This was followed by modest median EFS. We envisage that the latter may be improved in this patient group with the use of a higher cumulative bortezomib dose (≥26 mg/m2) which showed a trend for improved EFS although without statistical significance (P =.13), and with the use of a higher cumulative cyclophosphamide doses (≥7000 mg, P =.02), subject to tolerability and close monitoring. [ABSTRACT FROM AUTHOR]

In the 15 patients who died, nine remained on therapy, ( I n i = 9/18, 50%), five ( I n i = 5/18, 27-8%) had their treatment paused for up to eight weeks, one patient had his treatment stopped altogether ( I n i = 1/18, 5-6%) and the exact modification was missing in the remaining three cases ( I n i = 3/18 = 16-7%). Baseline characteristics of patients who continued myeloma treatment (as per pre-COVID-19 plan) and those who had their myeloma disease management modified as a result of the COVID-19 pandemic (including stopping therapy), and their haematological response at the time and treatment regimen. Keywords: infection; myeloma; myeloma treatment EN infection myeloma myeloma treatment e136 e139 4 03/19/21 20210315 NES 210315 Concern for higher mortality in myeloma patients was reflected in the response to the first wave of the novel coronavirus SARS-CoV-2 (COVID-19) pandemic. In conclusion, this descriptive study of 219 MM patients illustrates how a systematic approach to a patient's risk of infection and individualised treatment modifications are possible and may have contributed to a low incidence rate of COVID-19 infection. [Extracted from the article]

Twenty-nine patients (97%) received at least two cycles of therapy and one patient discontinued carfilzomib after one cycle. Carfilzomib therapy is ongoing in 17 patients and was discontinued in 13 patients. Five patients received full twice-weekly dosing throughout therapy, and six patients were dose-reduced to weekly upfront (i.e. from cycle 1). Depending on the severity of hypertension, management consisted of introducing an antihypertensive (e.g., amlodipine) in two patients, an antihypertensive dose increase in two patients, carfilzomib dose reduction in two patients, and an antihypertensive plus carfilzomib dose reduction in one patient. [Extracted from the article]

Background: Bortezomib is a cornerstone in the management of multiple myeloma. It remains an attractive treatment option because it is efficacious, reasonably well tolerated and easy to administer. However, data on resource implications in the UK for both patients and healthcare providers are limited. Methods: We conducted a retrospective study of 127 patients to assess implications of bortezomib therapy on patients and healthcare resources. A patient-episode was defined as a patient attending the chemotherapy day treatment unit solely for bortezomib administration. Data were collected for the duration of therapy as follows: cost of drug calculated using the UK's bortezomib indicative price as per British National Formulary, cost of drug administration in the chemotherapy day treatment unit calculated using the National Health Service's schedule of service cost, time from check-in to drug administration, patient travel time and distance calculated using Google maps, and cost of travel. Results: Median drug cost and administration cost per patient were £8336 (£2084–£108,368) and £4640 (£290–£15,080), respectively. Median time from check-in to administration was 63 min (range 5–433), median travel time was 90 min (range 8–270) and 80 min (range 8–280) during peak and off-peak periods, respectively. Median return travel distance was 33.4 miles (range 1.2–224) for travel cost per patient per trip was £8.35–£13.20. Conclusions: Our real-world resource analysis demonstrated that delivering bortezomib therapy can be associated with significant cost and time implications for patients and healthcare providers. Our study method sets a basis for evaluating resource implications of other novel approaches to myeloma therapy. [ABSTRACT FROM AUTHOR]

Keywords: myeloma; COVID-19; clinical trials EN myeloma COVID-19 clinical trials e14 e16 3 12/21/20 20210101 NES 210101 COVID-19 - caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - has spread to over 213 countries and territories, with 24,021,218 cases, including 821,462 deaths, reported to WHO by 28 August 2020.1 In the UK alone, there were 328,846 laboratory-confirmed cases and 41,465 COVID-19-associated deaths.2 Self-isolation and physical distancing measures were implemented in most jurisdictions to limit the spread of the virus. PIs may be potentially biased to alter treatment based on local COVID-19 clusters and patients' favourable MM response. Therefore, sensitivity analyses will be performed with and without the inclusion of affected patients to assess the significance of the measures taken on patient outcomes. [Extracted from the article]

Keywords: DPACE; DTPACE; efficacy; myeloma; survival; VRDPACE; VTDPACE EN DPACE DTPACE efficacy myeloma survival VRDPACE VTDPACE 231 233 3 07/24/20 20200801 NES 200801 The use of dexamethasone plus thalidomide in combination with a continuous infusion of cisplatin, doxorubicin, cyclophosphamide and etoposide (DTPACE) was first described in relapsed myeloma (MM) and showed effectiveness as induction therapy before autologous stem cell transplant (ASCT).1 The addition of bortezomib to DTPACE (VTDPACE) led to improved outcomes.2,3 Historical indications for DPACE-based therapies include salvage treatment of aggressive MM, plasma cell leukaemia and initial presentation with extra-medullary disease. Baseline patient, disease and treatment characteristics were collected from the local chemotherapy database and patient records between 2009 and 2017. The majority of patients who received >2 lines of therapy had received a prior ASCT (15/17:88.2%) and only a small group (3/17:17.6%) consolidated DPACE with a further ASCT (2 SP nd sp ASCT in all 3 patients). [Extracted from the article]

Treatment options are limited in myeloma relapsed or refractory to both bortezomib and lenalidomide (double-relapsed/refractory multiple myeloma; DRMM). Bendamustine is an antitumour agent that has efficacy in relapsed myeloma. We retrospectively analysed data from 30 DRMM patients who received a combination of bendamustine, thalidomide and dexamethasone (BTD) in 28-day treatment cycles. Bendamustine was administered with a cumulative dose of up to 200 mg/m. Thalidomide (50-150 mg) was given daily as tolerated, and dexamethasone was given at an equivalent dose of up to 160 mg per cycle. A median of 5 (2-9) treatment cycles were administered per patient. Twenty-six patients (87 %) achieved stable disease or better. At a median follow-up time of 12.1 (2.3-21.5) months, median (95 % CI) progression-free survival and overall survival were 4.0 (2.6-5.3) months and 7.2 (5.2-9.2) months, respectively. The most common grade 3-4 adverse events were haematological: anaemia ( n = 8, 34.8 %), neutropenia ( n = 16, 69.6 %) and thrombocytopenia ( n = 10, 43.5 %). Non-haematological toxicities included pain ( n = 3, 13.0 %), infection ( n = 7, 30.4 %) and sensory neuropathy ( n = 1, 4.3 %). We propose that BTD is a viable salvage treatment option for DRMM patients. [ABSTRACT FROM AUTHOR]