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ispartof: HEMASPHERE vol:6 issue:12 ispartof: location:United States status: published

In de gerandomiseerde fase III- CASSIOPEIA-studie werd het effect van het toevoegen van daratumumab aan de standaardbehandeling met bortezomib, thalidomide en dexamethason onderzocht bij 1.074 patiënten met nieuw gediagnosticeerd multipel myeloom (MM). De patiënten ontvingen zes cycli (vier inductiecycli, twee consolidatiecycli) van 28 dagen, bestaande uit subcutaan (SC) bortezomib (1,3 mg/m2 dagen 1, 4, 8, 11), oraal thalidomide (100 mg per dag), dexamethason (20–40 mg) (VTD) en, afhankelijk van de onderzoeksgroep, daratumumab intraveneus (IV). Deze studie is geregistreerd onder EudraCT-nummer NCT02541383. Met resultaten in het voordeel van dara-VTD werd dit regime vervolgens goedgekeurd door EMA voor gebruik bij nieuw gediagnosticeerd MM en zal in de nabije toekomst in Nederland als standaardbehandeling worden geïmplementeerd. Polyneuropathie (PNP) is een veel voorkomende bijwerking tijdens de behandeling van MM. De incidentie van PNP-graad 2–4 (CTCAE-gradering) werd in de CASSIOPEIA-studie geanalyseerd. In totaal ontwikkelden 394/1.074 (37%) patiënten graad 2-PNP en 105/1.074 (10%) graad 3. Significante risicofactoren geassocieerd met PNP-graad 2 waren graad 1-neuropathie in de voorgeschiedenis en overgewicht (BMI >25). In deze studie is de hoge incidentie van PNP-graad 2–4 gedurende MM-behandeling bevestigd. Hiermee wordt de noodzaak van screening op risicofactoren, frequente beoordeling van PNP en strikte naleving van de richtlijnen benadrukt om de incidentie van ernstige PNP te verminderen.

8033 Background: As multiple myeloma (MM) negatively affects patients’ (pts) health-related quality of life (HRQoL), assessment of patient-reported outcomes (PROs) in addition to clinical outcomes is important. Teclistamab (tec; JNJ-64007957) is an off-the-shelf bispecific antibody that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing MM cells. Initial results from the pivotal cohort of the phase 1/2 MajesTEC-1 study demonstrated that tec was well tolerated with encouraging efficacy in pts who received ≥3 prior lines of treatment (LOT; including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody). Here we report PROs from this cohort. Methods: Pts (aged ≥18 years) had documented RRMM (International Myeloma Working Group criteria), progressive/measurable disease, and had previously received ≥3 prior LOT; prior anti-BCMA treatment (tx) was not allowed. Pts received weekly subcutaneous tec at the recommended phase 2 dose (1.5 mg/kg with step-up doses of 0.06 and 0.3 mg/kg). PROs were assessed at screening and every even cycle (cycles 2–8 reported here) using the EORTC QLQ-C30 (range: 0–100; higher scores indicate better global health status [GHS] but greater symptom severity [symptom scales]) and the EuroQol 5-dimensional descriptive system (visual analog scale [VAS] range: 0 [worst imaginable health state] to 100 [best imaginable]). Tx effect was assessed by a mixed-effects model with repeated measures; the proportion of pts with meaningful improvement was defined as a change ≥10 points. Time to worsening was determined using the Kaplan-Meier estimate. Results: A total of 110 pts were included (median follow-up: 7.8 mos). Overall PRO compliance rates were high (baseline [BL]: 85–90%; cycles 2–8: 80–94%). Tec improved overall HRQoL as evidenced by improvements in GHS scores (cycles 2–8) and reduction in pain (-4.2 [cycle 2] to -15.1 [cycle 8]; Table), with no overall change in physical functioning and fatigue. The proportions of pts with meaningful improvements from BL at cycle 8 were GHS: 50%; physical functioning: 35%; pain: 65%; fatigue: 73%; 50% of pts reported meaningful improvement in their overall health (VAS). Median time to improvement from baseline was ̃1.5 months (with nausea/vomiting and fatigue taking longer to improve), while median time to worsening (all symptoms) ranged from 2 months to not estimable. Conclusions: Consistent with clinical outcomes, pts treated with tec reported rapid, clinically meaningful improvements in HRQoL. Clinical trial information: NCT04557098. [Table: see text]

Additional file 1 Table 1. Patients with improvement, no change, or decline in HRQoL based on minimal clinically important differences defined by ≥ 10% of the instrument range. Table 1 describes the number and proportion of patients with improvement, no change, or decline in HRQoL based on the minimal clinically important difference threshold defined as ≥10% of the instrument range. Data are shown for the FACT-MM, FACT-G, FACT-MM TOI, and the MM domain at treatment cycle 2–6 and end of treatment.

Additional file 2. Provides a list of IECs and IRBs for the STORM trial.

Background: Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM. Methods: FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders. Results: Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores. Conclusion: The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach.

Patients with multiple myeloma frequently present with substantial immune impairment and an increased risk for infections and infection-related mortality. The risk for infection with SARS-CoV-2 virus and resulting mortality is also increased, emphasising the importance of protecting patients by vaccination. Available data in patients with multiple myeloma suggest a suboptimal anti-SARS-CoV-2 immune response, meaning a proportion of patients are unprotected. Factors associated with poor response are uncontrolled disease, immunosuppression, concomitant therapy, more lines of therapy, and CD38 antibody-directed and B-cell maturation antigen-directed therapy. These facts suggest that monitoring the immune response to vaccination in patients with multiple myeloma might provide guidance for clinical management, such as administration of additional doses of the same or another vaccine, or even temporary treatment discontinuation, if possible. In those who do not exhibit a good response, prophylactic treatment with neutralising monoclonal antibody cocktails might be considered. In patients deficient of a SARS-CoV-2 immune response, adherence to measures for infection risk reduction is particularly recommended. This consensus was generated by members of the European Multiple Myeloma Network and some external experts. The panel members convened in virtual meetings and conducted an extensive literature research and evaluated recently published data and work presented at meetings, as well as findings from their own studies. The outcome of the discussions on establishing consensus recommendations for COVID-19 This study has been funded by the Austrian Forum against Cancer, which covered in part expenses for interaction between authors and for secretarial support.

Patients with multiple myeloma frequently present with substantial immune impairment and an increased risk for infections and infection-related mortality. The risk for infection with SARS-CoV-2 virus and resulting mortality is also increased, emphasising the importance of protecting patients by vaccination. Available data in patients with multiple myeloma suggest a suboptimal anti-SARS-CoV-2 immune response, meaning a proportion of patients are unprotected. Factors associated with poor response are uncontrolled disease, immunosuppression, concomitant therapy, more lines of therapy, and CD38 antibody-directed and B-cell maturation antigen-directed therapy. These facts suggest that monitoring the immune response to vaccination in patients with multiple myeloma might provide guidance for clinical management, such as administration of additional doses of the same or another vaccine, or even temporary treatment discontinuation, if possible. In those who do not exhibit a good response, prophylactic treatment with neutralising monoclonal antibody cocktails might be considered. In patients deficient of a SARS-CoV-2 immune response, adherence to measures for infection risk reduction is particularly recommended. This consensus was generated by members of the European Multiple Myeloma Network and some external experts. The panel members convened in virtual meetings and conducted an extensive literature research and evaluated recently published data and work presented at meetings, as well as findings from their own studies. The outcome of the discussions on establishing consensus recommendations for COVID-19 vaccination in patients with multiple myeloma was condensed into this Review.

Leukemia accepted article preview online, 20 November 2017. doi:10.1038/leu.2017.335. ispartof: Leukemia issue:1 pages:1-7 ispartof: location:England status: published

Pomalidomide is a distinct oral IMiD immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30. ispartof: Haematologica vol:100 issue:10 pages:1334-9 ispartof: location:Italy status: published

BACKGROUND: The combination melphalan-prednisone-thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches. METHODS: We randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide-dexamethasone versus MPT. RESULTS: The median progression-free survival was 25.5 months with continuous lenalidomide-dexamethasone, 20.7 months with 18 cycles of lenalidomide-dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide-dexamethasone vs. MPT and 0.70 for continuous lenalidomide-dexamethasone vs. 18 cycles of lenalidomide-dexamethasone; P

Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of “heavy chain MGUS” have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma.

ispartof: HEMASPHERE vol:2 pages:117-117 status: published

In a prospective multicenter phase II study, we evaluated the effect of three courses of vincristine, doxorubicin and dexamethasone followed by High-dose melphalan and autologous stem cell transplantation on an intention to treat basis. Sixty-nine newly diagnosed patients with AL amyloidosis were included between November 2000 and January 2006: 37 men and 32 women with a median age of 56 years, including 46% of patients with cardiac and 22% of patients with involvement of 3 or 4 organs. Initial results presented in 2008 (New England Journal of Medicine 358;1) showed a 4-year overall survival rate of 62 % among all the patients, while the 4-year survival rate after transplantation was 78%. Here we report the long term follow up data after median follow-up of 115 months of the patients still alive. Median survival of all patients was 96 months from registration and for the transplanted patients 10 years from the date of transplantation. Twelve (12%) of patients died during induction therapy with vincristine, doxorubicin and dexamethasone including 8 patients (12%) due to treatment related mortality. Two patients died within 1 month following High-dose melphalan. We conclude that vincristine, doxorubicin and dexamethasone should not be applied as induction therapy for intensification in AL amyloidosis. However a 2-step approach consisting of a non-intensive less toxic induction therapy followed by High-dose melphalan and autologous stem cell transplantation may result in extended survival in newly diagnosed patients with AL amyloidosis. (ISRCTN01207094). ispartof: Haematologica vol:100 issue:5 pages:677-82 ispartof: location:Italy status: published

The treatment of multiple myeloma has undergone significant changes and has resulted in the achievement of molecular remissions, the prolongation of remission duration, and extended survival becoming realistic goals, with a cure being possible in a small but growing number of patients. In addition, nowadays it is possible to categorize patients more precisely into different risk groups, thus allowing the evaluation of therapies in different settings and enabling a better comparison of results across trials. Here, we review the evidence from clinical studies, which forms the basis for our recommendations for the management of patients with myeloma. Treatment approaches depend on “fitness,” with chronological age still being an important discriminator for selecting therapy. In younger, fit patients, a short three drug-based induction treatment followed by autologous stem cell transplantation (ASCT) remains the preferred option. Consolidation and maintenance therapy are attractive strategies not yet approved by the European Medicines Agency, and a decision regarding post-ASCT therapy should only be made after detailed discussion of the pros and cons with the individual patient. Two-and three-drug combinations are recommended for patients not eligible for transplantation. Treatment should be administered for at least nine cycles, although different durations of initial therapy have only rarely been compared so far. Comorbidity and frailty should be thoroughly assessed in elderly patients, and treatment must be adapted to individual needs, carefully selecting appropriate drugs and doses. A substantial number of new drugs and novel drug classes in early clinical development have shown promising activity. Their introduction into clinical practice will most likely further improve treatment results. The Oncologist 2014; 19: 829-844

The MM-015 trial assessed the effect of lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance; or lenalidomide, melphalan, and prednisone, or melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life (P