Belantamab mafodotin, pomalidomide and dexamethasone in refractory multiple myeloma: a phase 1/2 trial.

Due to evolving treatment standards for newly diagnosed multiple myeloma, many patients will be triple-class exposed after initial relapses and have poor survival. Novel therapies and combinations are therefore required to improve outcomes. B cell maturation antigen (BCMA)-targeted biologics have emerged as an important new area of therapeutics for relapsed multiple myeloma. The two-part ALGONQUIN trial evaluated various doses and schedules of the anti-BCMA antibody-drug conjugate belantamab mafodotin plus pomalidomide and dexamethasone for patients who are lenalidomide refractory and proteosome inhibitor exposed. The primary endpoints, including evaluating dose-limiting toxicities, establishing the recommended Part 2 dose (RP2D) and overall response rate for patients treated at the RP2D, were met. Secondary efficacy endpoints included progression-free survival and overall survival. Patients treated on study (N = 87) had a median of three previous regimens and 55.2% were triple-class refractory. At the RP2D the most common adverse events were decrease in best-corrected visual acuity (71.1%), keratopathy (65.8%), fatigue (57.9%), infection (47.4%; 7.9% grade ≥3), neutropenia (39.5%) and thrombocytopenia (39.5%). For RP2D patients (n = 38), the overall response rate was 85.3%, ≥very good partial response 75.7% and estimated two-year progression-free survival 52.8% (95% confidence interval, 33.9% to 82.4%), at a median follow-up of 13.9 months. The RP2D schedule was associated with manageable antibody-drug conjugate-associated corneal adverse events and improved tolerability without compromising efficacy. Belantamab mafodotin plus pomalidomide and dexamethasone induced durable responses with promising overall survival in relapsed multiple myeloma, the results of which are yet to be confirmed in the phase 3 DREAMM-8 study. ClinicalTrials.gov Identifier: NCT03715478 .

First Line Treatment of Newly Diagnosed Transplant Ineligible Multiple Myeloma: Recommendations from the Canadian Myeloma Research Group Consensus Guideline Consortium.

Although the availability of effective novel treatments has positively impacted the quality of life and survival of newly diagnosed multiple myeloma (MM) patients, benefits in the transplant ineligible MM population may be limited by functional/frailty status. The Canadian Myeloma Research Group Consensus Guideline Consortium proposes consensus recommendations for the first-line treatment of transplant ineligible MM. To address the needs of physicians and people diagnosed with MM, this document further focuses on eligibility for transplant, frailty assessment, management of adverse events, assessment of treatment response, and monitoring for disease relapse. The Canadian Myeloma Research Group Consensus Guideline Consortium will periodically review the recommendations herein and update as necessary.

Management of Myeloma Manifestations and Complications: The Cornerstone of Supportive Care: Recommendation of the Canadian Myeloma Research Group (formerly Myeloma Canada Research Network) Consensus Guideline Consortium.

Multiple myeloma (MM) is a hematological cancer associated with significant symptomatic burden. Bone disease, renal insufficiency, cytopenias, infection, and peripheral neuropathy, among other disease manifestations and complications, impair patients' quality of life. The Canadian Myeloma Research Group Consensus Guideline Consortium, formerly Myeloma Canada Research Network Consensus Guideline Consortium, proposes national consensus recommendations for the management of MM-related manifestations and complications. To address the needs of Canadian physicians and people living with MM across the country, this document focuses on the improvement and maintenance of patient care by clarifying best-practice approaches for the prevention, detection and management of disease manifestations and complications. The Canadian Myeloma Research Group Consensus Guideline Consortium will periodically review the recommendations herein and update as necessary.

Retrospective study of treatment patterns and outcomes post-lenalidomide for multiple myeloma in Canada.

Lenalidomide is an important component of initial therapy in newly diagnosed multiple myeloma, either as maintenance therapy post-autologous stem cell transplantation (ASCT) or as first-line therapy with dexamethasone for patients' ineligible for ASCT (non-ASCT). This retrospective study investigated treatment patterns and outcomes for ASCT-eligible and -ineligible patients who relapsed after lenalidomide as part of first-line therapy, based on data from the Canadian Myeloma Research Group Database for patients treated between January 2007 and April 2019. Among 256 patients who progressed on lenalidomide maintenance therapy, 28.5% received further immunomodulatory derivative-based (IMiD-based) therapy (lenalidomide/pomalidomide) without a proteasome inhibitor (PI) (bortezomib/carfilzomib/ixazomib), 26.2% received PI-based therapy without an IMiD, 19.5% received both an IMiD plus PI, 13.5% received daratumumab-based regimens, and 12.1% underwent salvage ASCT. Median progression-free survival (PFS) was longest for daratumumab-based therapy (22.7 months) and salvage ASCT (23.4 months) and ranged from 6.6 to 7.3 months for the other treatments (P < .0001). Median overall survival (OS) was also longest for daratumumab and salvage ASCT. A total of 87 non-ASCT patients received subsequent therapy, with 66.7% receiving bortezomib-based therapy and 13.8% receiving other PI-based therapy. Median PFS was 15.4 and 24.8 months for bortezomib-based and other PI-based therapy, respectively (P = .404). During most of the study period, daratumumab was not funded; in this setting, switching to a different therapeutic class following relapse on lenalidomide produced the longest remissions for non-ASCT patients. Further prospective studies are warranted to determine optimum treatment following relapse on lenalidomide, especially in the light of increased access to daratumumab.

Consensus Guidelines on the Diagnosis of Multiple Myeloma and Related Disorders: Recommendations of the Myeloma Canada Research Network Consensus Guideline Consortium.

Multiple myeloma (MM) is a plasma cell (PC) malignancy of terminally differentiated B lymphocytes that is typically associated with the secretion of partial and/or complete monoclonal immunoglobulins and a constellation of particular symptoms and signs. MM is a treatable condition, and timely diagnosis is essential to limit or avoid irreversible target-organ damage and to prolong survival. The Myeloma Canada Research Network Consensus Guideline Consortium (MCRN-CGC) proposes national consensus recommendations for the diagnosis of MM and associated PC neoplasms. The focus is on widely available tests but also highlights recent advancements that are important to include in the diagnostic paradigm. By clarifying and updating the required laboratory, radiographic, and bone marrow investigations, the MCRN-CGC hopes to address the needs of Canadian physicians and people living with MM across the country through accurate and timely diagnosis of MM, as well as appropriate initial stratification to improve treatment selection and outcomes. The MCRN-CGC will periodically review the recommendations herein and update as necessary. Recommendations on the therapeutic approaches and associated monitoring of MM will follow.

Randomized double-blind safety comparison of intravenous iron dextran versus iron sucrose in an adult non-hemodialysis outpatient population: A feasibility study.

BACKGROUND: Intravenous iron therapy is a treatment option for iron deficient patients who are intolerant to oral iron or where oral iron is ineffective, but with possible adverse effects. Currently, prospective studies comparing different intravenous iron formulations are needed to determine safety and efficacy of these agents. METHODS: We conducted a prospective, double-blind, randomized controlled trial (RCT) to assess the feasibility of a trial comparing the safety of high molecular weight intravenous iron dextran, Infufer®, with intravenous iron sucrose, Venofer®, in non-hemodialysis adult outpatients. Primary outcome was the occurrence of immediate severe drug reactions. RESULTS: We enrolled 143 patients in a one-year period. Overall, 45/143 (31.5 %) patients (20 iron dextran, 25 iron sucrose) developed 48 infusion reactions (14 immediate, 28 delayed, and 3 both). The risk of an immediate reaction was similar in both groups, 9/73 (12.3 %) iron dextran versus 8/70 (11.4 %) iron sucrose, RR = 0.93 (95 % CI; 0.38 to 2.27). The risk of a delayed reaction was significantly higher in the iron sucrose group 22/70 (31.4 %) versus the iron dextran group 9/73 (12.3 %), RR = 2.55 (95 % CI; 1.26 to 5.15; p = 0.0078). CONCLUSION: In this limited feasibility study, no major differences in immediate reactions were seen, but a significantly higher number of delayed reactions were seen in the iron sucrose group. Further, under our assumptions and design a full RCT to evaluate the safety of different intravenous iron preparations is not feasible. Future studies should consider modifying the clinical outcomes, utilize multiple centers, and consider other emerging parenteral iron formulations. (ClinicalTrials.gov NCT005936197 January 3, 2008).

Screening of patients with idiopathic venous thromboembolism for paroxysmal nocturnal hemoglobinuria clones.

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon disorder characterized by hemolysis, thrombosis and marrow failure. Whereas venous and arterial thrombosis is a very common symptom of the disease, the frequency of PNH clones in patients with unexplained venous thromboembolism, including deep vein thrombosis and pulmonary embolism, has not been studied. We conducted a cross sectional study evaluating the presence of PNH clones in patients with prevalent venous thromboembolism using a high sensitivity flow cytometry assay for erythrocytes and neutrophils. Among the 388 patients enrolled in the study one patient had a detectable PNH clone of 0.02% in the neutrophil population (0.26%; 95% CI 0.05 to 1.45) and no detectable erythrocyte clone. We conclude that the presence of PNH clones in patients with idiopathic venous thrombosis is rare. Screening for PNH clones among VTE patients might be better reserved for patients with signs of hemolysis.

Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism.

BACKGROUND: Long-term low-molecular-weight heparin (LMWH) is the current standard for treatment of venous thromboembolism (VTE) in cancer patients. Whether treatment strategies should vary according to individual risk of VTE recurrence remains unknown. We performed a retrospective cohort study and a validation study in patients with cancer-associated VTE to derive a clinical prediction rule that stratifies VTE recurrence risk. METHODS AND RESULTS: The cohort study of 543 patients determined the model with the best classification performance included 4 independent predictors (sex, primary tumor site, stage, and prior VTE) with 100% sensitivity, a wide separation of recurrence rates, 98.1% negative predictive value, and a negative likelihood ratio of 0.16. In this model, the score sum ranged between -3 and 3 score points. Patients with a score ≤ 0 had low risk (≤ 4.5%) for recurrence and patients with a score >1 had a high risk (≥ 19%) for VTE recurrence. Subsequently, we applied and validated the rule in an independent set of 819 patients from 2 randomized, controlled trials comparing low-molecular-weight heparin to coumarin treatment in cancer patients. CONCLUSIONS: By identifying VTE recurrence risk in cancer patients with VTE, we may be able to tailor treatment, improving clinical outcomes while minimizing costs.

Psychological impact of thrombophilia testing in asymptomatic family members.

INTRODUCTION: Psychological distress and worry are commonly described as potential consequences of genetic screening for various disorders. Thrombophilia testing may be offered to asymptomatic persons with a family history of venous thrombosis and thrombophilia. Our objectives were to measure the psychological impacts of thrombophilia testing in first degree relatives and to determine if our intervention, a more intensive care strategy to heighten awareness of both risk and symptoms of thrombosis, caused psychological distress. MATERIALS & METHODS: First degree relatives of patients with a known thrombophilia and history of venous thrombosis were tested for thrombophilia. The Perceived Risk Questionnaire and validated psychological instruments (POMS-SF; SCL-90-R Somatization subscale) were administered before testing, one week after receiving results and a year later. Thrombophilia carriers were randomized in family clusters to receive Standard Care or the Intensive Care intervention. RESULTS: There were 100 carriers who were randomized to Standard (n=48) or Intensive Care (n=52) and 103 non-carriers. One week after receiving results, we did not observe any difference in psychological distress between carriers and non-carriers, with low levels overall. At 1 year, psychological distress scores were similar between the Standard and Intensive Care arms and did not differ from baseline. CONCLUSIONS: The results of this pilot study do not support the concern that thrombophilia screening in asymptomatic relatives triggers psychological distress and worry. Furthermore, our intensive educational approach did not appear to induce undue distress. While the positive benefits of thrombophilia screening remain unproven, clinicians should not be deterred from offering screening by the fear of causing psychological harm.

Risk of recurrent venous thromboembolism according to malignancy characteristics in patients with cancer-associated thrombosis: a systematic review of observational and intervention studies.

Patients with cancer-associated venous thromboembolism (VTE) should be treated with low molecular weight heparin. The ideal duration of anticoagulation in this population is unknown. It is important to evaluate whether there is variation in susceptibility for recurrent VTE according to malignancy characteristics. In this systematic review we sought to evaluate cancer characteristics that may influence the risk for VTE recurrence and the success of anticoagulation in patients with cancer-associated VTE. A systematic literature search strategy identified potential studies on MEDLINE, Embase, the Cochrane Register of Controlled Trials, MEDLINE In-Process and other nonindexed citations using the Ovid interface. There was no restriction to study design or language. No randomized controlled trials fulfilled our inclusion criteria. We included four retrospective and six prospective studies. VTE recurrence rate according to tumour stage suggested an increased risk for patients with metastatic malignancy compared with patients with localized disease (relative risk 1.36; 95% confidence interval 1.06-1.74, P = 0.01). We were unable to pool data to evaluate VTE recurrence according to tumour site and histology. The isolated evaluation of the included studies suggested that younger patients with adenocarcinoma, lung or gastrointestinal malignancy have the highest risk. There is paucity of data regarding detailed malignancy characteristics in patients with cancer-associated VTE. It appears that metastatic malignancy, or adenocarcinoma, or lung malignancy confers a higher risk of VTE recurrence than patients with localized malignancy, nonadenocarcinoma or breast cancer.

A pilot study to assess the feasibility of a multicenter cluster randomized trial for the management of asymptomatic persons with a thrombophilia.

There is controversy whether asymptomatic first-degree relatives (FDRs) of patients with venous thromboembolism (VTE) and thrombophilia should be screened, followed, and prescribed prophylaxis during risk periods. We recruited consecutive probands with idiopathic VTE and thrombophilia from our thrombosis clinics. Those FDRs with thrombophilia were randomized in family clusters to receive one-time verbal counseling and no organized follow-up or counseling, educational material, reminder aids and follow-up. Only 203 of 1,129 FDRs were eligible and consented. Dropouts were common; 1 FDR (1.7%) developed VTE. VTE risk, ability to treat and prevent were underestimated by the participants. Patients with VTE and thrombophilia and their FDRs are often not interested in thrombophilia testing. Despite education to inform their knowledge, interest and follow-up were less than ideal. The question of the best educational approach in these patients remains unanswered. The value of testing and following asymptomatic carriers of probands with VTE and thrombophilia remains unknown.

Efficacy of low- molecular- weight- heparin versus vitamin K antagonists for long term treatment of cancer-associated venous thromboembolism in adults: a systematic review of randomized controlled trials.

BACKGROUND: Patients with malignancy have a 4-fold increase in the risk of developing a venous thrombosis and a 3-fold increase in risk of bleeding. Both low-molecular-weight-heparin (LMWH) and vitamin K antagonists (VKA) have been used for treatment of cancer-associated thrombosis. However, the best anticoagulation approach remains a matter of debate. OBJECTIVE: In adult patients with cancer and an acute venous thromboembolic event we sought to determine the rates of recurrent venous thromboembolism (VTE) and major hemorrhage when treated with prolonged LMWH therapy compared to vitamin-K antagonists. PATIENTS/METHODS: A systematic literature search strategy was used to identify potential trials on MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and Medline in-process using an OVID interface. Risk assessment of bias of randomized controlled trials (RCTs) was performed according to the Cochrane Collaboration-Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome measure was symptomatic VTE recurrence rate during the anticoagulation period. Relative risk (RR) was used as the primary measurement with 95% confidence intervals (CIs). Pooled measurements were calculated using random -effects and fixed-effects model. RESULTS: Five articles met our inclusion criteria. All compared LMWH and VKA for secondary prevention of VTE. The pooled RR of VTE recurrence was 0.53 (95% CI: 0.36-0.76; p=0.007). The pooled RR of major bleeding was 0.98 (95% CI: 0.49-1.93, p=0.95). Minor bleeding events and all cause mortality were similar between the 2 intervention arms. CONCLUSIONS: The results of our review suggest that the long term use of LMWH after the acute first week of treatment is superior to VKAs for secondary prevention of venous thromboembolism in adult patients with cancer.