Elizabeth Bilotti

Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib

Ibrutinib is an orally administered inhibitor of Bruton tyrosine kinase that antagonizes B-cell receptor, chemokine, and integrin-mediated signaling. In early-phase studies, ibrutinib demonstrated high response rates and prolonged progression-free survival (PFS) in chronic lymphocytic leukemia (CLL). The durable responses observed with ibrutinib relate in part to a modest toxicity profile that allows the majority of patients to receive continuous therapy for an extended period. We report on median 3-year follow-up of 132 patients with symptomatic treatment-naïve and relapsed/refractory CLL or small lymphocytic lymphoma. Longer treatment with ibrutinib was associated with improvement in response quality over time and durable remissions. Toxicity with longer follow-up diminished with respect to occurrence of grade 3 or greater cytopenias, fatigue, and infections. Progression remains uncommon, occurring primarily in some patients with relapsed del(17)(p13.1) and/or del(11)(q22.3) disease. Treatment-related lymphocytosis remains largely asymptomatic even when persisting >1 year and does not appear to alter longer-term PFS and overall survival compared with patients with partial response or better. Collectively, these data provide evidence that ibrutinib controls CLL disease manifestations and is well tolerated for an extended period; this information can help direct potential treatment options for different subgroups to diminish the long-term risk of relapse.

Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib

This phase 1 dose-escalation study determined the maximum tolerated dose (MTD) of oral pomalidomide (4 dose levels) administered on days 1 to 21 of each 28-day cycle in patients with relapsed and refractory multiple myeloma (RRMM). After four cycles, patients who progressed or had not achieved minimal response (serum and urine M-protein reduction of ≥ 25% and ≥ 50%) could receive dexamethasone 40 mg per week. Safety and efficacy were evaluated. Thirty-eight patients who had received both bortezomib and lenalidomide (median 6 prior therapies) were enrolled; 63% were refractory to both lenalidomide and bortezomib. There were four dose-limiting toxicities (grade 4 neutropenia) at 5 mg per day and so the MTD was 4 mg per day. Rates of peripheral neuropathy and venous thromboembolism were low (≤ 5%). Among the 38 patients enrolled (including 22 with added dexamethasone), 42% achieved minimal response or better, 21% achieved partial response or better, and 3% achieved complete response. Median duration of response, progression-free survival, and overall survival were 4.6, 4.6, and 18.3 months, respectively. Pomalidomide 4 mg per day on days 1 to 21 of each 28-day cycle, with or without dexamethasone (40 mg/week), has encouraging activity with manageable toxicity in RRMM, including those refractory to both lenalidomide and bortezomib. This study is registered at http://www.clinicaltrials.gov as #NCT00833833.

Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial

BACKGROUND In the era of widespread rituximab use for Waldenströms macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenströms macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. METHODS This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenströms macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. FINDINGS Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenström Macroglobulinaemia, median number of previous therapies was four (IQR 2-6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5-18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66-94), and the estimated 18 month overall survival rate was 97% (95% CI 79-100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3-11·7) increased to 11·4 g/dL (10·9-12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8-13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. INTERPRETATION The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenströms macroglobulinaemia. FUNDING Pharmacyclics LLC, an AbbVie Company.

Steroid-associated side effects in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board.

Steroids have been the foundation of multiple myeloma therapy for more than 30 years and continue to be prescribed as single agents and in combination with other antimyeloma drugs, including novel therapies. Steroids cause a wide range of side effects that affect almost every system of the body. Identification and prompt management of the toxicities contribute to the success of steroid-containing antimyeloma regimens. By following patients carefully and educating them and their caregivers, nurses can promote adherence to therapy and improve quality of life. The International Myeloma Foundations Nurse Leadership Board developed this consensus statement for the management of steroid-associated side effects to be used by healthcare providers in any medical setting.

Extended Treatment with Single-Agent Ibrutinib at the 420 mg Dose Leads to Durable Responses in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Purpose: Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase, promotes apoptosis, and inhibits B-cell proliferation, adhesion, and migration. Ibrutinib has demonstrated single-agent efficacy and acceptable tolerability at doses of 420 and 840 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were treatment-naïve (TN) or had relapsed/refractory (R/R) CLL after ≥1 prior therapy in a phase Ib/II study (PCYC-1102). Subsequently, the ibrutinib 420 mg dose was approved in CLL. Experimental Design: We report data with 44 months of follow-up on 94 patients with TN and R/R CLL/SLL receiving ibrutinib 420 mg once-daily in PCYC-1102 and the long-term extension study PCYC-1103. Results: Ninety-four CLL/SLL patients (27 TN, 67 R/R) were treated with ibrutinib (420 mg/day). Patients with R/R disease had received a median of four prior therapies (range, 1–12). Responses were rapid and durable and median duration of response was not reached. Best overall response was 91% [85% TN (complete response, CR 26%) and 94% R/R (9% CR)]. Median progression-free survival (PFS) was not reached in either group. The 30-month PFS rate was 96% and 76% for TN and R/R patients, respectively. Ibrutinib was well tolerated with extended follow-up; rates of grade ≥3 cytopenias and fatigue, as well as discontinuations due to toxicities decreased over time. Conclusions: Single-agent ibrutinib at 420 mg once-daily resulted in durable responses and was well tolerated with up to 44 months follow-up in patients with TN and R/R CLL/SLL. Currently, 66% of patients continue on ibrutinib. Clin Cancer Res; 23(5); 1149–55. ©2017 AACR.

Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma.

Research has shown that proteasome inhibitors (e.g., carfilzomib), immunomodulatory agents (e.g., lenalidomide), histone deacetylase inhibitors (e.g., vorinostat) and corticosteroids (e.g., dexamethasone) have synergistic anti‐multiple myeloma (MM) activity. This phase I dose‐escalation study evaluated a regimen combining carfilzomib, lenalidomide, vorinostat and dexamethasone (QUAD) in patients with relapsed and/or refractory MM. Seventeen patients received carfilzomib (15, 20, or 20/27 mg/m2; 30‐min infusion; days 1, 2, 8, 9, 15, 16), lenalidomide (15 or 25 mg; days 1–21), vorinostat (300 or 400 mg; days 1–7, 15–21), and dexamethasone (40 mg; days 1, 8, 15, 22) in 28‐d cycles. No dose‐limiting toxicities were observed; the maximum tolerated dose was not reached. The maximum administered dose was carfilzomib 20/27 mg/m2, lenalidomide 25 mg, vorinostat 400 mg, and dexamethasone 40 mg. Common grade ≥3 adverse events included neutropenia (53%), thrombocytopenia (53%) and anaemia (41%). The overall response rate was 53%: 12% of patients achieved a very good partial response (PR) and 41% of patients achieved a PR. At a median follow‐up of 10 months, median progression‐free survival was 12 months and median overall survival was not reached. Treatment with QUAD was feasible and had encouraging activity in patients with relapsed and/or refractory MM.

Survivorship care guidelines for patients living with multiple myeloma: consensus statements of the International Myeloma Foundation Nurse Leadership Board.

Novel therapies approved over the past decade for the management of multiple myeloma have contributed to improved overall survival in patients with newly diagnosed and relapsed disease. Nurses play a key role in educating, advocating for, and supporting patients throughout the continuum of care. Identifying potential and actual comorbid conditions associated directly with multiple myeloma and its treatment is important, as is confirming those that are patient specific so that prompt intervention can take place; therefore, the International Myeloma Foundation Nurse Leadership Board identified the most significant needs of patients diagnosed with multiple myeloma as bone health, health maintenance, mobility and safety, sexual dysfunction, and renal health. The Nurse Leadership Board then developed a survivorship care plan to assist healthcare providers and patients with multiple myeloma, their partners, and their caregivers to identify these needs.

Management of Side Effects of Novel Therapies for Multiple Myeloma: Consensus Statements Developed by the International Myeloma Foundation’s Nurse Leadership Board

Nurses play an essential role in managing the care of patients with multiple myeloma, who require education and support to receive and adhere to optimal therapy. The International Myeloma Foundation created a Nurse Leadership Board comprised of oncology nurses from leading cancer centers and community practices. An assessment survey identified the need for specific recommendations for managing key side effects of novel antimyeloma agents. Myelosuppression, thromboembolic events, peripheral neuropathy, steroid toxicities, and gastrointestinal side effects were selected for the first consensus statements. The board developed recommendations for healthcare providers in any medical setting, including grading of side-effect toxicity and strategies for managing the side effects in general, with specific recommendations pertaining to the novel agents.

Serum Free Light Chain Analysis for Diagnosis, Monitoring, and Prognosis of Monoclonal Gammopathies

Measurement of free kappa and free lambda light chains plays a key role in diagnosis, monitoring, and prognosis for many patients with a monoclonal gammopathy. These assays are advocated by the International Myeloma Working Group (IMWG) as an essential component of the primary screening algorithm for suspected monoclonal plasma cell disorders.[18][1] Markedly increased baseline clonal free light chain concentrations are associated with poor prognosis in amyloid light chain (AL) amyloidosis, multiple myeloma, and virtually every plasma cell disorder.[18][1] An abnormal serum free light chain ratio at baseline is predictive of an increased risk of progression in patients with monoclonal gammopathy of undetermined significance.[20][2] Serial monitoring with serum free light chain analysis is recommended by the IMWG for patients with oligosecretory myeloma and AL amyloidosis. Additional data is needed to critically assess the utility of serum free light chain analysis as a serial monitoring technique in patients with multiple myeloma. The significance of isolated serum free light chain ratio abnormalities (“free light chain monoclonal gammopathy of undetermined significance”) also needs to be explored. [1]: #ref-18 [2]: #ref-20

Inaccuracies in 24-Hour Urine Testing for Monoclonal Gammopathies Serum Free Light Chain Analysis Provides a More Accurate Measure of Light Chain Burden Than Urine Protein Electrophoresis

Background Urine testing is important to measure monoclonal proteins and to evaluate renal function in patients with monoclonal gammopathies. Methods Creatinine clearance (CrCl), urine protein electrophoresis (UPEP), 24-h urine protein, and serum free light chain results were analyzed during an 11-mo period. Normal ranges for CrCl were 97–137 mL/min (men) and 88–128 mL/min (women). Results Among 623 urine samples from 207 patients with a monoclonal gammopathy, CrCl was abnormally increased (≥150 mL/min) in 119 samples (19%). For CrCl ≥300 mL/min, the median percent increase in CrCl from prior samples was 61%, and the median percent decrease in subsequent samples was 71%. Unexpected increases in urinary M protein and total protein were observed when CrCl was unexpectedly increased, but clonal serum free light chain results were not unexpectedly increased. Conclusions Results requiring 24-hour urine samples were highly susceptible to error. Serum free light chain analysis was unaffected by these errors.