Process, resource and success factors associated with chimeric antigen receptor T-cell therapy for multiple myeloma.

Background: Chimeric antigen receptor T-cell (CAR-T) therapy represents a new frontier in multiple myeloma. It is important to understand critical success factors (CSFs) that may optimize its use in this therapeutic area. Methods: We estimated the CAR-T process using time-driven activity-based costing. Information was obtained through interviews at four US oncology centers and with payer representatives, and through publicly available data. Results: The CAR-T process comprises 13 steps which take 177 days; it was estimated to include 46 professionals and ten care settings. CSFs included proactive collaboration, streamlined reimbursement and CAR-T administration in alternative settings when possible. Implementing CSFs may reduce episode time and costs by 14.4 and 13.2%, respectively. Conclusion: Our research provides a blueprint for improving efficiencies in CAR-T therapy, thereby increasing its sustainability for multiple myeloma.

Patients with multiple myeloma can now be treated with chimeric antigen receptor T-cell (CAR-T) therapy. We studied how CAR-T therapy is used for multiple myeloma. We also studied things that could help make this therapy easier for doctors to use. The CAR-T process takes 13 steps and 177 days. It begins with the choice to use the therapy and ends about 100 days after it is used. The process uses 46 different healthcare professionals and ten different locations. We found several possible changes that can improve this process. Of these changes, three stand out. First, improved teamwork between members of the care team can help them prepare for and resolve possible problems. Second, reducing insurance red tape will make it easier to provide CAR-T therapy to patients. Third, allowing use of CAR-T therapy in places other than hospitals can help more patients receive this therapy. If applied, these three things may lower the time needed to treat patients by 14.4% and may reduce costs by 13.2%.

A phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed or relapsed/refractory multiple myeloma: Final analysis of second dose-expansion cohort.

The maximum tolerated dose of the panobinostat and carfilzomib combination in patients with relapsed/refractory multiple myeloma (RRMM) was not reached in our previous dose-escalation study. We report additional dose levels in the phase I/II, single-arm, multicenter, standard 3 + 3 dose-escalation expansion-cohort study (NCT01496118). Patients with RRMM were treated with panobinostat 30 mg, carfilzomib 20/56 mg/m2 (N = 3), or panobinostat 20 mg, carfilzomib 20/56 mg/m2 (N = 33). Treatment cycles lasted 28 days; panobinostat: days 1, 3, 5, 15, 17, 19; carfilzomib: days 1, 2, 8, 9, 15, 16. For dose level 6 (DL 6), median age was 63 years (range, 49-91 years), 60.6% were male, 42.4% were high risk. Patients received a median of two prior therapies (range 1-7); proteasome inhibitors (PI; 100%), immunomodulatory imide drugs (IMiD; 78.8%), and stem cell transplant (36.4%); 48.5%, 51.1%, and 24.2% were refractory to prior PI or prior IMiD treatment or both, respectively. Patients completed a median of seven (range 1-40) treatment cycles. Overall response rate (primary endpoint) of evaluable patients in the expansion cohort (N = 32): 84.4%; clinical benefit rate: 90.6%. With a median follow-up of 26.1 months (range, 0-72.5 months), median (95% CI) progression-free survival, time-to-progression and overall survival of patients was 10.3 (6.1, 13.9), 11.7 (5.6, 14.5), and 44.6 (20.8, N/A) months, respectively. Common adverse events (AEs) included thrombocytopenia (78.8%), nausea (63.6%), fatigue (63.6%), diarrhea (51.5%), and vomiting (51.5%). Seven patients had serious treatment-related AEs. There was one treatment-related death. In conclusion, panobinostat plus carfilzomib is an effective steroid-sparing regimen for RRMM.

Pluronic block copolymers enhance the anti-myeloma activity of proteasome inhibitors.

Proteasome inhibitors (PIs) have markedly improved response rates as well as the survival of multiple myeloma (MM) patients over the past decade and have become an important foundation in the treatment of MM patients. Unfortunately, the majority of patients either relapses or becomes refractory to proteasome inhibition. This report describes that both PI sensitive and resistant MM cells display enhanced sensitivity to PI in the presence of synthetic amphiphilic block copolymers, Pluronics (SP1017). SP1017 effectively overcomes both acquired resistance and tumor microenvironment-mediated resistance to PIs. The combination of bortezomib and SP1017 augments accumulation of ubiquitinated proteins, increases markers of proteotoxic and ER stress, and ultimately induces both the intrinsic and extrinsic drug-induced apoptotic pathways in MM cells. Notably, co-treatment of bortezomib and SP1017 intensifies SP1017-induced disorganization of the Golgi complex and significantly reduces secretion of paraproteins. Using a human MM/SCID mice model, the combination of bortezomib and SP1017 exerted enhanced antitumor efficacy as compared to bortezomib alone, delaying disease progression, but without additional toxicity. Collectively, these findings provide proof of concept for the utility of combining PI with SP1017 and present a new approach to enhance the efficacy of current treatment options for MM patients.

A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.

This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3-4·0% in studies in relapsed/refractory MM and 1·2-4·7% in previously untreated MM (2·0-7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3-5·9% grade ≥2; 0·6-4·1% grade ≥3), IHD (1·2-2·9% all grades; 0·4-2·7% grade ≥3) and cardiac death (0-1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.

Phase 1 Study of Tabalumab, a Human Anti-B-Cell Activating Factor Antibody, and Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma.

PURPOSE: Tabalumab, a human mAb that neutralizes B-cell-activating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib. EXPERIMENTAL DESIGN: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter. RESULTS: The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia, and peripheral sensory neuropathy. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than dose-proportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months, and the median response duration (4 patients censored) was 7.2 months. CONCLUSIONS: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation. Clin Cancer Res; 22(23); 5688-95. ©2016 AACR.

Multiple myeloma, version 1.2013.

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of relapsed or progressive disease in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include the addition of new regimens as options for salvage therapy and strategies to mitigate the adverse effects and risks associated with newer regimens for the treatment of multiple myeloma.

Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma, version 2.2013.

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma. These include the addition of regimens containing novel agents as primary and salvage therapy options, inclusion of the updated summary of response categories and criteria from the sixth international workshop on Waldenström's Macroglobulinemia, and a section on management of peripheral neuropathy in the accompanying discussion.

The role of hematopoietic stem cell transplant in follicular lymphoma.

Substantial progress has been made in the clinical management of patients with follicular lymphoma over the past 2 decades. However, the role of autologous and allogeneic stem cell transplantation in these patients remains controversial. Myeloablative chemotherapy or radioimmunotherapy supported by autologous hematopoietic cell transplantation has been shown to lead to a longer progression-free survival and, in some studies, improved survival over standard therapy. However, in the era of rituximab-based therapies used as part of induction or salvage, these historical trials may not be representative. Allogeneic stem cell transplantation offers the advantages of a tumor-free graft and some immunologic graft-versus-lymphoma effects. However, fully myeloablative transplants have high morbidity and mortality rates. Dose-reduced conditioning regimens followed by allogeneic hematopoietic cell transplantation have substantially reduced treatment-related mortality and perhaps will produce better outcomes long-term. This article outlines some historical information regarding stem cell transplantation for follicular lymphoma and discusses recent modifications that may improve outcomes, such as adding radioimmunotherapy to autologous stem cell transplantation or using alternative dose-reduced regimens that could benefit patients with reduced toxicities.