Joshua R. Richter

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.

Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

A Phase I/II Study of Escalating Doses of Bortezomib in Conjunction with High-Dose Melphalan as a Conditioning Regimen for Salvage Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma

Escalating doses of bortezomib with high-dose melphalan was evaluated as as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory multiple myeloma (MM). MM patients with less than a partial remission (PR) (or 50% reduction) compared to their pretransplantation paraprotein parameters after a prior ASCT with melphalan conditioning, or who were in relapse after a prior autologous transplantation, were eligible for study. Bortezomib was dose escalated in steps of 1, 1.3, and 1.6 mg/m2 (3 × 3 design) on days -4 and -1 before transplantation with melphalan 200 mg/m2 given on day -2. Thirty-two patients were enrolled: 12 in the phase I dose escalation phase and an additional 20 in phase II to gain additional experience with the regimen. Twenty-four (75%) patients were Durie Salmon stage III, and 12 (37.5%) had >2 prior lines of therapy. The overall response rate (≥PR) was 44% with 22% complete remission. Two-year overall survival and progression-free survival were 76% and 39%, respectively, with a median follow-up of 31.7 months. The most common grade 3 and 4 nonhematologic adverse events were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious adverse events included intensive care unit admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain-Barre syndrome (3.1%). Two patients (6%) died of sepsis. There was no emergent peripheral neuropathy nor increase in any pre-existing peripheral neuropathy. The addition of bortezomib to melphalan as conditioning for salvage ASCT was well tolerated. More importantly, it can provide durable remission for patients who have a suboptimal response to prior single-agent melphalan conditioning for ASCT, without requiring a reduction in the dose of melphalan. Larger randomized prospective studies to determine the effect of combination conditioning are being conducted.

Carfilzomib as salvage therapy in Waldenstrom macroglobulinemia: a case series

Waldenstrom macroglobulinemia (WM) is an incurable disease with frequent relapse after frontline therapy [1]. With one approved agent (ibrutinib) and no standard of care [1,2], new treatment option...

A phase IIb trial of vorinostat in combination with lenalidomide and dexamethasone in patients with multiple myeloma refractory to previous lenalidomide‐containing regimens

Clinical trials of vorinostat, a Class I/II histone deacetylase inhibitor, in combination with proteasome inhibitors and immunomodulatory agents have shown activity in relapsed/refractory multiple myeloma. This phase IIb, open‐label, single‐institution study evaluated the efficacy of vorinostat in combination with lenalidomide and dexamethasone in lenalidomide‐refractory patients. Patients were considered lenalidomide‐refractory if they had no clinical response (

Atypical IgG4+ Plasmacytic Proliferations and LymphomasCharacterization of 11 Cases

Objectives To report the clinicopathologic features of monotypic immunoglobulin G4+ (IgG4+) lymphoid and plasmacytic proliferations. Methods Cases were identified from the pathology files. Pathology and clinical materials were reviewed. Results Eleven cases of monotypic IgG4+ proliferations were identified at nodal, orbital, or salivary sites. Six cases (three men, three women; age, 57-94 years) met criteria for lymphoma or plasma cell neoplasia. Most contained frequent Mott cells. Five cases (three men, two women; age, 40-80 years) had restricted proliferations of atypical/monotypic IgG4+ plasma cells in a background of reactive lymphoid hyperplasia or inflammation. Conclusions Monotypic IgG4+ proliferations include lymphomas, plasmacytic neoplasms, and a previously uncharacterized group of proliferations not meeting criteria for conventional hematolymphoid neoplasia. Distinct features included prominent Mott cells and/or monotypic plasma cells within follicles. The proliferations were infrequently associated with IgG4-related disease (IgG4-RD). Our findings raise questions regarding the relationship between clonal IgG4+ proliferations, reactive/inflammatory processes, and IgG4-RD.

Subepithelial Corneal Immunoglobulin Deposition as a Manifestation of Multiple Myeloma: A Case Report and Literature Review

Introduction Multiple myeloma (MM) and other paraproteinemias may rarely cause subepithelial crystalline deposition disease in the cornea. These deposits have been shown to be immunoglobulins, usually IgG, although rare cases of other immunoglobulins have been reported. There are limited reports in the literature regarding the treatment and prognosis of patients with subepithelial corneal crystals. We report the diagnosis and treatment of a patient whose presenting manifestation of symptomatic MM was blurry vision with corneal involvement secondary to paraprotein-associated subepithelial corneal crystalline deposits.

Society of Hematologic Oncology State of the Art Update and Next Questions: Multiple Myeloma

&NA; During the past decade, the survival outcomes of patients with multiple myeloma (MM) have dramatically improved, not only owing to the advent of a number of novel therapies, but also to the deepening insight regarding how to best use these options. Triplet‐based induction regimens can yield overall response rates of ≤ 100%. In the relapsed and refractory setting, we have a multitude of doublet and triplet options available with high and durable response rates. The addition of monoclonal antibodies has provided a new class of agents to augment our standard approach with novel therapies. Minimal residual disease status testing has worked its way into the lexicon of the myeloma‐treating physician and provides both prognostic and potentially therapeutic insight into management. Despite the influx of novel therapies, high‐dose melphalan with autologous stem cell rescue remains a vital tenet of induction therapy for our younger and more fit patients. The current generation of clinical trials using immunologic approaches such as bifunctional antibodies and chimeric antigen receptor T cells is extremely promising and will likely become the future standard of care. Although the disease remains, on the whole, incurable, we now possess therapeutic modalities that can provide deep and durable remissions and, potentially, cure for some.

Safety and tolerability of pomalidomide-based regimens (pomalidomide-carfilzomib-dexamethasone with or without cyclophosphamide) in relapsed/refractory multiple myeloma and severe renal dysfunction: a case series

Renal dysfunction negatively impacts outcomes in patients with multiple myeloma (MM). Few treatment options are currently available for patients with MM and comorbid renal dysfunction, and as they are generally excluded from clinical trials, data on the use of immunomodulatory drugs in this population are scarce. In this paper, we describe a case series of five women with MM and severe renal dysfunction or dialysis dependency who were refractory to both bortezomib and either lenalidomide or thalidomide and were treated with full‐dose (4 mg) pomalidomide. As part of their treatment regimen, these patients also received carfilzomib and dexamethasone with or without cyclophosphamide. All five patients achieved at least a partial response to pomalidomide‐based therapy, which was relatively well tolerated. Our findings suggest that pomalidomide may represent a valuable and tolerable treatment option for MM patients with severe renal impairment. The fact that pomalidomide is extensively metabolized prior to urinary excretion may explain the improved tolerability of pomalidomide versus lenalidomide in such patients. Copyright

Vorinostat in Combination With Lenalidomide and Dexamethasone in Lenalidomide-Refractory Multiple Myeloma

BACKGROUND This is a retrospective chart review to evaluate the efficacy of the addition of vorinostat to lenalidomide and dexamethasone in patients with multiple myeloma relapsed/refractory to lenalidomide and dexamethasone. METHODS Charts from 26 consecutive patients able to obtain commercial vorinostat were analyzed for response and safety data. RESULTS The overall response rate was 31%, and the clinical beneficial rate was 50%. The median duration of response was 3 months, and the median overall survival was 28.5 months. The most common grade 3 and 4 toxicities were hematologic and metabolic, including neutropenia (44%), thrombocytopenia (53%), and transaminase elevations (aspartate aminotransferase 9% and alanine aminotransferase 6%). No thromboembolic events or febrile neutropenia were observed. CONCLUSION These observations demonstrate that the addition of vorinostat to patients with lenalidomide- and dexamethasone-refractory multiple myeloma was associated with moderate response and was well-tolerated, warranting further assessment in a larger prospective study.