Vishala Neppalli

Multiple Myeloma, version 3.2018: Featured updates to the NCCN guidelines

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, evaluation, treatment, including supportive-care, and follow-up for patients with myeloma. These NCCN Guidelines Insights highlight the important updates/changes specific to the myeloma therapy options in the 2018 version of the NCCN Guidelines.

Anaplastic Multiple Myeloma: An Aggressive Variant With a Poor Response to Novel Therapies

Introduction Anaplastic multiple myeloma (AMM) is a very rare and aggressive morphologic variant of multiple myeloma with a historically poor prognosis. The term “anaplastic myeloma” is used to describe a plasma cell malignancy involving immature plasma cells of pleomorphic morphology with high-grade transformation and extramedullary involvement with large, poorly differentiated cells. Anaplastic morphology can be present at the initial diagnosis or can appear later in the disease course. Historically, this disease has been very resistant to chemotherapy. We have described 2 cases of anaplastic myeloma and the poor response to novel myeloma therapies.

Synchronous presentation of monoclonal gammopathy and Fabry nephropathy; diagnostic renal biopsy obviates initiation of myeloma therapy

Dear Editor, Adult patients with new onset renal insufficiency are frequently screened for plasma cell dyscrasias which may cause light chain or amyloid nephropathy. Patients with monoclonal gammopathy may have kidney disease unrelated to the monoclonal protein (M-protein). We report the case of a patient with renal insufficiency and immunoglobulin G (IgG) kappa monoclonal gammopathy, who was found to have Fabry’s disease (FD) on kidney biopsy. A 60-year-old female presented with new onset asymptomatic decrease in renal function (estimated glomerular filtration rate of 31 mL/min). Further workup showed an IgG kappa Mprotein of 0.63 g/dL, serum free light chain ratio of 70, and proteinuria (387 mg/24 h). Bone marrow biopsy showed 10% plasma cells without evidence of amyloid deposition. Cytogenetics/FISH was normal. Skeletal survey and positron emission tomography scan were unremarkable. She was referred to our institute for a second opinion regarding the initiation of myeloma treatment. We recommended that she undergo a kidney biopsy to confirm that her nephropathy was a consequence of the M-protein. Renal biopsy revealed interstitial scarring, global sclerosis, and occasional epithelial cells with bubbly cytoplasm on light microscopy, suggestive of a lysosomal storage disorder. Electron microscopy revealed numerous Bzebra^ bodies in the glomerular epithelial cells (Fig. 1). She had decreased alphagalactosidase A (α-Gal A) enzyme levels in plasma (4.2 nmol/ h/mL; normal range 6.2 to 18.6), and genetic testing disclosed a missense mutation, R301G, in one of the α-Gal A alleles. These features were consistent with heterozygous FD causing nephropathy and concomitant monoclonal gammopathy of undetermined significance (MGUS). She was started on enzyme replacement therapy (ERT) using agalsidase beta. She has now received ERT over 1.5 years, and her renal function, proteinuria, and M-protein levels remain stable. Bone marrow biopsy performed 10 months after the start of ERT revealed a stable plasma cell percentage. This case underscores the importance of pursuing a kidney biopsy prior to initiation of myeloma treatment in a patient with M-protein and renal insufficiency. FD is an X-linked recessive disorder of glycosphingolipid catabolism caused by deficiency of lysosomal enzyme α-Gal A. Kidney involvement is a prominent feature of FD [1] and may be found in up to 40 % of adult heterozygotes [2, 3]. Accumulation of neutral glycosphingolipids produces laminated inclusion bodies in the cytoplasm of glomerular cells V. K. Pokuri (*) : S. A. Holstein : P. L. McCarthy (*) Department of Clinical Hematology-Oncology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA e-mail: venkata.pokuri@roswellpark.org e-mail: Philip.McCarthy@RoswellPark.org

All-trans-retinoic-acid and arsenic trioxide induced remission in promyelocytic blast crisis

A 78-year-old-male with chronic myeloid leukemia (CML) treated for seven years with dasatinib developed an acute promyelocytic leukemia complicated by disseminated intravascular coagulopathy. A promyelocytic blast crisis was diagnosed by demonstrating co-expression of chimeric BCL/ABL and PML/RARα translocations by karyotyping, fluorescence in situ hybridization, and quantitative real-time polymerase chain reaction. Promyelocytic blast crisis of CML is a rare event with historically poor outcomes. Treatment of our patient with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) resulted in complete morphologic remission. We review here the relevant literature of promyelocytic blast crisis and highlight the potential of ATRA/ATO as first line management.

A Phase II Trial of Rituximab Combined With Pegfilgrastim in Patients With Indolent B-cell Non-Hodgkin Lymphoma

Background To explore the role of augmenting neutrophil function in B‐cell lymphoma, we conducted a phase II study evaluating the safety and clinical efficacy of pegfilgrastim and rituximab in low‐grade CD20+ B‐cell non‐Hodgkin lymphoma (B‐NHL). Patients and Methods Twenty patients with indolent B‐NHL were treated with rituximab (375 mg/m2) every other week for 4 doses, followed by every 2 months for 4 additional doses. Pegfilgrastim was administered subcutaneously 3 days before each dose of rituximab. Clinical activity and tolerability were assessed using standard criteria. Biologic monitoring included phenotype characteristics of the host neutrophils, changes in oxidative burst, and functional assays. Results The patient demographics included median age of 64 years, 70% were male, 70% had follicular lymphoma, and 90% had stage III‐IV disease. The median number of previous therapies was 2 (range, 0‐5); 90% had received previous anti‐CD20 monoclonal antibody therapy. The addition of pegfilgrastim to rituximab did not increase rituximab‐related toxicities. The overall response rate was 60% (12 of 20), with a complete response (CR) rate of 35% (7 of 20). The median progression‐free survival (PFS) duration was 17.9 months (95% confidence interval, 9.9‐27.6 months); the median overall survival was not reached. A shorter time‐to‐peak oxidative burst after the first dose of pegfilgrastim was associated with greater CR rates (P = .04) and longer PFS (P = .03). Conclusion The pegfilgrastim‐rituximab combination was well tolerated, with favorable outcomes compared with historical controls. A shorter time‐to‐peak oxidative burst was associated with higher CR rates and longer PFS. Our results support further evaluation of strategies that enhance the innate immune system to improve rituximab activity in B‐NHL. Micro‐Abstract The present phase II study has demonstrated that augmenting neutrophil function by the addition of pegfilgrastim can potentiate the clinical activity of rituximab in indolent B‐cell non‐Hodgkin lymphoma while retaining the excellent safety profile. Strategies to boost the innate immune system such as this combination warrant further study, especially in the frail, elderly population for whom therapeutic options are limited owing to poor tolerance.

Reduced intensity conditioning with fludarabine, melphalan, and total body irradiation for allogeneic hematopoietic cell transplantation: the effect of increasing melphalan dose on underlying disease and toxicity

Disease relapse and toxicity are the shortcomings of reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (alloHCT). We hypothesized that adding total body irradiation (TBI) to and decreasing melphalan (Mel) from a base RIC regimen of fludarabine (Flu) and Mel would increase cytoreduction and improve disease control while decreasing toxicity. We performed a phase II trial of Flu 160 mg/m2, Mel 50 mg/m2, and TBI 400 cGy (FluMelTBI-50, n = 61), followed by a second phase II trial of Flu 160 mg/m2, Mel 75 mg/m2, and TBI 400cGy (FluMelTBI-75, n = 94) as RIC for alloHCT. Outcomes were compared with a contemporaneous cohort of 162 patients who received Flu 125 mg/m2 and Mel 140 mg/m2. Eligibility criteria were equivalent for all 3 regimens. All patients were ineligible for myeloablative/intensive conditioning. The median (range) follow-up for all patients was 51 (15 to 103) months. Day 100 donor lymphoid chimerism and transplant-related mortality, neutrophil and platelet engraftment, acute and chronic graft versus host disease incidence, overall survival (OS), and progression-free survival (PFS) were equivalent between FluMel, FluMelTBI-50, and FluMelTBI-75. Stomatitis wasdecreased for FluMelTBI versus FluMel (P < .01). PFS for patients not in complete remission on alloHCT was improved for FluMelTBI-75 versus FluMel (P = .03). On multivariate analysis, OS (P = .05) and PFS (P = .05) were significantly improved for FluMelTBI-75 versus FluMel. FluMelTBI-75 is better tolerated than FluMel, with improved survival and disease control.

Abstract 3038: Investigating novel targeted therapies for double hit diffuse large B-cell lymphoma (DH-DLBCL)

Background: Molecular studies divide DLBCL into three subtypes with distinct pathogenesis and clinical outcomes: activated B-cell (ABC), germinal center B-cell (GCB) and primary mediastinal lymphoma (PML). Florescence in situ hybridization (FISH) studies identified another subgroup of DLBCL, classified as DH-DLBCL, with a poor clinical outcome harboring concurrent gene rearrangements of the c-MYC, BCL2 and/or BCL6 proto-oncogenes, resulting in the over-expression of c-Myc, Bcl2 and Bcl6 proteins. Previously, our retrospective review from single institution series revealed that 30 out of 611 DLBCL patients had aberrations in c-MYC and BCL2 or BCL6 by FISH. These patients exhibited inferior response rates (RR) to rituximab-based chemotherapy, and a shorter progression-free survival (PFS)/overall survival (OS), suggesting that newer therapies are in dire need. DH-DLBCL is characterized by de-regulation of apoptosis and cell cycle progression, resulting in rapid cellular proliferation and resistance to apoptotic stimuli. In ABC-DLBCL, anti-apoptotic factor MCL-1 is implicated in poor prognosis leading to resistance to standard chemotherapy. C-MYC transcriptionally upregulates Mcl1. Translocation of c-MYC in DH-DLBCL may contribute to the aggressive phenotype and chemotherapy resistance via the MCL-1 pathway. We hypothesize that dual inhibition of both anti-apoptotic proteins BCL2 and MCL1 is an effective strategy in inducing lymphoma cell death in DH-DLBCL. Materials & Methods: At the pre-clinical level, we studied 3 novel therapeutic agents targeting BCL2 (ABT-199), c-MYC (JQ-1), and various cell cycle regulatory proteins (p21) and other BCL2 family members affecting ABT-199 activity (irreversible proteasome inhibitor carfilzomib(CFZ)) using DH lymphoma (DHL) cell lines (Val, DOHH-2, ROS-50). DHL cell lines were exposed to ABT-199 (0-10 uM), JQ-1 (0-100 uM) and carfilzomib (CFZ) (0-50 nM) at 24, 48 and 72 hours. Changes in cell viability were evaluated using Presto Blue assay. Subsequently, DHL cells were exposed to doublet combinations of ABT-199, JQ-1 and CFZ for 48 hours. Coefficient of synergy was calculated using CalcuSyn. Results: In vitro, ABT199, JQ-1, and CFZ induced cell death in a dose- and time-dependent manner. Significant synergistic activity was observed by combining ABT199 with CFZ and to a lesser degree with JQ-1. Conclusion: ABT199 exhibited strong synergistic activity with CFZ. Dual targeting of BCL2 and c-MYC pathways results in synergistic activity in DHL cell lines. Of interest, this pharmacological interaction could be related to the effects of proteasome inhibition on MCL1 and p21 levels in lymphoma cells, further enhancing the activity of ABT199. Using combination therapy to inhibit c-MYC and the proteasome and in turn decreasing MCL1 will render ABT-199 more effective and be a more potent combination in causing apoptosis and lymphoma cell death. Further pre-clinical work is ongoing. Citation Format: Priyank P. Patel, Alison Zeccola, Juan Gu, Cory Mavis, Sheila N. J. Sait, Vishala Neppalli, Francisco J. Hernandez-Ilizaliturri. Investigating novel targeted therapies for double hit diffuse large B-cell lymphoma (DH-DLBCL). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3038.

Case study interpretation

The Case Study Interpretation (CSI) cases presented at the 2014 International Clinical Cytometry Society (ICCS) meeting in Seattle illustrate the utility of state‐of‐the art multiparameter flow cytometry in the diagnosis of hematolymphoid neoplasms. Download the listmode files (Supporting Information) and test your analysis skills before reading the case reports, keeping in mind the following questions. How many separate abnormal mature B‐cell populations can you identify, and how many of these represent different subtypes of B‐cell neoplasm? How many separate abnormal mature T‐cell populations can you identify, and do these represent different subtypes of T‐cell neoplasm or phenotypic heterogeneity in one neoplasm? How many separate immature/blastic cell populations can you identify, and do they meet criteria for mixed phenotype leukemia? Is there a population of blasts that lacks T‐cell, B‐cell, and myeloid lineage defining antigens and if so, what entities should you consider and what additional antigens should you assess for?

Case study interpretation: Report from the ICCS Annual Meeting, Seattle, 2014: CASE STUDY INTERPRETATION

The Case Study Interpretation (CSI) cases presented at the 2014 International Clinical Cytometry Society (ICCS) meeting in Seattle illustrate the utility of state‐of‐the art multiparameter flow cytometry in the diagnosis of hematolymphoid neoplasms. Download the listmode files (Supporting Information) and test your analysis skills before reading the case reports, keeping in mind the following questions. How many separate abnormal mature B‐cell populations can you identify, and how many of these represent different subtypes of B‐cell neoplasm? How many separate abnormal mature T‐cell populations can you identify, and do these represent different subtypes of T‐cell neoplasm or phenotypic heterogeneity in one neoplasm? How many separate immature/blastic cell populations can you identify, and do they meet criteria for mixed phenotype leukemia? Is there a population of blasts that lacks T‐cell, B‐cell, and myeloid lineage defining antigens and if so, what entities should you consider and what additional antigens should you assess for?

Remarkable Response to Methylprednisolone in a Multiple Myeloma Patient with Nodal Disease Refractory to High-Dose Chemotherapy.

Multiple myeloma is a disorder of malignant plasma cells, which is characterized by paraprotein production, lytic bone lesions, hypercalcemia, susceptibility to infections, and renal impairment. Here, we describe a patient with IgA myeloma with extensive nodal involvement who obtained significant benefit from high-dose methylprednisolone after failing aggressive induction chemotherapy and high-dose melphalan with autologous stem cell support.