Noa Biran

Controversies in the Assessment of Minimal Residual Disease in Multiple Myeloma: Clinical Significance of Minimal Residual Disease Negativity Using Highly Sensitive Techniques

Minimal residual disease (MRD) assessment has gained importance in the response evaluation of multiple myeloma. As discussed in part 1 of this two-part series, techniques such as multiparameter flow cytometry, polymerase chain reaction, and next-generation sequencing, of both bone marrow and peripheral blood, have the potential to achieve a high level of sensitivity, up to 1 in 10−6 cells, enabling analysis of genetically diverse subclones. Here, we review the clinical utility of MRD assessment using these techniques. Specifically, we review the association between MRD-negativity and progression-free or overall survival in various clinical settings (post-induction, post-auto or allo-stem cell transplant, transplant ineligible, maintenance, and relapsed/refractory). Currently, the goal of assessing MRD in multiple myeloma (MM) is to allow for a risk-stratified approach to therapy and for earlier identification of response to novel agents, particularly in the setting of clinical trials.

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...

What We Mean When We Talk About MRD in Myeloma. A Review of Current Methods. Part 1 of a Two-Part Series

Assessment of minimal residual disease (MRD) is becoming standard of care for potentially curable cancers, like some leukemias. For diseases not currently curable, like multiple myeloma (MM), the optimal methodology to assess MRD is much less clear, let alone the clinical significance. In this two-part series, we review each of these aspects of MRD in MM. In part 1, we review different methodologies available for MRD assessment, with an emphasis on multiparameter flow cytometry (MFC) and duplex immunohistochemistry. There is currently a strong push in the MM community for the use of MFC, based on studies demonstrating MRD negativity by MFC being associated with delayed time to relapse. After participating in a recent international meeting of leaders in the field, convened to discuss this topic, we review and assess the voiced opinions and published data. While great strides have been made toward the standardization of MFC for MRD, we review not only intrinsic biologic differences between MM and leukemia but also the technical challenges that follow from these differences, including the need for live cells, a difficult to characterize immunophenotype, and significant interlaboratory variability in MFC testing and interpretation.

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 (

Ixazomib: an oral proteasome inhibitor for the treatment of multiple myeloma

Introduction: Over the past decade, the introduction of proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) has dramatically improved the progression-free and overall survival of patients with multiple myeloma (MM). Ixazomib, a second-generation oral reversible 20S PI, is one of the first oral PIs in development for patients with MM. Areas covered: The current literature examining the outcomes of MM patients treated with ixazomib. A literature search using PubMed and abstracts presented at international conferences was conducted to include relevant preclinical and prospective clinical trials using ixazomib in MM. Preclinical studies have demonstrated both independent and synergistic antitumor activity of ixazomib. Phase I and II studies have established safety and efficacy of ixazomib in once and twice weekly dosing in the upfront and relapsed/refractory disease in transplant and non-transplant eligible populations. Commonly seen adverse events include cytopenias, skin toxicities and gastrointestinal effects. Grade 3 peripheral neuropathy was not commonly observed. Phase 3 trials are ongoing, evaluating ixazomib, dexamethasone and lenalidomide for patients with newly diagnosed and relapsed/refractory MM. Expert opinion: It is likely that ixazomib will be a notable addition to the MM therapeutic armamentarium given the convenience of oral dosing, its relative tolerability, and efficacy.

Outcome of patients with multiple myeloma and hypotension during high-dose chemotherapy

1. SEER Cancer Statistics Review 1975-2009. Available at: http://seer.cancer.gov/archives/csr/ 1975_2009_pops09/index.html and http://seer.cancer.gov/faststats. Accessed May 2014. 2. D€ohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an International expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453–474. 3. Ossenkoppele G, L€owenberg B. How I treat the older patient with acute myeloid leukemia. Blood 2015;125:767–774. DOI 10.1182/blood-2014-08-551499 4. Ferrara F, Barosi G, Venditti A, et al. Consensus-based definition of unfitness to intensive and nonintensive chemotherapy in acute myeloid leukemia: A project of SIE, SIES and GITMO group on a new tool for therapy decision making. Leukemia 2013;27:997–999. 5. Wetzler M, Mrozek K, Kohlschmidt J, et al. Intensive induction is effective in selected octogenarian acute myeloid leukemia patients: Prognostic significance of karyotype and selected molecular markers used in the European LeukemiaNet classification. Haematologica 2014;99: 308–313. 6. Estey EH. Acute myeloid leukemia: 2014 update on risk-stratification and management. AJH 2014;89:1064–1081.

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

Abstract 2639: Survival prognosis of MGUS patients by clinical and risk subgroup: a result from a nationally representative prospective cohort

Introduction: Monoclonal gammopathy of unknown significance (MGUS) is a premalignant disorder preceding multiple myeloma that is present in 2.4% of the general population ages 50 years or older. MGUS can be categorized into conventional MGUS that includes IgM MGUS and non-IgM MGUS, and light chain MGUS (defined as those with abnormal free light chain ratio with complete lack of immunoglobulin heavy chain expression on immunofixation). Our objective was to investigate the prognosis of MGUS patients by clinical subgroup and risk stratification suggested by Mayo Clinic. Methods: Data is obtained from National Health and Nutrition Examination Survey (NHANES) III and NHANES 1999-2004, a nationally representative health survey with follow-up mortality data updated in December 2011. Subjects who were diagnosed with MGUS were included in the study. They were divided into three groups; IgM MGUS, non-IgM MGUS, and light chain MGUS (LC-MGUS). Median overall survival of three groups was obtained using log-rank test and age-adjusted hazard ratio for death between the groups was obtained using cox-proportional regression model. Finally, we also analyzed median survival and age adjusted hazard ratio on conventional MGUS subjects by Mayo clinic MGUS risk stratification based on risk factors of M-protein>1.5g/dL, non-IgG MGUS, and abnormal free light chain (FLC) ratio. Analyses were performed in R software version 3.2.2, and a P-value Results: 22,523 subjects in the cohort were screened for MGUS with serum protein electrophoresis, serum protein immunofixation, serum FLC assay, and M-protein typing. There were 483 subjects with MGUS (47 IgM-MGUS, 385 non-IgM MGUS, and 51 LC-MGUS). The median ages of total MGUS subjects, and subgroups were 70, 72.3, 69 and 73 years old, respectively. Median follow-up was 116 months. Median overall survival was 117 months for IgM MGUS, 173 months for non-IgM MGUS, and 109 months for LC-MGUS (p = 0.03). However, the age adjusted hazard ratio (aHR) did not show significant difference between the sub-groups. Likewise, median overall survival of Mayo Clinic MGUS risk group 0, 1, 2 and 3 was 185 months, 163 months, 137 months, and 76.5 months, respectively (p Conclusion: There was no statistically significant mortality difference between MGUS subgroup. Only high-risk group defined by the Mayo Clinic MGUS risk stratification showed inferior survival and higher risk of death compared to rest of MGUS subjects. Further prospective studies are needed to validate our findings and to investigate whether early interventions for MGUS patients by clinical subgroup and risk stratification are needed rather than the current standard management of watchful-waiting. Citation Format: Hyun-Seok Kim, Jieqi Liu, Brittany L. Gladney, Neil Kothari, Noa Biran, Victor Chang, David S. Siegel. Survival prognosis of MGUS patients by clinical and risk subgroup: a result from a nationally representative prospective cohort. [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 2639.