Irwindeep Sandhu

Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

BACKGROUND Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. METHODS In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival. RESULTS Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. CONCLUSIONS The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).

Addressing heterogeneity of individual blood cancers: the need for single cell analysis

Cancer heterogeneity is a significant factor in response to treatment and escape leading to relapse. Within an individual cancer, especially blood cancers, there exists multiple subclones as well as distinct clonal expansions unrelated to the clinically detected, dominant clone. Over time, multiple subclones and clones undergo emergence, expansion, and extinction. Although sometimes this intra-clonal and inter-clonal heterogeneity can be detected and/or quantified in tests that measure aggregate populations of cells, frequently, such heterogeneity can only be detected using single cell analysis to determine its frequency and to detect minor clones that may subsequently emerge to become drug resistant and dominant. Most genetic/genomic tests look at the pooled tumor population as a whole rather than at its individual cellular components. Yet, minor clones and cancer stem cells are unlikely to be detected against the background of expanded major clones. Because selective pressures are likely to govern much of what is seen clinically, single cell analysis allows identification of otherwise cryptic compartments of the malignancy that may ultimately mediate progression and relapse. Single cell analysis can track intra- or inter-clonal heterogeneity and provide useful clinical information, often before changes in the disease are detectable in the clinic. To a very limited extent, single cell analysis has already found roles in clinical care. Because inter- and intra-clonal heterogeneity likely occurs more frequently than can be currently appreciated on a clinical level, future use of single cell analysis is likely to have profound clinical utility.

Impact of prior therapy on the efficacy and safety of oral ixazomib-lenalidomide-dexamethasone vs. placebo-lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in TOURMALINE-MM1

Prior treatment exposure in patients with relapsed/refractory multiple myeloma may affect outcomes with subsequent therapies. We analyzed efficacy and safety according to prior treatment in the phase 3 TOURMALINE-MM1 study of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd. Patients with relapsed/refractory multiple myeloma received ixazomib-Rd or placebo-Rd. Efficacy and safety were evaluated in subgroups defined according to type (proteasome inhibitor [PI] and immunomodulatory drug) and number (1 vs. 2 or 3) of prior therapies received. Of 722 patients, 503 (70%) had received a prior PI, and 397 (55%) prior lenalidomide/thalidomide; 425 patients had received 1 prior therapy, and 297 received 2 or 3 prior therapies. At a median follow up of ~15 months, PFS was prolonged with ixazomib-Rd vs. placebo-Rd regardless of type of prior therapy received; HR 0.739 and 0.749 in PI-exposed and –naïve patients, HR 0.744 and 0.700 in immunomodulatory-drug-exposed and -naïve patients, respectively. PFS benefit with ixazomib-Rd vs. placebo-Rd appeared greater in patients with 2 or 3 prior therapies (HR 0.58) and in those with 1 prior therapy without prior transplant (HR 0.60) versus those with 1 prior therapy and transplant (HR 1.23). Across all subgroups, toxicity was consistent with that seen in the intent-to-treat population. In patients with relapsed/refractory multiple myeloma, ixazomib-Rd was associated with a consistent clinical benefit vs. placebo-Rd regardless of prior treatment with bortezomib or immunomodulatory drugs. Patients with 2 or 3 prior therapies, or 1 prior therapy without transplant seemed to have greater benefit than patients with 1 prior therapy and transplant. TOURMALINE-MM1 registered at clinicaltrials.gov identifier: 01564537.

A phase II study of AT9283, an aurora kinase inhibitor, in patients with relapsed or refractory multiple myeloma: NCIC clinical trials group IND.191

Annette E. Hay, Alli Murugesan, Ashley M. DiPasquale, Tom Kouroukis, Irwindeep Sandhu, Vishal Kukreti, Nizar J. Bahlis, Johan Lategan, Donna E. Reece, John F. Lyons, Joana Sederias, Hao Xu, Jean Powers, Lesley K. Seymour & Tony Reiman NCIC Clinical Trials Group, Queen’s University, Kingston, ON, Canada, Department of Biology, University of New Brunswick, Saint John, NB, Canada, Department of Medicine, Dalhousie University, Saint John, NB, Canada, Juravinski Cancer Centre, Hamilton, ON, Canada, Department of Medicine, Division of Hematology, University of Alberta, Edmonton, AB, Canada, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada, Division of Hematology and Hematologic Malignancies, University of Calgary, Calgary, AB, Canada, Astex Pharmaceuticals, Inc., Dublin, CA, USA, and Department of Oncology, Saint John Regional Hospital and Department of Medicine, Dalhousie University, Saint John, NB, Canada

Cardio-oncology interventions in outpatients referred for autologous bone marrow transplantation.

137 Background: Cancer patients (PTS) referred for autologous bone marrow transplantation (autoBMT) are frequently pre-treated with established cardiotoxins and as a result may not have adequate cardiac function to meet eligibility criteria for autoBMT. Furthermore, mobilizing and consolidation chemotherapy result in additional serial exposures with acute and long-term negative cardiac sequelae. Accordingly, these PTS represent a population with a major unmet need for appropriate cardiovascular screening and interventions. AIM to evaluate the need and effectiveness of prospective multidisciplinary cardio-oncology assessment and intervention in an unselected outpatient population referred for autoBMT. METHODS From January 1, 2013 - December 31, 2013, PTS referred for autoBMT were systematically screened for comorbid conditions, cardiovascular risk factors and eligibility for transplant. Physical exam, laboratory (ECG, complete profile) and transthoracic echocardiogram with contrast were performed. Those with EF < 50%, increased IVsd/LVpWd, ECG abnormalities +/- significant cardiac history underwent proBNP and high sensitivity troponin testing. PTS with abnormal findings or decreased left ventricular (LV) function were referred to the Edmonton Cardio-Oncology REsearch (ENCORE) program. RESULTS 73 unique PTS were screened by the Edmonton autoBMT program. Of these, 16 (20%) were reviewed by ENCORE. Reasons for referral included: decreased LV function (n = 6, 38%); increased IVsd (n = 5, 31%); arrhythmia (n = 4, 25%); angina (n = 1, 5%). Pharmacotherapy was initiated for 6 PTS; additional modality or serial cardiac imaging for 12 PTS; urgent stent for 1 PT. 100% proceeded to autoBMT without adverse cardiovascular outcomes or mortality. CONCLUSIONS With systematic screening, a high proportion of PTS referred for autoBMT required cardio-oncology assessment and interventions, with 100% proceeding safely as a result. ENCORE represents a novel approach in the provision of cardio-oncology expertise for autoBMT PTS acutely during the mobilizing and transplantation period. Future examination of our prospective dataset will elucidate the longer term effects of our interventions.

Feasibility and acceptability of integrated cardiac rehabilitation in outpatients referred for autologous bone marrow transplantation.

139 Background: High-dose chemotherapy (HDCT) and bone marrow/hematopoietic cell transplantation (BMT) is established therapy for many malignancies. While advances in transplant practise have led to improved cancer-specific outcomes, HDCT negatively impacts healthy organ function via direct effects (ie high-dose cytotoxic injury to organ systems) and indirect effects (i.e., functional disability). The resulting cardiometabolic sequelae such as dyslipidemia, hypertension, diabetes, and weight gain (with lean body mass loss) contribute to the significantly increased rates of cardiovascular (CV) mortality and heart failure (HF) observed in HDCT survivors. Cardiac rehabilitation/secondary prevention (CR/SP) programs are a level 1 recommendation in multiple CV diseases, reducing CV risk and events. Currently, the feasibility of integrating standard CR/SP programs in outpatients (PTS) referred for HDCT is unknown. AIM To prospectively evaluate feasibility and acceptability of routine referral tocardiovascular rehabilitation/secondary prevention (CR/SP) in unselected lymphoma PTSreferred for autologous HDCT/BMT. METHODS Lymphoma PTS referred for HDCT/BMT were screened and referred to the CR/SP program. Baseline exercise testing was performed prior to HDCT/BMT. Upon recovery (6 weeks) testing was repeated, and PTS were invited to participate in a 6-week standard CR/SP program of exercise rehabilitation and CV risk reduction education. RESULTS 20 PTS were referred for HDCT/BMT from January 1, 2015 to July 1, 2015. All were referred to the CR/SP program. 100% underwent exercise testing, and all proceeded to BMT without adverse cardiovascular outcomes or mortality. High levels of satisfaction of CR/SP program components were reported. CONCLUSIONS In unselected PTS, seamless integration of CR/SP within standard HDCT/BMT care is feasible and acceptable. We expect short term measurable impacts including reduced symptom burden and improved quality of life. Longer term impacts will evaluate CV morbidity and mortality. This work will inform patient-centered care and improve supportive and survivorship care across the cancer continuum.

Persistent cytogenetic abnormalities in patients undergoing intensive chemotherapy for acute myeloid leukemia

Abstract We evaluated the impact of bone marrow sample characteristics on the detection of persistent cytogenetic abnormalities (PCA) following induction chemotherapy for acute myeloid leukemia (AML). PCA’s were identified in 20.4% of patients and were more common with complete remission without count recovery (CRi) vs. those with count recovery (CR, 45.8 vs. 13.5%, p = .001), with  >2% blasts vs.  ≤2% blasts (42 vs. 12%, p =  .001) and with hypocellular trephine biopsies relative to those with normo/hypercellular biopsies (42.1 vs. 17.3%, p  = .03), although in a multivariate analysis only CRi and blast count >2% were independently associated with a PCA. PCA’s were not observed in patients with favorable risk karyotype. Amongst patients with intermediate and unfavorable risk karyotypes PCA were not associated with differences in overall or, amongst non-transplanted patients, relapse free survival. Thus, although PCAs are common post-induction it is unclear whether they provide any independent prognostic information beyond the diagnostic karyotype.

Constitutive Activation of STAT3 in Myeloma Cells Cultured in a Three-Dimensional, Reconstructed Bone Marrow Model

Malignant cells cultured in three-dimensional (3D) models have been found to be phenotypically and biochemically different from their counterparts cultured conventionally. Since most of these studies employed solid tumor types, how 3D culture affects multiple myeloma (MM) cells is not well understood. Here, we compared MM cells (U266 and RPMI8226) in a 3D culture model with those in conventional culture. While the conventionally cultured cells were present in single cells or small clusters, MM-3D cells grew in large spheroids. We discovered that STAT3 was the pathway that was more activated in 3D in both cell lines. The active form of STAT3 (phospho-STAT3 or pSTAT3), which was absent in MM cells cultured conventionally, became detectable after 1–2 days in 3D culture. This elevated pSTAT3 level was dependent on the 3D environment, since it disappeared after transferring to conventional culture. STAT3 inhibition using a pharmacological agent, Stattic, significantly decreased the cell viability of MM cells and sensitized them to bortezomib in 3D culture. Using an oligonucleotide array, we found that 3D culture significantly increased the expression of several known STAT3 downstream genes implicated in oncogenesis. Since most primary MM tumors are naturally STAT3-active, studies of MM in 3D culture can generate results that are more representative of the disease.

The fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) chemotherapy regimen is an alternative to anthracycline-based therapy for the treatment of acute myeloid leukemia for patients with pre-existing cardiac disease

We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony‐stimulating factor) as first‐line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline‐based treatment due to advanced age, significant comorbidities, or pre‐existing cardiac disease. The median age was 69 (21–80); 46% received FLAG for pre‐existing cardiac disease and others due to age (32%), non‐cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre‐existing cardiac disease. Among non‐transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse‐free survival was 14.7 months. The median overall survival was 9.3 months with 1‐ and 2‐yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline‐based induction for Acute myeloid leukemia in those with significant comorbidities including pre‐existing cardiac disease.