Stockerl‐Goldstein, Keith

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS–CoV‐2) has given rise to a pandemic of unprecedented proportions in the modern era because of its highly contagious nature and impact on human health and society: coronavirus disease 2019 (COVID‐19). Patients with cardiovascular (CV) risk factors and established CV disease (CVD) are among those initially identified at the highest risk for serious complications, including death. Subsequent studies have pointed out that patients with cancer are also at high risk for a critical disease course. Therefore, the most vulnerable patients are seemingly those with both cancer and CVD, and a careful, unified approach in the evaluation and management of this patient population is especially needed in times of the COVID‐19 pandemic. This review provides an overview of the unique implications of the viral outbreak for the field of cardio‐oncology and outlines key modifications in the approach to this ever‐increasing patient population. These modifications include a shift toward greater utilization of cardiac biomarkers and a more focused CV imaging approach in the broader context of modifications to typical practice pathways. The goal of this strategic adjustment is to minimize the risk of SARS–CoV‐2 infection (or other future viral outbreaks) while not becoming negligent of CVD and its important impact on the overall outcomes of patients who are being treated for cancer.

Abstract Abstract 680 Cytogenetics play an essential role in determining the prognosis of patients with AML. However, there is still no validated cytogenetics grouping scheme that specifically applies to patients undergoing allogeneic stem cell transplantation, which hampers accurate prognostication and risk stratification. We studied 821 adult patients (median age 41, range 18–74) who underwent SCT between 1999 and 2004 for AML (excluding APL) in CR1 or CR2 and who were reported to the CIBMTR from centers with >20 patients meeting study criteria. 75% of patients received a myeloablative conditioning. 496 patients had a normal karyotype. The primary cytogenetics reports were manually reviewed for 92% of the patients with an abnormal karyotype. We compared the ability of the 6 existing grouping schemes (MRC, CALGB, EORTC/GIMEMA, SWOG/ECOG, DFCI, and Monosomal Karyotype (MK) classifications) to stratify patients, using both the Akaike Information Criterion in multivariable models and the C-statistic. Among all existing schemes, the DFCI system provided a marginally superior stratification for overall and leukemia-free survival. We also built a new classification using individual cytogenetic abnormalities in a Cox model that included other significant covariates (performance status, therapy-related disease, conditioning intensity, graft source, donor match, duration of CR1, and gender match). This CIBMTR scheme (see Table), which is similar to the DFCI scheme except for the inclusion of patients with t(8;21) in the intermediate group, could stratify patients into 3 groups with similar treatment-related mortality but significantly different overall survival, leukemia-free survival, and incidence of relapse. This scheme appeared to apply to both patients in CR1 and in CR2 (see FiguresF2). This transplant-specific scheme could be adopted for prognostication purposes and to stratify patients with karyotypic abnormalities entering transplantation clinical trials. Future studies may clarify the relative outcome of patients with t(8;21) and refine this scheme with the inclusion of molecular abnormalities. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2965 Background: Alkylating agents have been the mainstay of multiple myeloma (MM) therapy for decades and despite introduction of several new therapies, it continues to play a significant role in its management as part of various drug combinations. While melphalan has been the most commonly used alkylator in MM, recent studies have suggested significant activity for bendamustine, a bifunctional alkylator. The combination of lenalidomide and melphalan has been associated with high response rates in relapse and newly diagnosed MM. Based on these promising results we designed a trial to evaluate the maximally tolerated dose of lenalidomide and bendamustine when used in combination as well as the efficacy of the combination in relapsed disease. Patients and Methods: Patients with relapsed MM and measurable disease were enrolled on this phase 1/2 trial provided they had not more than 4 prior lines of therapy for MM, had adequate performance status and organ and hematological function. Patients refractory to lenalidomide were allowed to enroll. The primary objectives were to (i) to determine the MTD of bendamustine and lenalidomide in combination with dexamethasone in subjects with relapsed MM (phase 1) and (ii) to evaluate the confirmed response rate of bendamustine in combination with lenalidomide and dexamethasone in patients with relapsed MM (phase 2). Bendamustine (B) was administered on days 1 and 2 of a 28-day cycle at doses of 50–100 mg/m2. Lenalidomide (R) was given days 1–21 at doses of 15–25 mg daily. Dexamethasone (D) was administered at 40 mg weekly. Dose escalation was done using a 3+3 design and MTD was defined as one dose level below that resulted in >=2 DLTS among 6 patients. The primary end point for this trial was the proportion of patients with confirmed hematologic response (sCR, CR, VGPR, or PR) over the first 6 cycles of treatment. Results: A total of 72 patients were accrued to this study from March 2010 to May 2012: 21 patients in phase 1 and 51 in phase 2. The 6 patients from the MTD dose level of phase 1 were also included in phase 2. The median age of all 72 patients was 62.1 (range, 40–86) and 57% were male. Majority (75%) of patients had previously been exposed to lenalidomide and 69% had prior exposure to bortezomib. Median # of prior therapies was 3 (range, 1–5) and 74% of patients had a prior autologous stem cell transplant. Patients have received a median of 4 cycles (range, 1–25), with 27 patients still continuing on active treatment. Disease progression led to study discontinuation in 22 (49%) and adverse events were the reason for discontinuation in 14 (31%). In phase I, two DLTs (Grade (Gr) 2 neuropathy and Gr 4 neutropenia) were seen at the highest dose level (100 mg/m2 B, 25 mg R), and the MTD was determined as 75 mg/m2 of B given days 1 and 2 and 25 mg of R days 1–21, along with D 40 mg weekly. Overall patients, 12/21 (57%) had a PR or better. In phase 2, 17 (40%) confirmed responses (>=PR) were seen among the 43 patients evaluable for response (received at least 6 cycles of treatment or have gone off study prior to 6 cycles); including 9 (21%) VGPR and 8 (19%) PR. An additional 5 patients had a minor response. Over all dose levels, a gr 3 or higher adverse event at least possibly attributed to the study was seen in 75% of patients. The most common toxicities were all hematological (thrombocytopenia and leukopenia), and most common non-hematological toxicity was infection. Prolonged time to recovery of blood counts was seen in a few patients, but majority of patients were able to tolerate the regimen with adequate dose reductions. Conclusion: The recommended dose of the combination for further studies is bendamustine at 75 mg/m2 days 1 and 2, lenalidomide 25 mg daily on days 1–21 and dexamethasone days 1, 8, 15, 22; with cycles repeated every 28 days. The regimen is well tolerated with hematological toxicity being the most common and manageable with dose reductions. The regimen is effective with high response rates and durable responses seen. Updated results with response rates and time to event analyses will be available for the entire cohort at the time of meeting. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Krishnan:celgene: Consultancy, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Novartis: Expert Testimony, Expert Testimony Other. Vij:Teva: Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Onyx: Honoraria, Research Funding.

Abstract BACKGROUND: Azacitidine and decitabine are indicated for the first line treatment of intermediate and high risk MDS. About 40% to 47% of patients respond to 1st line hypomethylating agents. The median duration of response is 13 months. There are no effective therapies for patients who fail to respond to or progress on hypomethylating agents. A phase II trial of high dose lenalidomide (50mg/day) induction therapy followed by low dose (10mg/day) maintenance therapy in elderly patients with AML had demonstrated a high CR/CRi of 30%. CR was restricted to patients with presenting WBC counts <10000/µL, peripheral blast counts <1000/ µL and < 30%, many of whom could have been classified as having MDS rather than AML by FAB criteria. With the rationale that MDS and AML represent a continuum of disease, and the promising results in AML we aimed to assess the clinical activity of high dose lenalidomide by conducting a clinical trial of high dose Lenalidomide induction followed by low dose maintenance in patients with hypomethylating agent refractory MDS. METHODS: We conducted an open label, single arm, multi-center phase II trial of high dose lenalidomide induction (50mg/day for two 28 day cycles) followed by low dose lenalidomide maintenance therapy (10mg/day for 12 cycles) for patients with MDS (as defined by FAB criteria) refractory to hypomethylating agents. Patients who had failed to show CR, PR or HI (hematological improvement) after at least 6 cycles of azacytidine or decitabine or who had progressed on treatment were considered eligible. Patients were enrolled in a Simon's optimal two-stage design with an intended sample size of 43. The primary endpoint was proportion of confirmed responses (CR, PR or HI), as defined by international working group criteria, during the 14 cycles of treatment. RESULTS: 24 patients were enrolled in the first stage of the study. 16 patients completed at least one cycle of therapy and were considered evaluable for efficacy. Efficacy: Characteristics and outcomes of patients are detailed in Table 1. There were no complete or partial remissions. Marrow complete remission (MCR) was seen in 8/16 patients (50%). One of the 8 patients with a MCR had 5q- karyotype; 3/8 had trisomy 8 and one patient had a complex karyotype with monosomy 7. Median duration of MCR was 70 days (range 28-336 days). MCR lasted beyond the high dose induction period in 2 patients, one of whom had a 5q interstitial deletion (112 days) and one patient with trisomy 8 (336 days). Hematologic improvement (HI) was seen in 2/16 patients (12.5%) (Refer to table below). Toxicity: ≥grade 3 toxicities included pneumonia (12/24, 50%), sepsis (4/24, 17%), febrile neutropenia (8/24, 33%), rash (2/24, 8%), thromboembolic event (1/24), MI (1/24), new cancer -mammary analogue salivary carcinoma- (1/24). TABLE 1 Pt No: Age IPSS Prior cycles of 5-aza/ decitabine Cycles of Lenalidomide Reason off trial Best Response 1 69 1.5 2 4 Pancytopenia MCR 2 78 3 8 1 Death-Unrelated SD 3 73 2 7 1 Consent withdrawn SD 4 87 2 14 12 Progression MCR, HI-p&n 6 72 2 13 2 Thrombocytopenia MCR 7 69 2 13 1 PE SD 8 75 1 7 2 New Cancer MCR 9 74 1 4 3 Progression SD 10 75 2 0 2 Progression SD 11 72 1 13 3 Thrombocytopenia MCR 12 75 3 6 1 Progression PD 13 78 1 9 3 Gr3 Fatigue MCR 14 70 0 19 2 Progression MCR, HI-p 15 72 1 23 1 Progression PD 16 73 1 8 2 Gr 3 fatigue MCR CONCLUSIONS: High dose lenalidomide followed by standard dose maintenance in hypomethylating agent refractory MDS resulted in a marrow complete remission rate of 50% and hematological improvement rate of 12.5%. Future protocols should explore whether an extended schedule of intermittent dosing of high dose lenalidomide would allow for improved efficacy with acceptable toxicity. Disclosures Off Label Use: Lenalidomide is used in this study in patients with MDS both with and without deletion 5q.Use in patients without deletion 5q is off label use.. Tibes:Tetralogic Pharmaceuticals: Research Funding. Stockerl-Goldstein:Celgene: Speakers Bureau. Jacoby:Norvo Nordisk: Consultancy. Cashen:Celgene: Speakers Bureau. Vij:Onyx: Honoraria, Research Funding; Sanofi: Honoraria; Jannsen: Honoraria; Novartis: Honoraria; Millennium: Honoraria; Celgene: Honoraria, Research Funding.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.

Abstract HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy–based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor–based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P &lt; .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease–donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy–based Haplo-HCT vs MSD using calcineurin inhibitor–based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.

BACKGROUND/OBJECTIVES The incidence of myeloma in older adults is increasing, yet little is known about geriatric impairments in these patients. We aimed to examine the prevalence of geriatric impairments in older adults with myeloma and the association between geriatric assessment and autologous stem cell transplant eligibility. DESIGN Prospective cohort study. SETTING Two academic medical centers. PARTICIPANTS A total of 40 adults 65 years and older with newly diagnosed myeloma were enrolled. MEASUREMENT Participants completed a primarily self‐administered geriatric assessment, including measures of functional status, comorbidities, polypharmacy, psychosocial status, social support, quality of life, cognition, and physical performance. Outcomes were autologous stem cell transplant eligibility and receipt. RESULTS Forty patients enrolled; their mean age was 71 years. Geriatric impairments were common: 62% reported dependence in one or more instrumental activities of daily living (IADL), 76.9% had polypharmacy (four or more medications), and 47.5% had one or more comorbidities. Median time on the Timed Up and Go was 13.3 ± 4.9 seconds. Those considered candidates for autologous stem cell transplant (N = 26) were younger, with fewer comorbidities, better performance status, and faster performance on the Timed Up and Go test. Factors independently associated with receiving autologous stem cell transplant (N = 21) included age and IADL dependence. CONCLUSION Impairments in geriatric domains are common in this population, even among those considered to have a good performance status. Geriatric assessment domains are associated with both transplant eligibility and receipt. J Am Geriatr Soc 67:987–991, 2019.

e18061 Background: Despite a favorable genetic profile, African-Americans (AAs) with mm have poorer outcomes secondary to inferior treatment. NCI-CCs provide the highest-quality of care and attendance has been associated with better outcomes in many cancers. AAs have greater access to NCI-CCs proximally; however, they attend these facilities at lower rates than their white peers. The impact of attendance at NCI-CCs on mediating racial disparities in mm outcomes has not been reported on to date. Methods: We reviewed cases of mm the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database from 2000-2011 who were enrolled in Medicare Part A and B > 1 year prior to diagnosis, excluding cases enrolled prior to age 65 and those where mm diagnosis occurred post-mortem. Any center designated a NCI-clinical or -comprehensive center in 2002, 2005, or 2010 was considered a NCI-CC; attendance was defined as 2 or more claims on separate dates (MEDPAR and Outpatient files) from a NCI-CC in the 12 months following mm diagnosis. Logistic regression was performed to determine if race was associated with attendance, Cox regression to determine the association of attendance with survival. Results: 21,843 cases were analyzed; the median age was 77 years; 80% were white, 15% AA/Black. Overall NCI-CC attendance was low, only 11% of the population. Compared to white patients, black patients had a 13% decreased odds (aOR 0.87, 95% CI 0.75-0.99) of NCI-CC attendance after controlling for age, gender, socioeconomic status, geographic, and overall health variables. Attendance was associated with a 28% decrease risk for death (aHR 0.72, 95% CI 0.68-0.76), but had little impact on black-white outcome disparities. Black patients had a 9% increase in risk (aHR 1.09, 95% CI 1.04-1.13) after controlling for NCI-CC attendance. Conclusions: Black patients with mm have lower NCI-CC attendance. This may be related to referral bias and/or patient declining referral. NCI-CC attendance was associated with superior outcomes; however, controlling for attendance did not mediate black-white outcome disparities suggesting that racial treatment disparities pervade beyond access to NCI-CCs.

Objective Assess the effects of linezolid on hematologic outcomes in newly diagnosed patients with acute myeloid leukemia ( AML ) following induction chemotherapy. Design Single‐center, retrospective, observational, cohort study. Setting Large, tertiary care academic medical center. Patients A total of 225 patients ≥ 18 years admitted between December 2010 and 2013 with newly diagnosed AML were assessed for inclusion. Patients were identified through the use of ICD ‐9 codes and chemotherapy ordered via the computerized physician order entry system. Sixty‐eight patients met inclusion criteria and were grouped into two arms based on antimicrobial treatment: LZD group (linezolid plus gram‐negative antimicrobial, n=21) or control group (vancomycin or daptomycin plus gram‐negative antimicrobial, n=47). Interventions The LZD group received linezolid ≥ 72 hours. The control group received vancomycin or daptomycin ≥ 72 hours. If patients switched extended gram‐positive therapy, they were included in the LZD group as long as they had received ≥ 72 hours of linezolid. Measurements/Results The primary end point of time to neutrophil recovery was not statistically different (28 days for LZD group vs 26 days for control group; p=0.675). The preplanned subgroup analysis of patients who received ≥ 14 days of linezolid demonstrated statistically similar median times to neutrophil recovery (29 days for LZD group vs 26 days for control group; p=0.487). Total duration of extended gram‐positive antimicrobial therapy was significantly longer in the LZD group (27 days vs 16 days; p<0.001). Secondary end points not found to be statistically significant included platelet count at time of neutrophil recovery, duration of neutropenia, and length of hospital stay. Conclusions There were no significant differences in hematologic outcomes in newly diagnosed AML patients who received linezolid for extended gram‐positive antimicrobial coverage following induction chemotherapy. This study provides new insight with a primary focus on the effects of hematologic outcomes when using linezolid in a well‐defined acute leukemia population. Further study is warranted with larger populations to assess the potential adverse effects linezolid may have in patients with acute leukemia.