Kumar, Shaji

Abstract Purpose: Rearrangements involving the MYC protooncogene are common in newly diagnosed multiple myeloma, but their prognostic significance is still unclear. The purpose of this study was to assess the impact of MYC rearrangement on clinical characteristics, treatment response, and survival in patients with newly diagnosed multiple myeloma. Experimental Design: This is a retrospective study including 1,342 patients seen in Mayo Clinic in Rochester, MN, from January 2006 to January 2018, who had cytogenetic testing by FISH at diagnosis, including MYC testing using the break apart FISH probe (8q24.1). Results: A rearrangement involving MYC was found in 8% of patients and was associated with elevated β2-microglobulin, ≥50% bone marrow plasma cells, IgA multiple myeloma, and the cooccurrence of trisomies. There were no differences in overall response rates between patients with and without MYC rearrangement when induction chemotherapy was proteasome inhibitor (PI)-based, immunomodulatory drug (IMiD)-based or PI + IMiD-based. Overall survival was shorter in patients with MYC rearrangement compared with patients without MYC rearrangement (5.3 vs. 8.0 years, P < 0.001). MYC rearrangement was associated with increased risk of death on multivariate analysis when high-risk cytogenetic abnormalities, ISS stage III, and ≥70 years of age were included (risk ratio: 1.5; P = 0.007). Conclusions: MYC rearrangement is associated with high disease burden and is an independent adverse prognostic factor in patients with newly diagnosed multiple myeloma.

BackgroundMultiple myeloma (MM) with the translocation t(11;14) may have inferior outcomes in comparison with other standard‐risk MM, and it has been suggested to portend a worse prognosis in African Americans in comparison with Whites. This study used the Center for International Blood and Marrow Transplant Research (CIBMTR) database to examine the impact of t(11;14) on the clinical outcomes of patients with MM of African American and White descent.MethodsThis study evaluated 3538 patients who underwent autologous hematopoietic cell transplantation (autoHCT) for MM from 2008 to 2016 and were reported to the CIBMTR. Patients were analyzed in 4 groups: African Americans with t(11;14) (n = 117), African Americans without t(11;14) (n = 968), Whites with t(11;14) (n = 266), and Whites without t(11;14) (n = 2187).ResultsAfrican Americans with t(11;14) were younger, had lower Karnofsky scores, and had more advanced stage MM with a higher Hematopoietic Cell Transplantation–Comorbidity Index (HCT‐CI). Fewer African Americans with t(11;14) (21%) had a coexistent high‐risk marker in comparison with Whites with t(11;14) (27%). In a multivariate analysis, race and t(11;14) had no association with progression‐free survival. However, overall survival was superior among African Americans with t(11;14) in comparison with Whites with t(11;14) (hazard ratio, 0.53; 95% confidence interval, 0.30‐0.93; P = .03). Survival was also associated with female sex, stage, time from diagnosis to transplant, a low HCT‐CI, and receipt of maintenance.ConclusionsRace may have a differential impact on the survival of patients with t(11;14) MM who undergo autoHCT and needs to be further studied.

BackgroundUpfront autologous hematopoietic stem cell transplantation (AHCT) remains an important therapy in the management of patients with multiple myeloma (MM), a disease of older adults.MethodsThe authors investigated the outcomes of AHCT in patients with MM who were aged ≥70 years. The Center for International Blood and Marrow Transplant Research (CIBMTR) database registered 15,999 patients with MM in the United States within 12 months of diagnosis during 2013 through 2017; a total of 2092 patients were aged ≥70 years. Nonrecurrence mortality (NRM), disease recurrence and/or progression (relapse; REL), progression‐free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models with age at transplantation as the main effect. Because of the large sample size, a P value <.01 was considered to be statistically significant a priori.ResultsAn increase in AHCT was noted in 2017 (28%) compared with 2013 (15%) among patients aged ≥70 years. Although approximately 82% of patients received melphalan (Mel) at a dose of 200 mg/m2 overall, 58% of the patients aged ≥70 years received Mel at a dose of 140 mg/m2. On multivariate analysis, patients aged ≥70 years demonstrated no difference with regard to NRM (hazard ratio [HR] 1.3; 99% confidence interval [99% CI], 1‐1.7 [P = .06]), REL (HR, 1.03; 99% CI, 0.9‐1.1 [P = 0.6]), PFS (HR, 1.06; 99% CI, 1‐1.2 [P = 0.2]), and OS (HR, 1.2; 99% CI, 1‐1.4 [P = .02]) compared with the reference group (those aged 60‐69 years). In patients aged ≥70 years, Mel administered at a dose of 140 mg/m2 was found to be associated with worse outcomes compared with Mel administered at a dose of 200 mg/m2, including day 100 NRM (1% [95% CI, 1%‐2%] vs 0% [95% CI, 0%‐1%]; P = .003]), 2‐year PFS (64% [95% CI, 60%‐67%] vs 69% [95% CI, 66%‐73%]; P = .003), and 2‐year OS (85% [95% CI, 82%‐87%] vs 89% [95% CI, 86%‐91%]; P = .01]), likely representing frailty.ConclusionsThe results of the current study demonstrated that AHCT remains an effective consolidation therapy among patients with MM across all age groups.

Abstract Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. There are over 15 types of systemic amyloidosis, each caused by a different precursor protein which promotes amyloid formation and tissue deposition. Amyloidosis can be acquired or hereditary and can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin and soft tissues. Symptoms are usually insidious and nonspecific resulting in diagnostic delay. The field of amyloidosis has seen significant improvements over the past decade in diagnostic accuracy, prognosis prediction and management. The advent of mass spectrometry‐based shotgun proteomics has revolutionized amyloid typing and has led to the discovery of new amyloid types. Accurate typing of the precursor protein is of paramount importance as the type dictates a specific management approach. In this article, we review each type of systemic amyloidosis to provide the practitioner with practical tools to improve diagnosis and management of these rare disorders.

Abstract Daratumumab in combination with lenalidomide‐dexamethasone (D‐Rd) recently received FDA approval for the treatment of transplant‐ineligible patients with newly diagnosed multiple myeloma (NDMM). The present PEGASUS study compared progression‐free survival (PFS) in patients treated with D‐Rd in the MAIA trial and patients treated with common standard‐of‐care regimens from the Flatiron Health electronic health record‐derived deidentified database, which has data from patients treated primarily at community‐based oncology practices in the United States. Individual‐level patient data from both data sources were used to perform an anchored indirect treatment comparison (ITC) of D‐Rd to bortezomib‐lenalidomide‐dexamethasone (VRd) and bortezomib‐dexamethasone (Vd); lenalidomide‐dexamethasone (Rd) was the common anchor for the ITC. Hazard ratios (HRs) reflecting direct comparisons of PFS within MAIA (D‐Rd vs Rd) and Flatiron Health (VRd vs Rd; Vd vs Rd) were used to make ITCs for D‐Rd vs VRd and Vd, respectively. After application of MAIA inclusion/exclusion criteria and propensity‐score weighting, the Flatiron Health patients resembled the MAIA trial population on measured baseline characteristics. Based on the direct comparison within MAIA, treatment with D‐Rd was associated with a significantly lower risk of progression or death compared to Rd (HR 0.54; 95% CI 0.42, 0.71). Based on the ITCs, D‐Rd was associated with a significantly lower risk of progression or death compared to VRd (HR 0.68; 95% CI 0.48, 0.98) and Vd (HR 0.48; 95% CI 0.33, 0.69). In the absence of head‐to‐head trials comparing D‐Rd to VRd or Vd, the present ITC may help inform treatment selection in transplant‐ineligible patients with NDMM.

8603 Background: Steroids, primarily dexamethasone (Dex), remains an integral part of the therapy for myeloma. Prior to the advent of novel agents, Dex as a single agent was demonstrated to produce overall response rates of around 50%. The toxicity associated with pulsed high dose Dex has led to this approach being abandoned. This study investigates whether responsiveness to Dex correlates with biological qualities of the plasma cell clone that predicts outcome. Methods: We identified from our prospectively maintained database, patients with newly diagnosed myeloma, who were seen at Mayo Clinic within 30 days of diagnosis and were treated with single agent Dex. The M-protein measurements and responses were assessed using the IMWG criteria. Results: 182 patients seen between March 1998 and June 2007, initially treated with single agent Dex for at least 4 weeks, were included in the analysis. The median age at diagnosis was 63 (range; 39–81) and 59% were male. The actuarial median survival for the entire group was 55 months. The median duration of Dex therapy was 15 weeks (range; 4–193). Ninety one (50%) had a partial response or better and 11 (6%) were not evaluable, with the remaining patients (44%) having less than PR or progression. 10 patients (5%) achieved a VGPR or CR. The median overall survival from diagnosis for the 91 responders was 75 months compared to 71 months for the remaining patients; p = 0.6. There was no correlation between baseline disease characteristics and Dex responsiveness. One hundred thirty (70%) patients proceeded to an autologous SCT after a median of 15 weeks (range 1–46 months) of Dex. While the median overall survival was longer among the group of patients who underwent SCT, among either group, there were no survival benefit between those with a PR or better to Dex compared to the rest. Conclusions: Among this group of patients with newly diagnosed myeloma treated with single agent Dex, failure to respond to Dex induction therapy did not impact overall survival. Failure to respond to single agent steroid does not have an adverse impact on outcome in newly diagnosed myeloma. [Table: see text]

7039 Background: Erythropoiesis-stimulating agents are known to increase the risk for VTE events, especially in patients with underlying malignancies. However, there is a paucity of information on other hematopoietic growth factors such as granulocyte colony-stimulating factor (GSCF) granulocyte-macrophage colony stimulating factor (GM-CSF) AMD 3001 and risk for VTE. Methods: Between January 2000 and October 2008, a total of 631 patients underwent peripheral blood stem cell mobilization (PBSCM) using either GCSF, GMCSF, cyclophosphamide, AMD 3100, or with any of the above combination. We included only patients with a diagnosis of AL amyloidosis (AL), multiple myeloma (MM) Hodgkin's lymphoma (HL) and non Hodgkin's lymphoma (NHL). Patients’ demographic details and diagnosis of VTE were collected from electronic medical records. Results: Of the 631 patients who underwent PBSCM the median age of the patients was 57 years (range 17–77). 448 patients (71%) received single agent GCSF, 82 (13%) received combination of GMCSF and cyclophosphamide, 52 (8%) received cyclophosphamide and GCSF, 30 patients received a combination of GMCSF and GCSF, 10 (1.5%) patients received GCSF and AMD 3100. Of the 631 patients, 278 (44%) MM, 209 (33%) NHL, 114 (18%) AL, and 20 (3%) had HL. We found 7 (1.1%) patients with symptomatic VTE occurring between administration of growth factors and stem cell transplant. The median duration from the administration of growth factors to detection of VTE was 5 days (range 1–30). Two AL,3 MM and 2 NHL. Of the 7 patients, 2 patients had pulmonary embolism and 1 patient developed deep vein thrombosis. Two patients with AL developed heparin induced thrombocytopenia (HIT). The remaining 4 patients developed symptomatic catheter related thrombosis. Only 1 patient had past history of VTE. Of the 7 patients, 5 received GCSF alone, 1 received GMCSF, and cyclophosphamide, 1 received GCSF and cyclophosphamide. Of the 4 patients who developed catheter related thrombosis, catheter was removed in 2 patients. None of the patients developed VTE related morality. Conclusions: The risk for symptomatic VTE during PBSCM is low. HIT should be considered as a possible cause for VTE in patients undergoing PBSCM. No significant financial relationships to disclose.

Abstract A gain in chromosome 1q (+1q) is among the most common cytogenetic abnormalities in multiple myeloma (MM). It is unclear whether +1q is independently associated with decreased overall survival (OS). The objective of this study was to evaluate the impact of +1q on clinical characteristics, treatment response, and survival outcomes. We included 1376 Mayo Clinic patients diagnosed with MM from 2005 to 2018 who underwent fluorescence in situ hybridization testing at diagnosis with a panel including the +1q probe. A gain in 1q was found in 391 patients (28%) and was associated with anemia, hypercalcemia, high tumor burden, International Staging System (ISS) stage 3, high-risk (HR) translocations, and chromosome 13 abnormalities. There was no difference in overall response or deeper responses to proteasome inhibitor (PI)–, immunomodulatory drug (iMiD)–, or PI plus IMiD–based induction. Time to next treatment was shorter in patients with +1q compared with those without +1q (19.9 vs 27.7 months; P &lt; .001). On univariate analysis, +1q was associated with increased risk of death (risk ratio [RR], 1.9; P &lt; .001), and decreased OS was seen in all treatment groups. +1q was independently associated with decreased OS on multivariate analysis when other HR cytogenetic abnormalities, ISS stage 3, and age ≥70 years were included (RR, 1.5; P &lt; .001). Gain of &gt;1 copy of 1q was not associated with worse OS compared with gain of 1 copy (4.9 vs 4.3 years; P = .21). +1q was associated with high tumor burden, advanced disease stage, and HR translocations. It is independently associated with decreased OS, even in the setting of novel therapy and transplant.