Citations

Abstract Abstract 986 In 2011, we described the TEMPI syndrome in three patients, a rare condition characterized by the pentad of (1) Telangiectasias, (2) elevated Erythropoietin and resulting erythrocytosis, (3) Monoclonal gammopathy, (4) Perinephric fluid collections, and (5) Intrapulmonary shunting. Since this publication, two additional living patients have been identified. Of note, all patients carried a diagnosis of unexplained polycythemia for many years to decades prior to the realization that the erythrocytosis was only one part of a more complex syndrome. The underlying pathophysiology of the TEMPI syndrome is unknown. Given that the patients did not exhibit symptoms until their 3rd or 4th decade, we felt that the TEMPI syndrome was more likely to be acquired and less likely to be congenital. We hypothesized that the monoclonal paraprotein may play a role in triggering this very unusual pattern of symptoms. Based on this hypothesis, the patients began empiric treatment with the proteasome inhibitor bortezomib, either alone, or as part of an induction regimen prior to autologous stem cell transplantation. The first patient to receive bortezomib, a 48 year old woman, received 8 cycles of intravenous bortezomib, given in standard fashion. Her telangiectasias, which were concentrated over her lips and torso, disappeared rapidly. Her bilateral perinephric fluid collections disappeared and her serum erythropoietin normalized from a peak of >5000 mIU/ml. By the end of the 8 cycles, her IgG kappa paraprotein became undetectable. Before treatment, she was hypoxic to such a degree that she required a wheelchair and continuous supplemental oxygen. Following treatment, her intrapulmonary shunting resolved, her oxygen saturation normalized, and she has resumed jogging. She remains in a complete remission, now fifteen months after her last dose of bortezomib. The second patient, a 55 year old woman, had undergone surgical fenestration of the renal capsule to allow for drainage of the perinephric fluid into her abdomen. The fluid was produced at such a rate that she required regular paracentesis to remove the resulting ascites. She received 6 cycles of intravenous bortezomib. Her telangiectasias resolved, her serum erythropoietin normalized from a peak of 507 mIU/ml, her paO2 improved, and production of perinephric fluid decreased. However, after four months off treatment, the concentration of her IgG kappa paraprotein began to increase, as did her serum erythropoietin. Furthermore, she has developed pulmonary hypertension, which we suspect may represent a rare paraneoplastic condition seen in some patients with multiple myeloma. The third patient, a 52 year old man, has received ten cycles of intravenous bortezomib. He has tolerated therapy well without side-effects. His serum erythropoietin has decreased from 5500 to 2500 mIU/ml. However, he has not shown the same dramatic reduction in the level of his IgG kappa paraprotein, nor has he shown resolution of his telangiectasias, perinephric fluid, or intrapulmonary shunting. The response of the fourth patient to bortezomib was recently described as a letter to the editor in the New England Journal of Medicine. The fifth patient, a 49 year old woman, was referred for evaluation of unexplained and progressive hypoxia requiring the use of continuous supplemental oxygen. She had been diagnosed at age 34 with polycythemia vera and treated with periodic phlebotomy. Telangiectasias were present on the face, chest, abdomen, and back. Erythropoietin was elevated to >8000 mIU/ml and an IgG-kappa paraprotein was identified. Her cardiovascular shunt fraction was 27%. Given the variable response of the other patients to single-agent bortezomib, she began an induction regimen that included cyoclophosphamide, bortezomib, and dexamethasone (CyBorD) with plans for autologous SCT. The efficacy of treatment with bortezomib, as well as the reversible nature of the symptoms, lends support to the hypothesis that the abnormal plasma cell clone and monoclonal gammopathy are the cause of the TEMPI syndrome. Efforts to identify the antigenic target of the paraprotein are underway, using protein microarray and immunohistochemical techniques. We suspect that more patients with the TEMPI syndrome exist. The constellation of the described pentad should raise the potential of this syndrome. We welcome any reader insights into this unusual condition. Disclosures: Raje: Onyx: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding. Somer:BioPat Holdings, Inc.: Consultancy. Off Label Use: We use bortezomib in the treatment of a newly described syndrome, the TEMPI syndrome.

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.

Background:Carfilzomib (CFZ) combined with dexamethasone is approved to treat patients (pts) with relapsed and/or refractory multiple myeloma (RRMM), with CFZ given once‐weekly at 70 mg/m2 (Kd70 QW) or twice‐weekly at 56 mg/m2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW.Aims:We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION‐1 trials.Methods:Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION‐1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION‐1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW.Results:Among BTZ non‐refractory pts with 2–3 lines of prior therapy, median progression‐free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well‐tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69).Summary/Conclusion:This post hoc analysis suggests that once‐weekly Kd70 has a comparable benefit‐risk profile to twice‐weekly Kd56.© 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO Annual Meeting. All rights reserved.

PURPOSE To provide evidence-based recommendations on the treatment of multiple myeloma to practicing physicians and others. METHODS ASCO and Cancer Care Ontario convened an Expert Panel of medical oncology, surgery, radiation oncology, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and some phase II studies published from 2005 through 2018. Outcomes of interest included survival, progression-free survival, response rate, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 124 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Evidence-based recommendations were developed for patients with multiple myeloma who are transplantation eligible and those who are ineligible and for patients with relapsed or refractory disease.

3010 Background: To test the safety and efficacy of the CAR T cell modality in relapsed/refractory multiple myeloma (MM), we have designed a second-generation CAR construct targeting B cell maturation antigen (BCMA) to redirect T cells to MM. bb2121 consists of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an anti-BCMA scFv, a 4-1BB costimulatory motif and a CD3-zeta T cell activation domain. We will report updated safety and efficacy following initial results (Berdeja et al, ENA 2016). Methods: CRB-401 (NCT02658929) is a multi-center phase 1 dose escalation trial of bb2121 in patients with relapsed and/or refractory MM who have received ≥ 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have ≥ 50% BCMA expression on plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis. Patients undergo lymphodepletion with Flu (30 mg/m 2 ) / Cy (300 mg/m 2 ) daily for 3 days then receive 1 infusion of bb2121. The study follows a standard 3+3 design with planned dose levels of 5, 15, 45, 80 and 120 x 10 7 CAR+ T cells. Results: As of November 18, 2016, 11 patients had been infused with bb2121 in the first 4 dose cohorts, and 9 patients had reached at least 1 month of follow-up. As of data cut-off, no dose-limiting toxicities and no > Grade 2 neurotoxicities or cytokine release syndrome (CRS) had been observed. Grade 1-2 CRS had been reported in 8/11 (73%) treated patients. All patients treated with doses of 15.0 x 10 7 or higher remained on study and the overall response rate (ORR) in the 6 evaluable patients at these doses was 100%, including 2 sCRs and 2 MRD-negative responses (1 sC, 1 VGPR). CAR+ T cell expansion has been demonstrated consistently. An additional 6 months of follow up on previously reported results and initial data from an additional ~10 patients will be presented. Conclusions: bb2121 shows promising efficacy at dose levels above 5 x 10 7 CAR+ T cells, including 2 sCRs and ongoing clinical responses at 6 months, with mild and manageable CRS to date. These initial data support the potential of CAR T therapy with bb2121 as a new treatment paradigm in MM. Study sponsored by bluebird bio. Clinical trial information: NCT02658929.