Citations

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.

Purpose To update guideline recommendations on the role of bone-modifying agents in multiple myeloma. Methods An update panel conducted a targeted systematic literature review by searching PubMed and the Cochrane Library for randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies. Results Thirty-five relevant studies were identified, and updated evidence supports the current recommendations. Recommendations For patients with active symptomatic multiple myeloma that requires systemic therapy with or without evidence of lytic destruction of bone or compression fracture of the spine from osteopenia on plain radiograph(s) or other imaging studies, intravenous administration of pamidronate 90 mg over at least 2 hours or zoledronic acid 4 mg over at least 15 minutes every 3 to 4 weeks is recommended. Denosumab has shown to be noninferior to zoledronic acid for the prevention of skeletal-related events and provides an alternative. Fewer adverse events related to renal toxicity have been noted with denosumab compared with zoledronic acid and may be preferred in this setting. The update panel recommends that clinicians consider reducing the initial pamidronate dose in patients with preexisting renal impairment. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended in this setting. The update panel suggests that bone-modifying treatment continue for up to 2 years. Less frequent dosing has been evaluated and should be considered in patients with responsive or stable disease. Continuous use is at the discretion of the treating physician and the risk of ongoing skeletal morbidity. Retreatment should be initiated at the time of disease relapse. The update panel discusses measures regarding osteonecrosis of the jaw. Additional information is available at www.asco.org/hematologic-malignancies-guidelines and www.asco.org/guidelineswiki .

Key Points Pomalidomide plus low-dose dexamethasone significantly improved PFS vs pomalidomide alone in relapsed and refractory multiple myeloma. Pomalidomide plus low-dose dexamethasone is an important new treatment option for RRMM patients who have received multiple prior therapies.

Purpose The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) –related bone disease. Methodology An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members. Recommendations Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.