Pharmacologic and nonpharmacologic interventions were evaluated, resulting in recommended for practice rating for catheter care bundles, antimicrobial prophylaxis, vaccination for specific populations, and implementation of contact precautions for resistant organisms.
Introduction: Modern therapy for multiple myeloma including generations of thalidomide analogues, proteasome inhibitors and alkylating agents has substantially improved the survival for this disease. Patients who have progressed through these agents have limited options and a very poor prognosis. Programmed death ligand 1 (PD-L1) is expressed by myeloma cells and associated cells in the microenvironment. Blockade of the PD1-PDL1 axis enhances anti-myeloma activity in pre-clinical models. Pembrolizumab, a monoclonal antibody that blocks PD1-PD-L1 signaling, has shown clinical activity when combined with pomalidomide and dexamethasone in pomalidomide naïve patients with relapsed or refractory multiple myeloma (Badros et al, ASH 2015). Here we report the clinical experience of a previously pomalidomide exposed patient population receiving PEMBRO/POM/DEX. Methods: We retrospectively analyzed the efficacy of PEMBRO/POM/DEX in 9 heavily, pre-treated pomalidomide exposed patients with relapsed or refractory multiple myeloma between February 2016 and July 2016. All patients had been treated with ≥ 5 prior lines of therapy, including proteasome inhibitors, immunomodulatory drugs, and alkylating agents including high dose melphalan and autologous stem cell transplantation. The PEMBRO/POM/DEX regimen included pembrolizumab 2 mg/kg administered intravenously over 30 minutes every 2 or 3 weeks with pomalidomide 4 mg (range 2-4 mg) orally daily 21/28 days and dexamethasone 40 mg (range 4-40 mg) weekly until evidence of progression (PD) or unacceptable toxicity. Adverse events were captured via chart review. Responses were assessed as per IMWG criteria. Results: The median age of the patients was 65 years (range 51-77) with 66% females. The patients had a median of 8 prior lines of therapy (range 5-14). The majority of subjects (78%) had cytogenetic abnormalities: 33% were gain of 1q21, 44% monosomy 17, and 11% t(11;14). Prior to therapy, 89% had significant anemia, 78% lytic bone lesions and 2 with significant renal insufficiency (creatinine 2.32 and 3.32 mg/dl respectively) though no one was on dialysis. Isotype included 5 IgA, 2 IgG, 2 lambda light chain. All patients progressed after prior lenalidomide and 8 of 9 patients progressed on previous pomalidomide the other one having stable disease. Patients received a median 3 cycles (range 2-7) of PEMBRO/POM/DEX, with modifications of pomalidomide and dexamethasone dosage dependent on toxicity. Seven patients received aspirin DVT prophylaxis. The overall response rate of PEMBRO/POM/DEX was 33%. Eighty-nine percent of patients achieved clinical benefit (3 PR, 2 MR, 3 SD). Median PFS was 57 days (0-85 days). There were no observed discontinuations of treatment or deaths attributed to drug toxicity and no pneumonitis was seen. However, adverse events consistent with previous reports from pembrolizumab as well as pomalidomide and dexamethasone were observed across all 9 patients. These AEs included: fatigue (n=9), anemia (n=9), thrombocytopenia (n=7), neutropenia (n=5), diarrhea (n=5), fevers (n= 4), shortness of breath (n=4), lower extremity edema (n=4), nausea/ vomiting (n=3), and renal insufficiency (n=3). Two patients experienced non-infectious colitis that responded to prednisone. Overall survival at 6 months for the 9 patients was 56%. 4 patients have died from progressive disease. Conclusion: PEMBRO/POM/DEX is an active regimen for relapsed and refractory multiple myeloma with acceptable toxicity even in a heavily treated pomalidomide exposed patient population. Further investigation of this combination earlier in the course of the disease is warranted. Disclosures Cohen: Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy, Research Funding. Weiss:Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy; Prothena: Other: Travel, accommodations, Research Funding; Millennium: Consultancy, Other: Travel, accommodations; GlaxoSmithKline: Consultancy. Vogl:Constellation: Research Funding; Karyopharm: Consultancy; Teva: Consultancy; Calithera: Research Funding; GSK: Research Funding; Acetylon: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy. Garfall:Medimmune: Consultancy; Bioinvent: Research Funding; Novartis: Consultancy, Research Funding. Mangan:Novartis: Speakers Bureau. Stadtmauer:Janssen: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Teva: Consultancy.
Background Circulating plasma cells (PCs) have been identified as a prognostic factor in patients with myeloma precursor states (MGUS and SMM) and active multiple myeloma (MM). Enumeration of circulating PCs by available methods is not suitable for widespread use and does not provide molecular characterization. We developed and evaluated a novel method for enumeration and molecular characterization of circulating PCs (circulating multiple myeloma cells, “CMMC”), based on the CELLSEARCH® System (Janssen Diagnostics LLC, Raritan, NJ), an automated technology for the capture, enumeration and characterization of rare cells in the peripheral blood. Methods We are performing a prospective study of patients with MGUS and SMM to evaluate CMMCs as biomarker for progression to active MM. Utilizing the CELLSEARCH® System CMMCs were captured by CD138 ferrofluid magnetic particles and identification was defined as CD38+ and CD19-, CD45-. Nonviable cells were excluded by DAPI. Isolated CMMCs were stored and FISH for t(4:14), t(14;16) and del17 was performed. Results We have enrolled 16 patients, MGUS = 3, SMM = 11, and newly diagnosed MM = 2. The Mayo Risk stratification for MGUS patients was: low risk = 2, low-intermediate = 1. All SMM patients were low risk by Mayo Model incorporating serum free light chains. The median number of bone marrow plasma cells for MGUS patients was 7 (range 7-9) and for SMM patients was 15 (range 10-40). The median CMMCs for MGUS = 6 (range 2-55), median CMMCs for SMM = 31 (5-1918). The two patients with NDMM had 5870 and 5 CMMCs, respectively. A single patient with SMM progressed with a symptomatic solitary lumbar plasmacytoma and had CMMCs of 5 and 3 at baseline and progression, respectively. Abnormalities by FISH were detected in both bone marrow and CMMCs. Accrual is ongoing and additional data will be presented at the meeting. Conclusions The CELLSEARCH® CMMC assay can detect, quantify and provide molecular characterization of circulating PCs in MGUS/SMM/MM; longer prospective follow-up is needed to test the prognostic value of CMMCs. Disclosures Weiss: Janssen: Consultancy, Research Funding. Sasser:Janssen: Employment. Rao:Janssen: Employment, Equity Ownership. Foulk:Janssen: Employment. Gross:Johnson & Johnson: Employment, Equity Ownership. Cohen:Janssen: Membership on an entity's Board of Directors or advisory committees. Vogl:Celgene Corporation: Consultancy; Amgen: Consultancy; Millennium/Takeda: Research Funding; GSK: Research Funding; Acetylon: Research Funding. Stadtmauer:Janssen: Consultancy.
Introduction: Venetoclax is an oral BCL2 inhibitor, effective in CLL and under investigation in multiple clinical trials to treat relapsed or refractory multiple myeloma (RRMM) in combination with a proteasome inhibitor (VPI) - either carfilzomib or bortezomib (Moreau P, 2017; Kumar S, 2017). VPI has shown promising initial results in a phase 2 trial with an overall response rate of 78% and a very good partial response or better (≥VGPR) rate of 56% (Costa L J, 2018; Terpos E, 2019). However, a separate phase 3 trial evaluating bortezomib given with venetoclax or placebo found improved response rates and progression free survival but a decrease in overall survival rate in the venetoclax arm of the study (data not published). The primary association with increased mortality was infection. Better characterizing infections in patients treated with VPI may give insight into the pathophysiology and suggest strategies for safe and effective use of this therapy in RRMM. Methods: We retrospectively reviewed charts of patients treated with VPI for infectious complications from initiation of treatment until one month after progression treated at the Hospital of the University of Pennsylvania. Infections were classified by site, pathogen and severity of infection. Additional data collected included demographics, blood cell counts, quantitative immunoglobulins, SPEP M-spike, light chain analysis, cytogenetics, prior lines of therapy, prophylactic antibiotics and IVIG use. We determined non-monoclonal IgG (NM-IgG) via the difference between serum M-spike and IgG for IgG patients. The two-sample Wilcoxon rank-sum was used to compare different subgroups within our study population. Results: We identified 18 patients treated with a VPI combination regimen of which 78% were male. The median age was 64.5 years (range 47-76) and a median of 3 (1-10) prior regimens. 14 were treated with carfilzomib and 4 with bortezomib combinations. 4 patients progressed by the time of data collection. 8 patients were positive for t(11;14). 11 patients experienced 35 discrete infectious episodes resulting in 4 hospitalizations. Respiratory infections predominated (29/35) with 24 upper respiratory infections or sinusitis. 4 were lower respiratory infections and comprised all the hospitalizations. Among respiratory infections, viruses were the only pathogens identified, including influenza, rhinovirus, coronavirus and RSV. Other sites of infection were gastrointestinal (including recurrent C. difficile) and urinary tract. No CNS, blood, or intra-abdominal infections were identified. Reductions in lymphocyte counts and non-monoclonal IgG were near universal but significant reductions in neutrophil counts were not observed. A greater proportional reduction of NM-IgG was noted in good-responders, defined as CR and VGPR (≥VGPR, n=9), with a mean of 78% decrease compared to 47% in poor-responders (PR/MR/SD/PD, n=4, p=0.045). Importantly, treatment of those with t(11;14) positive status demonstrated no significant difference in NM-IgG. Additionally, there was a relative risk ratio favoring a reduction in infections among those with t(11;14). Conclusion: Patients with RRMM treated with VPI experience frequent infectious complications, some severe, with sustained reductions in serum IgG and lymphocyte counts, but without neutropenia. Reduction in NM-IgG is associated with improved response depth. This phenomenon could explain the paradoxical improvement of response rate and progression free survival with concomitant reduction in overall survival due to infections noted by other reports. Interestingly, the presence of t(11;14) in this analysis was not associated with as great a drop in NM-IgG, as was seen in responders as whole, indicating a more differential effect. The absence of significant reduction in NM-IgG is a potential mechanism for relative reduction of infections in this subgroup. Suggestions of survival benefit among t(11;14) positive subgroups in other reports may be related to this preservation of NM-IgG. Replenishing NM-IgG with IVIG is a hypothetical mitigating strategy that could be of benefit in other subgroups treated with this combination of therapy. Disclosures Cohen: Poseida Therapeutics, Inc.: Research Funding. Garfall:Surface Oncology: Consultancy; Novartis: Patents & Royalties: inventor on patents related to tisagenlecleucel (CTL019) and CART-BCMA, Research Funding; Janssen: Research Funding; Amgen: Research Funding; Tmunity: Honoraria, Research Funding. Vogl:Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Active Biotech: Consultancy. Mangan:janssen: Speakers Bureau; celgene: Speakers Bureau; takeda: Speakers Bureau; amgen: Speakers Bureau. Stadtmauer:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding. OffLabel Disclosure: venetoclax for myeloma
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