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  • 1
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    Antibodies in Development for Multiple Myeloma: A Systematic Review
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5656-5656
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5656-5656
    Abstract: Introduction Immunotherapy using monoclonal antibodies (mAbs) have been gaining significance in the treatment of multiple myeloma (MM). These include naked antibodies, checkpoint inhibitors (CPIs), novel bispecific mAbs targeting two epitopes and antibody-drug conjugates (ADCs) having a mAb conjugated to a cytotoxic drug. This review aims to summarize phase I and I/II clinical trials using mABs for the treatment of MM. Methods A comprehensive literature search using data from PubMed, Embase, AdisInsight and Clinicaltrials.gov was performed for identification of early phase (I and I/II) trials of mAbs in MM treatment (January 2008 to December 2017). Studies involving mAbs including targeting antibodies, ADCs, CPIs and bispecific mAbs were included, without considering the geo-location, age, sex or specific eligibility criteria. Drugs already approved by FDA were excluded. Results Total of 2537 phase I and phase I/II studies were identified. After screening by two reviewers and categorization by their mechanism of action, 74 clinical trials (CTs) that involved mAbs as monotherapy or in combination with other chemotherapeutic drugs for the treatment of newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). 41 CTs are active, completed or discontinued (Table 1) and 33 CTs are recruiting, approved for recruitment or planned. Most explored mechanism of action in these trials was mAb therapy directed against CD38, IL-6, huCD40, PD-L1 and PD-1. Isatuximab (Anti-CD38) has shown objective response rate (ORR) of 〉 50% in combination with lenalidomide (R) or pomalidomide (P) plus dexamethasone (d) in ongoing phase I trials NCT01749969 (n=57) and NCT02283775 (n=89) respectively. According to Vij et al. (2016) and Mikhael et al. (2018), 54% ORR (n=31) and 62% ORR (n=28) was shown by combination of isatuximab with Rd and Pd in 57 and 45 evaluable RRMM patients, respectively. In Vij et al. (2016) study, stringent complete response (sCR) in 2 (3%) patients, very good partial response (VGPR) in 13 (23%) and partial response (PR) in 16 (28%) patients was observed. In Mikhael et al. (2018) study, sCR in 1 (2%) patient, CR in 1 (2%), VGPR in 10 (21%) and PR in 16 (34%) patients was observed. In comparison, Martin et al. (2014) mentioned ORR of only 24% with isatuximab monotherapy in 34 RRMM patients. Grade (G) ≥3 pneumonia (n=4) was the most common high-grade adverse events (AEs) being reported (Table 2). Siltuximab (Anti-IL-6) has shown clinical efficacy in combination with bortezomib (V) + d and RVd in phase I and I/II CTs. Shah et al. (2016) and Suzuki et al. (2015) found ORR to be 90.9% and 67% in 11 (NDMM) and 9 (RRMM) patients when siltuximab was given combined with RVd and Vd, respectively. Clinical benefit response (CBR) i.e. ≥ minimal response (MR) was 100% with siltuximab + RVd in NDMM patients. In comparison, siltuximab monotherapy in 13 RRMM patients yielded an ORR of 15% (2 CR) as reported by Kurzrock et al. (2012). G≥3 neutropenia (n=9), G≥3 thrombocytopenia (n=6) and G≥3 lymphopenia (n=8) were most common reported high-grade AEs. Checkpoint inhibitors including pembrolizumab (anti-PD-1) and pidilizumab (anti-PD-L1) are being investigated in RRMM treatment. According to Otero et al. (2017) and Ribrag et al. (2017), 50% ORR was obtained with pembrolizumab combined with Rd compared to 0% with monotherapy, respectively. However, combination therapy was associated with G≥3 neutropenia (n=17), thrombocytopenia (n=9) and anemia (n=6) while no high-grade AEs were observed with monotherapy. Antibody-Drug conjugates including lorvotuzumab mertansine and indatuximab ravtansine have been investigated in CTs for MM treatment. Lorvotuzumab mertansine has shown clinical efficacy in combination with Rd in a phase I trial (NCT00991562). Berdeja et al. (2012) reported an ORR of 59% (1 sCR, 1 CR, 8 VGPR, 9 PR) in 32 RRMM patients. In a phase I/II trial (NCT01638936) of indatuximab ravtansine combined with either Rd or Pd, Kelly et al. (2016) showed ORR of 77% with Rd (n=43) including at least 1 CR and 4 VGPR and 79% with Pd (n=14) including 4 VGPR in total 57 RRMM patients. Conclusion Combination regimens including monoclonal antibodies, CPIs and ADCs have shown clinically significant response in RRMM and NDMM patients. The mAbs caused hematological and nonhematological AEs like cytopenias and infections which needs to be monitored closely. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-114224
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 2
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    A Decade of Anti-Myeloma Vaccine Development through Early Phase Trials: A Systematic Review
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5635-5635
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5635-5635
    Abstract: Introduction: Rationale for anticancer vaccine therapy is based on humoral and/or cellular response against unique tumor antigens (Ag). Peptide vaccines specific for Ag are under investigation for patients with multiple myeloma (MM). Among cell-based vaccines, monocyte derived dendritic cell (MDDC) fused with myeloma cells serve as Ag presenting cells to develop an immune response against a variety of targets. The purpose of this study is to report clinical response and tolerability of anti-myeloma vaccines. Methods: We included phase I and I/II trials developed between January 2008 to December 2017, where vaccines or viruses were used against MM, irrespective of the geo-location, age, and sex. We performed a comprehensive literature search (last update 3-30-2018) using the following databases: PubMed, Embase, AdisInsight, and Clinicaltrials.gov. Results: The initial search identified 2537 early phase studies. After screening by 2 reviewers and categorization by mechanism of action, 25 clinical trials (CT) that involved vaccines and/or viruses were included. We added 1 CT after the manual search. Therapy was given to 3 distinct classes of patients: patients without prior treatment (high risk smoldering MM or stage I MM, 4 CT), as an adjunct therapy for patients undergoing FDA approved treatments [high dose chemotherapy (HDT), allogeneic (allo-SCT) or autologous stem cell transplant (ASCT), 9 CT], and patients with residual or relapsed/refractory (RR) disease after FDA approved therapies (11 CT). Of the included 25 CT, 14 have published results available for analysis. For patients without prior treatments, PVX-410, a multi-peptide vaccine, resulted in at least minimal response (MR) in 50% of patients when combined with lenalidomiden and achieved stable disease (SD) for 60% of patients when used alone at 12 months follow up. Treatment with Idiotype-pulsed mature MMDC targeting idiotype proteins in MM showed MR in 30% of patients and SD in 43% of patients at 12 months. For patients receiving vaccines as an adjuvant treatment, recMAGE-A3 resulted in complete response (CR) and very good partial response (VGPR) in 46% and 54% respectively, at 3 months post ASCT follow up. By 12 months post ASCT, these responses were 38% CR and 23% VGPR. Treatment with MDDC (MAGE3 + Survivin + BCMA) resulted in SD in 42% of patients at a median of 25 months post vaccination and 55 months post ASCT. ScFv-FrC, a DNA fusion vaccine, resulted in CR in 50% and MR/SD in 21% at 52 weeks post vaccination. Ongoing CR/PR was maintained for 3+ years in 57 % patients, 4+ years in 36%, and 5+ years in 14% of patients following ASCT; OS was 64% after a median follow up of 85.6 months . Patients treated with MDDCs/tumor cells fusion vaccine had 69% SD after vaccination and 20% SD at a median of 26 months. When vaccines were given as a salvage therapy in RR MM, ImMucin vaccine showed a CR in 30% of patients during treatment, 20% maintained CR, and 13% had SD at a median of 24 months. Galinpepimut-S vaccine showed CR or very good partial response (VGPR) in 37% of patients at a median of 12 months, and 26% CR and VGPR at 18 months, with a progression free survival rate of 23.6 months. Patients receiving mHag loaded host MDDC vaccination also showed 8% CR for 〉 6 years (n=1) and 8% PR for 19 weeks (n=1); 33% had SD. Reolysin (wild-type reovirus), a virus-based vaccine, was used in 3 trials for RR MM patients. When alone, 42% of patients had SD and 58% had PD. When combined with dexamethasone and bortezomib 37% of patients had SD lasting for 3 cycles. Whereas, when combined with dexamethasone and carfilzomib, all patients had decrease in monoclonal proteins, with VGPR reported in 28%, PR in 43%, MR in 8%, and SD in 8% patients after 8 cycles. Most vaccines were well tolerated by patients, only grade (G) 1 and G2 side effects (SE), which were mostly flu-like symptoms and local skin reactions. G3 SE included pneumonia with mHag DC and Bcl2 peptide vaccine, GVHD with hTERT tumor vaccine, DVT and rash seen with scFv-FrC DNA vaccines. G4 SE were rare, but seen with reolysin, requiring 2 patients to be removed from study, and with DC/tumor cell fusion vaccine (1 pulmonary embolism). Conclusion Anti-myeloma vaccination therapy appears to be well tolerated, which makes it a promising adjuvant therapeutic agent against MM. Current data reveals positive immunologic activity in most patients and there is possibility of promising clinical responses with further drug development. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-115922
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 3
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    Efficacy and Safety of Histone Deacetylase Inhibitors in Multiple Myeloma - a Systematic Review of Early Phase Clinical Trials
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5629-5629
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5629-5629
    Abstract: Introduction Recent studies in novel therapies have created opportunities for new treatment regimens to be used in the management of multiple myeloma. Histone deacetylase (HDAC) inhibitors lead to epigenetic manipulation of multiple myeloma (MM) cells by reducing resistance to pro-apoptotic signals. Panobinostat is an FDA approved HDAC inhibitor for multiple myeloma. The aim of this article is to study the safety, efficacy and dose limiting toxicities of HDAC inhibitors in the early phase clinical trials in multiple myeloma. Methods We performed a comprehensive literature search for phase I & I/II trials of HDAC inhibitors during last ten years using following databases: PubMed, Embase, AdisInsight, and Clinicaltrials.gov. Studies involving HDAC inhibitors in multiple myeloma other than panobinostat irrespective of the age, sex or specific eligibility criteria were included. Results Out of 2537 studies, we included 25 trials (23 phase I, 2 phase I/II) of HDAC inhibitors in this systematic review having a total of 518 patients. Of these, 471(90.9%) patients were evaluable for response. Vorinostat (Vor) is the most studied drug used in 13 trials (n=281). Two trials had Vor-only regimen and the remaining 11 had combination regimens mostly with lenalidomide and bortezomib. Vor, in combination with lenalidomide (R), bortezomib (V) and dexamethasone (d) has showed 100% overall response rate (ORR) in 30 newly diagnosed multiple myeloma (NDMM) patients, (Kaufmann et al., 2016), fifty two percent patients achieved very good partial response (VGPR) and 28% patients showed complete response (CR). Another study using Vor + R regimen after autologous stem cell transplant in 16 NDMM patients showed VGPR in 7, stringent complete response (sCR) in 4, partial response (PR) in 2 and CR in 3 patients (Sborov et al.). Grade 3 neutropenia was seen in 1 patient in this study. Richter et al, 2011 showed an ORR of 24% in 29 relapsed refractory multiple myeloma (RRMM) patients with Vor only regimen. Another study (Kaufmann et al., 2012) with Vor only regimen used in 10 RRMM patients showed stable disease (SD) in 9 and minimal response (MR) in 1 patient. ORR of 65% was achieved in 31 RRMM patients receiving Vor in combination with doxorubicin & bortezomib (Vorhees et al, 2017). Thrombocytopenia & neutropenia were reported in 94% and 59% patients respectively. Ricolinostat in combination with Rd and Vd achieved an ORR of 55% and 29% respectively in two studies with 38 and 57 evaluable patients (NCT01583283, NCT01323751). Another ricolinostat regimen with pomalidomide & dexamethasone achieved ≥PR in 6/11 RRMM patients (Madan et al., 2016). Table 1 illustrates the efficacy, number of patients and regimens used in all the studies in this systematic review. Quisinostat in a 2017 study by Moreau P et al. (NCT01464112) showed an ORR of 88% in a combination regimen with Vd in RRMM patients (N=18). Drug related adverse events were seen in 13 patients, thrombocytopenia being most common in 11 patients, 2 patients had grade 3 cardiac disorders and 1 patient had a cardiac arrest. Romidepsin in a phase I/II study (Harrison et al., 2011) combined with Vd was used in 25 RRMM patients. ORR was 60% with VGPR n=7, CR n=2, PR n=6, SD n=5 and PD n=1. Grade ≥3 thrombocytopenia in 16, neutropenia in 9 and peripheral neuropathy in 2 patients was seen. Popat et al used combination of two HDAC inhibitors CHR 3996 and tosedostat in 20 RRMM patients. ORR was 10% and SD was seen in 30% patients. Grade 3/4 toxicities seen were thrombocytopenia (n=12), leukopenia (n=6) and diarrhea (n=5). A phase I study on AR-42 drug in 17 RRMM patients (Sborov et al., 2017) showed SD in 10, PD in 4, MR in 3 patients with progression free survival (PFS) of 8.2 months. Thrombocytopenia, neutropenia and lymphopenia were seen in 11, 10 and 6 patients respectively. A detail of all grade 3 and higher adverse events along with dose limiting toxicity is given in table 2. Three trials (NCT02576496, NCT01947140, NCT03051841) of Edo-S101, romidepsin and CKD-581 are currently recruiting with 84, 93 and 18 planned number of patients. Conclusion Regimens containing vorinostat have shown an ORR up to 100% in NDMM patients. HDAC inhibitors have also shown promising efficacy up to 88% ORR in RRMM population. Majority of the patients developed cytopenias as hematological adverse events. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-114019
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 4
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    The Comparison of Unmanipulated Bone Marrow Versus Peripheral Blood Haploidentical Stem Cell Transplantation in Adult Acute Leukemia: A Systematic Review and Meta-Analysis
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5768-5768
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5768-5768
    Abstract: Background: The use of peripheral blood stem cell source (PBSC) continues to grow in the setting of haploidentical hematopoietic stem cell transplantation (haplo-SCT), mainly due to the ease of collection and rapid peripheral blood count recovery. We conducted a systematic review and meta-analysis of the published literature to evaluate the outcomes of unmanipulated bone marrow (BM) and PB haplo-SCT for adult leukemia patients. Method: A comprehensive literature search of electronic databases (Medline, Embase, and Cochrane library) for studies published between 1 January 2004 to 24 June 2018 was conducted. We included the studies of unmanipulated BM and/or PB haplo-SCT in adult acute myeloid leukemia (AML) and acute lymphoblastic leukemia ( ALL) . We excluded the studies which combined PB and BM stem cell sources and the studies which did not report the results of BM and PB haplo-SCT for ALL and AML separately. CMA software v.3 was used for the analysis. Heterogeneity among studies was assessed using the I2 test. Random-effect model was applied. Publication bias was assessed using funnel plots. Primary endpoints were engraftment, 2-year overall survival (OS), disease-free survival (DFS), relapse incidence (RI); grade II-IV, III-IV acute and chronic GVHD. Results: Out of 1548 publications, 3 studies (n = 672 patients; retrospective; multi-center) met our inclusion criteria. The sample size of the studies varied between 71 and 451 patients. The median follow-up ranged from 18 to 46 months. PB haplo-SCT was used in 191 patients (Ruggeri, A. et al. 2018) and BM haplo-SCT was used in 481 patients (Arcese, W. et al. 2015; Ruggeri, A. et al. 2018; Chiusolo, P. et al. 2018). Myeloablative (MA) conditioning was used in majority of patients. The pooled (95%CI) engraftment rate was 93% (88-95) in BM group and 95% (91-97) in PBSC group. The pooled estimates (95%CI) of BM studies showed a 2-year OS rate of 56.1% (51.6-60.4), 2-year DFS of 48.9% (43.5-54.2) and 2-year cumulative RI of 24.6%(20.7-29).There was no heterogeneity in BM group (I2=0%) for 2-year OS, DFS and RI. For PBSC group, the pooled estimates (95%CI) for 2-year OS, DFS and RI were 56 % (48.9-62.9; I2=0%), 54% (46.9-60.9; I2=0%) and 22% (16.7-28.4; I2=0%), respectively. Incidences of grade II-IV, grade III-IV aGVHD and cGVHD from a pooled analysis (95%CI) were 23.1% (17.2-30.3; I2=55%), 5.4% (3.4-8.3; I2=16%) and 19.5% (9.7-35.3; I2=88%) for BM group in comparison to 38% (31.4-45.1; I2=0%), 14% (9.8-19.7; I2=0%) and 32% (25.8-38.9; I2=0%) for PBSC group. Pooled estimates were shown in figure 1. Conclusions: In this analysis, higher pooled rates of grade II-IV aGVHD (38% vs 23.1%), III-IV aGVHD (14% vs 5.4%) and cGVHD (32% vs 19.5%) were observed in PBSC group vs BM group, respectively. Based on comparable OS, DFS and RI, PB haplo-SCT appears to be a good alternative option for adult AML and ALL patients. Large prospective randomized controlled trials are required to confirm these results. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-109924
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    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 5
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    Evidence Based Recommendations for Supportive Care in Multiple Myeloma
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1952-1952
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1952-1952
    Abstract: Introduction: Multiple myeloma (MM) is associated with end organ damage that negatively impacts the quality of life (QOL)and supportive care has a potential to improve symptoms. Methods: After detailed search on Pubmed, Cochrane, Embase and Clinical Trials.gov, we finalized total 36 articles on supportive care published after 2004. Results: Management of skeletal events: Mhaskar et al. (2017, n=3257) compared bisphosphonates (BPs) with placebo (PBO) in preventing pathological vertebral fractures, skeletal-related events (SRE), reported risk ratio (RR) of 0.74 in each; 95% CI 0.62-0.89 and 0.63-0.88 respectively. Both zoledronic acid (ZA) and clodronic acid prevent SRE, but mortality rate was better reduced with ZA (hazard ratio [HR]=0.84; p=0.0118), (Gareth et al. 2010, n=1960). In a study by Zuradelli et al. (2009, n= 240); hypocalcemia developed in 93 (38.8%) patients on ZA for a median of 2.3 months (range, 0-34.9). Vitamin D and calcium replacement is essential in patients developing hypocalcemia with BPs, (Kennel et al. 2009). Vertebral augmentation procedures improved pain after compression fracture (n=923) by 4.8, 4.6 and 4.4 points at 1 week, 1 year and beyond 1 year respectively, (Khan et al. 2014). Valerie et al. (2011, n=84) analyzed improvement in bone pain with radiotherapy (median 45 grays) in 92 % patients. Prophylaxis of infections: Leng et al. (2018, n=70,687) observed reduced risk of herpes zoster (HZ) reactivation in patients on bortezomib or carfilzomib + HZ prophylaxis (2.4%) vs 5.8% in non-prophylactic group, (attributable risk reduction: 0.42; 95% CI 0.31-0.56). Teh et al. (2016, n=199) reported reduced risk of varicella zoster virus reactivation with valacyclovir (500 mg) in patients on bortezomib based therapy and following autologous stem cell transplant (ASCT) vs no prophylaxis (HR=0.06 vs 16.9; p 〈 0.01). Dimopoulos et al. (2016, n=569) found higher risk of pneumonia, 8.2% in daratumumab group (n=286) vs 7.8% in control group (n=283). Prophylactic trimethoprim-sulfamethoxazole reduced risk of PCP in 85% patients after ASCT (RR=0.15; 95% CI 0.04-0.62), Stern et al. (2014, n=1000). Incidence of Community-acquired pneumonia (CAP), noninvasive CAP and invasive pneumococcal disease in elderly population (≥65 years) was seen in 49, 33 and 7 patients on Pneumococcal polysaccharide conjugate vaccine group as compared to 90, 60 and 28 patients in placebo group respectively, (Bonten et al. 2015, n=84,496). Role of plasmapheresis in renal impairment (RI): Alkhatib et al. (2017) showed that plasmapheresis reduced dialysis dependency by removing serum free light chains (sFLC) in patients with RI (n=147), (RR 0.45; P = 0.02). Yu-X et al. (2015, n=147), showed lower 6-month dialysis dependency ratio with plasmapheresis and chemotherapy (PP + CTH) vs CTH alone, (15.6% vs 37.2%; RR=2.02; p = 0.04). High cut-off hemodialysis lowered sFLC level in 61% (n=42) and 63% patients at day 12 and 21 respectively. Out of these, 71% and 69% patients became dialysis independent, (Hutchison et al. 2012, n=67). Peripheral neuropathy (PN): Bortezomib caused PN in 124/331 (37%) patients (Richardson et al. 2009) whereas with thalidomide, the incidence of PN was 38% and 73% at 6 and 12 months, respectively, (Mileshkin et al. 2006, n=75). PN improved in 68% patients on bortezomib with dose modifications (n=72) vs 47% patients, without dose modification (n=19). (Table 1 and 2). Significant improvement in PN was seen with duloxetine vs placebo (1.06 vs. 0.34; p= 0.003), (Smith et al. 2013, n=231). Arbaiza et al. (2007, n=36) showed improvement in neuropathic pain with tramadol (p= 〈 0.001). Epoetin and derivates for anemia: Castelli et al. (2017, n= 31; median creatinine 1.2 mg/dL (0.8-3.0)) reported hemoglobin (Hb) increase of ≥1g/dL and ≥2g/dL in 71% and 31.7% patients respectively with epoetin α, transfusions requirement reduced from 2.39 ± 1.05 to 1.23 ± 1.36 (p 〈 0.001). Begiun et al. (2013, n= 72) compared the effect of darbepoetin (D) ± iron (Fe) vs placebo on erythroid recovery after ASCT. All patients receiving D + Fe achieved Hb ≥13 g/dL (p 〈 0.0001). Tonia et al. (2012, n= 16,093) showed 35% decrease in transfusion need with erythropoietin stimulating agents (RR=0.65; 95% CI 0.62-0.68). (Table 3) Conclusion: Along with anti-myeloma chemotherapy therapy, management of complications (anemia, infections, renal insufficiency) and other associated symptoms is necessary to improve the quality of life. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-110748
    RVK:
    XA 33000
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 6
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    Efficacy of Lenalidomide Based Three Drug Versus Two Drug Regimen for Relapsed Multiple Myeloma: A Systematic Review and Meta-Analysis of Randomized Trials
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3239-3239
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    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3239-3239
    Abstract: Introduction: Survival of patients with multiple myeloma (MM) has improved over the last decade, mainly due to advent of newer drugs, three drug based induction, high dose chemotherapy consolidation and routine use of maintenance therapy for eligible patients. Despite advances in therapy, many cases of MM ultimately relapse and there is need to summarize evidence comparing efficacy and clinical outcome of combination regimens used in relapsed or refractory MM (RRMM) treatment. We performed a systematic review and meta-analysis of randomized controlled trials to compare the efficacy of lenalidomide based three drug regimens versus two drug regimens among relapsed and refractory myeloma (RRMM) patients. Methods: We conducted a literature search on PubMed, Embase, Wiley Cochrane Library, Web of Science and ClinicalTrials.gov which was completed on March 26, 2018. We used keywords like "relapsed multiple myeloma", "revlimid", "dexamethasone", "elotuzumab", "carfilzomib", "bortezomib", "ixazomib", "daratumumab", "doxorubicin", "pembrolizumab", "thalidomide", "cyclophosphamide" along with MeSH and Emtree terms. The primary meta-analytic approach was a random effects model using the Mantel-Haenszel method. It was used to calculate pooled risk ratio of objective response rates with 95% confidence interval. Cochrane Collaboration's tool was used for quality assessment of included studies. Systematic reviews, meta-analyses, combination regimen without lenalidomide, newly diagnosed MM patients, and other plasma cell dyscrasias were excluded. Results: Literature search retrieved 11,362 titles. Following initial screening, 72 articles were considered for full text review. Of these only five studies with 2844 patients met inclusion criteria and two studies qualified for meta-analysis. The study arm used daratumumab (Dara), ixazomib, carfilzomib, or elotuzumab in combination with lenalidomide (Len) and dexamethasone (Dex). The control arm used combination of Len and Dex (LenD). There was no difference in overall response rate (ORR) between ixazomib-Len-Dex regimen versus LenD (RR=1.33, 95% CI = 0.83 to 2.17, p= 0.236). However significantly higher complete response (CR) was observed in ixazomib-Len-Dex group compared to LenD (RR = 1.82, 95% CI = 1.14 to 2.93, p = 0.013). An absolute increase in ORR among carfilzomib-Len-Dex, elotuzumab-Len-Dex, and daratumumab-Len-Dex versus LenD was 20.4% (87.1% vs. 66.7%, p 〈 0.001), 13% (79% vs 66%, p 〈 0.001) and 16.5% (92.9% vs. 76.4%, p 〈 0.001) respectively. Conclusion: Daratumumab and carfilzomib in Len based three drug regimens have better clinical efficacy when compared to lenalidomide and dexamethasone based two drug regimens among relapsed and refractory multiple myeloma patients. There was no difference between the ORR of ixazomib based combination regimen and LenD but higher number of patients achieved deeper responses. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-111930
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 7
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    A Single Center Retrospective Evaluation of Daratumumab Infusion Related Reactions with Split-First Dose Day 1 and Day 2 Infusion
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5667-5667
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5667-5667
    Abstract: Introduction: Monoclonal antibody's infusion related reactions (IRRs) include anaphylaxis, anaphylactoid reactions and cytokine release syndrome. These reactions are related to the time of infusion. Incidence of IRRs in patients treated with daratumumab is reported to be about 42%. Severity of the most commonly reported IRRs, during the first dose of infusion are between grade I and II. Approved dosage of daratumumab is 16 mg/kg IV weekly given for 1 through 8 weeks, then every 2 weeks from 9th through 24th week, after which it is given every 4 weeks from 25th week onwards, its use is continued until disease progression. The goal of this study is to evaluate the IRRs at cycle 1 day 1 (C1D1) and C1D2, using split dose daratumumab (8 mg/kg) and to look for the impact of prior leukotriene receptor antagonist administration on the incidence of IRRs. Methods: To study the IRRs at day 1 using split dose daratumumab C1D1 (8 mg/kg) and C1D2 (8 mg/kg), we performed a retrospective review of medical records of relapsed/refractory (R/R) multiple myeloma patients receiving daratumumab between December 1st, 2015 to March 31st, 2018 at our center. Key variables related to each patient were recorded from Epic electronic database. Data were summarized using counts and percentages. Results: A total of 35 patients were included and the incidence of IRRs was measured. Overall, 13 (37.14%) patients developed IRRs on day 1. Out of these 13 patients, 11 (84.61%) patients had grade II IRRs, 1 (7.69%) patient had grade I IRRs and 1 (7.69%) patient had grade III IRRs. Nineteen (54.2%) patients out of a total 35 patients were pretreated with montelukast; out of these 19 patients, 5 (26.31%) patients had grade II IRRs and 1 (5.26%) patient had grade III IRRs. Thus, 31.57% patients had IRRs with montelukast pretreatment. No patient had grade I or grade IV IRRs. Sixteen (45.71%) patients out of total 35 patients were not pretreated with Montelukast; out of these 16 patients, 6 (37.5%) patients had grade II IRRs and 1 (6.25%) patient had grade I IRR. No patient had grade III or grade IV IRR. Thus, 43.75% patients had IRRs without montelukast. Overall, 12.18% reduction in IRRs was noted with pretreatment using montelukast. Conclusion: This single center study demonstrates that split dose model of daratumumab in the treatment of R/R multiple myeloma shows lower incidence of IRRs when compared to historical controls reported in the literature. Moreover, pretreatment with leukotriene receptor antagonist also appear to decreases the incidence of IRRs in our patient population. Future randomized prospective trials are needed to support these findings and improving the overall impact on tolerance for daratumumab. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-119736
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 8
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    The Use of Checkpoint Inhibitors before and after Allogeneic Stem Cell Transplantion: A Double-Edged Sword
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5722-5722
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5722-5722
    Abstract: Introduction: Allogenic stem cell transplantation (allo-SCT) is a potentially curative option for hematological malignancies. Checkpoint inhibitors (CPI) have been successful in achieving remission for patients that relapse after allo-SCT. CPI can help relapsed/refractory (RR) patients to respond and bridge towards allo-SCT after achieving remission. Check point inhibition after allo-SCT carries an increased benefit of graft vs malignancy effect (GvL) but it may exaggerate the risk of immune system related toxicity such as graft versus host disease (GvHD). Methods: To assess the safety and efficacy of CPI use in conjunction with allo-SCT, after a comprehensive literature search, we included data (n=283) from a total of twenty-four studies (11 original manuscripts, 13 case reports or case series) and analysed the results. Results: Most common indication for CPI use was Hodgkin lymphoma (n=182). CPIs used in various studies included CTLA-4 inhibitors (ipilimumab, n=93) and PD-1 inhibitors (nivolumab, n=167 and pembrolizumab, n= 27). In patients who were exposed to CPI before allo-SCT (n=107), 56% patients developed acute (a) GvHD and 29% patients developed chronic (c) GvHD. The overall mortality risk (11/107) associated with GvHD was 11%. Interval between last dose of CPI and allo-SCT ranged from 28-62 days. Median cycles of CPI therapy ranged from 4-9 cycles. The overall response rate (ORR) was observed (42/62) to be 68% patients with complete remission (CR) in 47% patients and partial remission (PR) in 21% patients. Most common adverse events reported were non-infectious febrile syndrome (12%), infections (5%), hepatic sinusoidal obstruction syndrome (4%) and encephalitis (3%). In patients (n=150) who received CPI after allo-SCT for treatment of disease relapse, 13% patients developed aGvHD and 11% patients developed cGvHD. The overall mortality risk with GvHD was around 7% in this population. The interval between allo-SCT and first dose of CPI ranged from 12.5 months to 29 months. Nivolumab was given at doses 1 mg/kg to 3 mg/kg, weekly or two-weekly. Ipilimumab dose ranged from 0.1 mg/kg to 5 mg/kg. A combination with lenalidomide was also tried. Pembrolizumab was administered at 200 mg/kg every three weeks. An ORR of 48% (59/123) was observed with CR in 34 (28%), PR in 25 (20%) and disease stabilization in 7 (6%) patients. Complications, other than GvHD, include hematological side effects (22%), most notably neutropenia followed by respiratory and hepatic complications (16% and 14% respectively). Thirteen case reports evaluated safety and efficacy of CPIs after allo-SCT. Among 26 cases, the reported ORR was 85% with fifteen and seven patients achieving CR and PR, respectively. Of the four patient deaths that occurred during the study period, one died of GvHD. Most common adverse reactions noted were in the GI tract, notably hepatitis (32%), followed by skin (25%) and pulmonary disease (25%). Conclusion: CPI use before and after allo-SCT can be highly effective for relapse disease control. For patients who received Allo-SCT, CPI exposure can lead to significantly increased risk of GvHD, GvHD related morbidity and mortality. There is need for caution while making decision for CPI use in this population. Prospective well-designed clinical trials are required to further explore the safety of CPIs in allo-SCT setting. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-110006
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
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  • 9
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    Clinical Response and Tolerability of Selinexor in Acute Myeloid Leukemia and Other Hematologic Malignancies - a Systematic Review
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5231-5231
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5231-5231
    Abstract: Introduction Selinexor, a SINE (selective inhibitor of nuclear export) compound, inhibits exportin 1 (XPO1) involved in transport of tumor suppressor proteins leading to apoptosis of tumor cells. XPO1 is overexpressed in variety of cancer including ovarian cancer, pancreatic cancer, glioma, osteosarcoma, leukemia, lymphoma, and multiple myeloma. The aim of this study is to summarize clinical response and adverse events of selinexor in hematological neoplasms. Methods A comprehensive literature search on PubMed, Embase, AdisInsight and Clinicaltrials.gov was completed on July 12, 2018. Studies focusing on efficacy and/or adverse events of selinexor in patients with hematological neoplasms were included for the review. Results Out of 321 studies found on initial search, we finalized 15 studies (8 phase I and 7 phase I/II) after screening by two reviewers. AML: Selinexor in combination with high-dose cytarabine and mitoxantrone has shown overall response rate (ORR) of 70% among 20 patients with acute myeloid leukemia (AML), Wang et al., 2018. Out of 12 newly diagnosed AML (ND AML) patients, 11 (92%) patients showed response with complete response (CR) in 7, CR with incomplete recovery (CRi) in 3 and partial response (PR) in 1 patient. Among 8 relapsed/refractory AML (R/R AML) patients, only 3 patients showed CR while 5 had treatment failure (TF), ORR in this subset was 38%. In 81 evaluable R/R AML patients receiving selinexor as monotherapy only 14% of the patients showed response while 31% patients had disease progression (PD) along with grade ≥3 hematological adverse events (AEs) of thrombocytopenia, anemia and neutropenia in 19%, 15% and 13% patients, respectively (Garzon et al., 2017). MM: Relapsed refractory multiple myeloma patients receiving selinexor combined with pomalidomide and dexamethasone have achieved ORR of 60% with CR in 1 and PR in 5 patients (Chen et al., 2016 n=10) with grade ≥3 neutropenia in 8 patients. In another regimen with doxorubicin and dexamethasone the clinical benefit rate (CBR) was 26% with 15% overall response (Rachid et al., 2017 n=27). Grade ≥3 neutropenia, thrombocytopenia and hyponatremia occurred in 33%, 33% and 30% of patients, respectively. NHL: Kuruvilla et al. observed ORR in 31% patients with relapsed refractory non-Hodgkin lymphoma with single-agent selinexor. Grade ≥3 thrombocytopenia, neutropenia and anemia occurred in 47%, 32% and 27% patients, respectively. The efficacy of selinexor in phase I and I/II clinical trials is given in table 1 while toxicity is mentioned in table 2. With selinexor, the most common hematological and nonhematological AEs noted were thrombocytopenia and hyponatremia, respectively. Conclusion: Selinexor based combination regimens have shown better clinical response against AML as compared to monotherapy. The efficacy results in multiple myeloma and other hematological malignancies are also encouraging. The adverse events like cytopenias were common as in other chemotherapy regimens. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-116819
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 10
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    Efficacy and Tolerability of Daratumumab in Heavily Pretreated AL Amyloidosis: A Systematic Review
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2025-2025
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2025-2025
    Abstract: Introduction Light chain (AL) amyloidosis is a low burden plasma cell disorder, characterized by deposition of misfolded lambda or kappa light chains. Kidney dysfunction is present in almost two-thirds of patients at the time of initial presentation, followed by diastolic heart failure in about 50% of cases, which is responsible for 75% of deaths in these patients. Autologous stem cell transplant (auto-SCT) remains the gold standard for the management of AL amyloidosis but is often impractical to perform by virtue of patients' age, medical comorbidities including cardiac involvement. Methods We conducted a literature search using three databases (PubMed, Embase,Web of Science). Our search strategy included MeSH terms and key words such as AL amyloidosis, daratumumab and darzalex from date of inception to March 2018. After excluding duplicates, reviews and non-relevant articles, we selected eight studies, including two case reports, two phase II prospective trials and four retrospective trials. Results Data on 129 patients was included, there ages ranged from 43-83 years. Median number of prior therapies were 3 (range: 2-6), 106 (82%) received proteasome inhibitor (bortezomib) based therapy, and 69 (53.5%) received immunomodulatory (lenalidomide) based therapy. Another 41 (32%) received high dose melphalan (HDM) followed by auto-SCT. The time from the diagnosis of AL to the start of daratumumab therapy varied from 0.7-150 months. Eighty-nine (69%) patients had cardiac and 64 (49.6%) patients had renal involvement. A total of 114 (88%) patients received a daratumumab dose of 16 mg/kg weekly for 8 weeks followed by every 2 weeks for the next 8 weeks. A total of 104 patients were evaluable for hematological response, assessed by improvement in free light chain (FLC) levels. Daratumamab achieved an impressive overall response rate (ORR) of 72% (n=75). Complete remission (CR) in 15 (14%) of patients, very good partial response (VGPR) in 44 (42%) and a partial response (PR) in 16 (15%) of patients was noted. Thirty-four patients with cardiac involvement and 26 patients with renal amyloidosis were assessed for organ response across four studies. Thirteen (38%) patients with cardiac amyloidosis demonstrated an improvement in N-terminal pro brain natriuretic peptide (NT-proBNP) levels. Ten (38%) patients with renal involvement responded according to consensus criteria [Palladini et al 2014] for organ response. Another two had improvement in serum creatinine levels. Among the 129 patients treated with daratumumab for AL amyloidosis, 36 (32%) reported infusion related reactions (IRR). Most were mild (grade 1-2). Daratumumab infusion was well tolerated in patients with cardiac (n=54) and renal involvement (n=48). Only one patient needed adjustment in his diuretic dose, another one developed decompensated heart failure and one died due to progression of cardiac disease. Seven patients had worsening of their NT-proBNP levels. Similarly, no dose adjustments were required for patients with renal amyloidosis and one patient tolerated daratumumab infusion at a GFR 〈 20 mL/min without any complications. Conclusion Daratumumab monotherapy is associated with deep and prompt hematological responses in patients with heavily pretreated AL amyloidosis, at the standard dosing regimens used for multiple myeloma, with a favorable safety profile. Furthermore, daratumumab performed well in patients with cardiac amyloidosis even though there is an increased risk of volume overload and infusion related morbidity. Given the high incidence of peripheral neuropathy with bortezomib, cardiotoxicity with carfilzomib based regimens in amyloidosis patients, daratumumab appears to be a suitable alternative. It has already been approved for relapsed amyloidosis (AL) patients in the European Union. Currently, it is being investigated as monotherapy for AL amyloidosis in phase 2 trials (NCT02841033 and NCT02816476) and in combination with bortezomib, cytoxin and dexamethasone (VCd) in a phase III trial (NCT03201965). Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-115214
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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