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  • 1
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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
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    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 2
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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
    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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    Safety and Efficacy of Venetoclax in Relapsed Refractory Multiple Myeloma: A Systematic Review and Meta-Analysis
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5625-5625
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5625-5625
    Abstract: Background: Management of relapsed or refractory multiple myeloma (RRMM) is challenging. Venetoclax (ABT-199) is an oral selective inhibitor of an anti-apoptotic protein Bcl-2 that showed activity in preclinical studies, especially for t(11;14) MM cell lines or in the cells with high bcl-2 expression. We conducted a systematic review and meta-analysis to evaluate the outcomes of venetoclax in RRMM. Method: Literature databases (Medline, Embase, and Cochrane) were searched for studies published up to June 19, 2018. Our search strategy included MeSH terms and key words for multiple myeloma and venetoclax including trade names and generic names. CMA software v.3 was used for analysis. Random-effects model was applied. Results: 163 patients (n=115 in dose escalation, n=48 in safety expansion) were identified from two clinical trials (phase Ib study by Moreau, P. et al. 2017, n=66 and phase I/II study by Kumar, S. et al. 2017, n=66) and one retrospective study (Galligan, D. et al. 2017, n=31). The median age was 63, 64, N/A in phase Ib, phase I/II and retrospective study, respectively. 47 patients (29%) had t(11;14). Other cytogenetic aberrations were del(17p) [n 〈 25]; t(4;14) [n=5] ; del(13q) [n=41]; t(14;16) [n 〈 5]; t(14;20) [n 〈 5]. 124 patients (76%) were refractory to bortezomib and/or lenalidomide; most patients had ≥3 prior therapies. Venetoclax doses escalated from 50 mg/day to 1200 mg/day in phase Ib and phase I/II studies. Safety expansion doses were 800 mg and 1200 mg in phase Ib and phase I/II studies, respectively. Median dose of venetoclax for the retrospective study was 800 mg daily. Bortezomib and dexamethasone doses from phase Ib study were 1.3 mg/m2 subcutaneous and 20 mg, respectively. The median duration on venetoclax and median time on study ranged from 2 to 6 months. Median duration of response (DOR) and median time-to-progression (TTP) were reported higher with combination therapy of bortezomib and dexamethasone (9.7 months and 9.5 months, respectively). 62% of patients have discontinued the therapy due to: progressive disease (48%), adverse events (6%), and various other reasons (8%). There were 13 deaths; 6 were due to disease progression. Most common side effect from three studies was gastrointestinal problems such as nausea, diarrhea and vomiting. The median duration of response was 9.7, 9.7, 2 months and the median time to progression was 9.5, 2.6, NA months for phase Ib, phase I/II and retrospective study, respectively. The pooled overall response rate (ORR) for all patients was 43% (n=163) with the highest rate (67%) being reported from phase Ib study using combined venetoclax, bortezomib and dexamethasone (Figure 1 and 2). Among 44 patients with t(11;14), ORR was 40% and 78% in phase I/II and phase Ib studies, respectively. Twenty-eight patients who expressed high-bcl2 showed ORR rates of 80% and 94%, whereas 50 patients who had low-bcl2 level showed ORR rates of 8% and 59% in phase I/II and phase Ib studies, respectively (Table 1). Conclusion: Single-agent venetoclax showed an ORR of 21%, the addition of bortezomib produced an ORR of 32%, and the addition of bortezomib and dexamethasone improved an ORR to 67%. Better ORR was observed in patients with t(11;14) and with high-bcl2 expression. The highest median DOR (9.7 months) and TTP (9.5 months) were reported with a combination therapy of venetoclax, bortezomib and dexamethasone. Most reported adverse events were related to gastrointestinal system. More clinical studies evaluating the combination therapies using venetoclax are needed. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-109925
    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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  • 4
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    Sequencing Therapy for Elderly Chronic Lymphocytic Leukemia Patients in the Era of Novel Therapies: An Overview of Randomized Clinical Trials
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5559-5559
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5559-5559
    Abstract: Background: For most of the elderly or unfit CLL patients, treatment algorithms focus on achievement of clinical response, relief of symptoms and prolongation of life expectancy. Comorbidities, frailty and reduced functional status in elderly patients make some of the standard treatments intolerable and less efficacious. However, recent advancements in understanding of CLL biology, approval of target agents including novel monoclonal antibodies and kinase inhibitors have expanded the horizons for treatment of CLL in elderly. Methods: We conducted a literature search on PubMed, Embase, Web of Science and ClinicalTrials.gov which was completed on July 1, 2018. To assess the CLL treatment protocols in the elderly population, we included data from phase II and phase III clinical trials from the last decade (Jan 2008 to Jan 2018). Results: From a total of 1259 studies, we selected 34 studies (n=3122) after inclusion criteria were met. The patients included are from the age group of ≥65 years with the mean age of 68.8 years. Male to female ratio was 3:2. On comparison of different parameters to look for the drug or regimen efficacy, we found that ibrutinib is very effective and tolerable in older (aged ≥65 years) treatment-naïve (TN) as well as relapsed refractory patients (RR), with overall response rate (ORR) of 91% for combined group in one study when compared to ofatumumab. When used in combination with ublituximab, the ORR peaked to 80% as compared to ibrutinib alone in patients with high risk cytogenetics (ORR=47%, p 〈 0.001). Phase III RESONATE trial showed a comparison between ibrutinib and chlorambucil treated del 17p negative elderly patients; ibrutinib was superior in terms of ORR (86% vs. 35%) and overall survival (OS) (2-year OS, 98% vs. 85%, p=0.001). The OS with ibrutinib turned out to be 89% showing better disease control as compared to idelalisib (OS= 61%) when used in combination with rituximab, with a 33% reduction in mortality with ibrutinib as compared with idelalisib in RR patients. The combination of rituximab with idelalisib has shown promising results in patients with specific mutations (i.e. 100% ORR in those with del (17)/ Tp53 mutations, 97% ORR in those with unmutated IGHV). Similarly, when compared with placebo and rituximab combination progression free survival (PFS) was 13%, idelalisib is found to have PFS of 66% at 12 months in patients with del 17p/ Tp53 mutations and unmutated IGHV status. Moreover, in a phase II study, ofatumumab monotherapy showed ORR of 72%. In newly diagnosed (ND) CLL, an ORR of 98% is found with the pentostatin, cyclophosphamide, rituximab, and lenalidomide regimen. Other worth sharing results include; complete remission (CR) in 71% (24 out of 34 included) patients who were given lenalidomide as an initial therapy, with OS of 88% and ORR of 65%. The OS is surprisingly as high as 97.9% in those who were given pentostatin and cyclophosphamide in combination with ofatumumab. Traditional chemotherapy with fludarabine and rituximab (FR) showed OS of 67% in one study with rates of grades II and III-IV acute GVHD as 60% and 15% respectively. The most common hematological side effects seen with ibrutinib in one of the studies are neutropenia (12%), thrombocytopenia (4%) and anemia (7%). The non-hematological complications may be secondary due to cytopenias (infections, pneumonia, bleeding, and neutropenic fever) or due to constitutional symptoms like myalgia, fatigue, vomiting, or nausea. Conclusion: The rapid clinical development of novel therapy agents has changed the prognosis for CLL patients. Ibrutinib is considered as a standard option and an up front therapy for high risk CLL patients especially who are elderly and have del 17p, despite its significant toxicity profile in very elderly patients (80 years and above) where multiple deaths were reported. Future prospects include ibrutinib combinations with frontline chemo-immunotherapy (CIT) and other novel agents for TN and RR del 17p negative patients. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-117084
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 5
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    Prognostic Impact of Red Cell Distribution Width on the Development of Contrast-Induced Nephropathy, Major Adverse Cardiac Events, and Mortality in Coronary Artery Disease Patients Undergoing Percutaneous Coronary Intervention
    Bentham Science Publishers Ltd. ; 2021
    In:  Current Cardiology Reviews Vol. 17, No. 6 ( 2021-11)
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    In: Current Cardiology Reviews, Bentham Science Publishers Ltd., Vol. 17, No. 6 ( 2021-11)
    Abstract: Red cell distribution width (RDW) serves as an independent predictor towards the prognosis of coronary artery disease (CAD) in patients undergoing percutaneous coronary intervention (PCI). A systematic search of databases such as PubMed, Embase, Web of Science, and Cochrane library was performed on October 10th, 2019, to elaborate the relationship between RDW and in hospital and long term follow up, all-cause and cardiovascular mortality, major adverse cardiac events (MACE) and development of contrast-induced nephropathy (CIN) in patients with CAD undergoing PCI. Twenty-one studies qualified this strict selection criterion (number of patients = 56,425): one study was prospective, and the rest were retrospective cohorts. Our analysis showed that patients undergoing PCI with high RDW had a significantly higher risk of in-hospital all-cause mortality (OR 2.41), long-term all-cause mortality (OR 2.44), cardiac mortality (OR 2.65), MACE (OR: 2.16), and odds of developing CIN (OR: 1.42) when compared to the patients with low RDW. Therefore, incorporating RDW in the predictive models for the development of CIN, MACE, and mortality can help in triage to improve the outcomes in coronary artery disease patients who undergo PCI.
    Type of Medium: Online Resource
    ISSN: 1573-403X
    URL: Article
    DOI: 10.2174/1573403X17666210204154812
    Language: English
    Publisher: Bentham Science Publishers Ltd.
    Publication Date: 2021
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  • 6
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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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  • 7
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    Comparative Efficacy and Safety of Once Versus Twice Weekly Carfilzomib Based Therapies in Relapsed Refractory Multiple Myeloma- a Systematic Review
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3150-3150
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3150-3150
    Abstract: Introduction: Carfilzomib use as a single agent or in combination has been shown to improve outcomes in relapsed refractory multiple myeloma (RRMM). Traditionally, carfilzomib has been administered in twice-weekly dosage schemes as compared to the newly approved once-weekly dosage scheme. The once-weekly dosing of carfilzomib is thought to provide same efficacy and has been evaluated in many clinical trials. We have performed a systematic review of comparative efficacy and toxicity profiles of once and twice-weekly carfilzomib dosing schemes in RRMM. Materials and methods: Systematic review was done according to PRISMA statement. PubMed, Embase, AdisInsight, & Clinicaltrials.gov databases were searched, without any filters, using the search terms "Multiple Myeloma" AND "Kyprolis" OR "Carfilzomib". Most recent reports of phase I/II/III clinical trials reporting the clinical efficacy and/or safety of carfilzomib in RRMM were considered for inclusion. After screening of 267 articles, 16 clinical trials (N=2393) evaluating twice-weekly carfilzomib and 4 trials (N=418) evaluating once-weekly dosing schedule were considered for inclusion. Results Once versus (vs.) twice-weekly carfilzomib regimens were evaluated in a total of 406 and 1869 patients, respectively. In our discussion, group-1 refers to patients receiving once weekly carfilzomib while group-2 refers to twice weekly dosing schedule group. For the evaluated population, high risk cytogenetics were reported in 15% (n=60) patients in group-1 and in 17% (n= 317) patients in group-2. The median no. of prior lines of therapy ranged 1-8 in group-1 as compared to 1-20 in group-2. All studies reported the patient responses according to International Myeloma Working Group (IWMG) response criteria. The cumulative overall response rate (ORR) was better in group 1: 70.4% (n= 286) vs. 48% (n= 896). Similarly, more patients in group-1 achieved stringent complete response (sCR) or complete response (CR): 11.5% (n= 47) patients in group 1 vs. 5.2% (n= 99) patients in group 2. The response rates were also non-inferior in group-1 for other responses as overall. In group-1, 30% (n= 123) patients achieved very good partial response (VGPR) compared to 21% (n=389) patients in group-2. The partial response (PR) rate was 28.5% (n= 116) vs. 22% (n= 412) in groups 1 and 2 respectively The rate of minimal response (MR) achievement was comparable in both groups: 5% (n= 21) in group-1 vs. 8% (n= 154) patients in group-2. But lesser proportion of patients in group-1 went on to develop progression of myeloma disease [5.6% (n= 23) vs. 15.6% (n= 293)]. Stable disease (SD) state was achieved by 12.3% (n=50) patients in group-1 compared to 20% (n= 379) patients in group-2. Owing to phase-1 design of most clinical trials evaluating the once-weekly dosing schedule, the survival data is immature at present, but the median progression free survival (PFS) ranged from 1 day to 12.6 months in group-1 while in group 2 it ranged from 3.7-44.4 months. (Table-1) The toxicity profiles were also comparable for both dosing schedules. The most common hematological adverse events (AEs) were anemia and thrombocytopenia and their incidences were 15.7% (n= 64) vs. 25.5% (n= 477) and 13.3% (n= 54) vs. 23.1% (n= 432) in groups 1 and 2 respectively. The most common non-hematological AEs were infections, fatigue, and nausea that were reported in 22% (n= 89), 19% (n= 77), and 17.4% (n= 71) patients in group 1, and 14.5% (n= 272), 19.3% (n= 362), and 19.1% (n= 357) patients in group 2, respectively. Overall, grade 3 or above cardiac AEs were reported in 3.4% (n= 14) patients in group 1 and 3.3% (63/1869) patients in group 2. The most common cardiac AE was hypertension which constituted 50% (n= 7) and 64% (n= 40) of all grade 3 or more cardiac AEs in groups 1 and 2, respectively. Conclusion Achievement of objective response rates for once-weekly carfilzomib appears to be better or at-least similar to twice-weekly carfilzomib regimens. There is paucity of prospective studies comparing once vs. twice-weekly carfilzomib in RRMM which highlights the need for more clinical trials evaluating this regimen. Apart from efficacy and safety profile, once-weekly carfilzomib dosing also carries the potential of becoming a preferred option in terms of lesser financial burden and number of patient visits to the infusion centers. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-132081
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    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 8
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    Efficacy and Toxicity Profile of Elotuzumab for Multiple Myeloma: A Systematic Review and Meta-Analysis
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5640-5640
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5640-5640
    Abstract: Background: Elotuzumab (elo) is a humanized monoclonal antibody, which has been approved by the FDA for use in combination with lenalidomide (lena) and dexamethasone (dexa) in patients (pts) with relapsed and refractory multiple myeloma (RRMM). Elotuzumab is effective as a single agent, as well as in combination for multiple myeloma treatments, supporting the use of elo in pts with RRMM and newly diagnosed multiple myeloma (NDMM) pts. Method: After review of literature using database searches was done on 6/27/18 (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), 9 prospective and 1 retrospective study with 1128 enrolled pts met the inclusion criteria to date in RRMM and 2 clinical trials including 123 pts in NDMM (Table 1). CMA software v.3 was used for meta-analysis. A random-effect model was applied. Result: Regimens used in RRMM: Based on pooled analysis (95% CI), an overall response rate (ORR) of 66% (54-76.2) was calculated in 685 evaluable pts treated with elo based regimens in RRMM (Figure 1). Most common grade (G) ≥ 3 hematological adverse events (HAE) and non-hematological adverse events (NHAE) based on regimen were calculated using pooled analysis in RRMM pts (Table 2). Anemia was noted in 12.1% ( 7.7-18.6) in 559 pts, while neutropenia in 14.5% (7.5-26.4) out of 591 pts and thrombocytopenia (tcp) in 11.9% (7.9-17.4) in 198 evaluable pts. Diarrhea 5.5% (3.6-8.3), pyrexia 2.4% (1.5-4), peripheral neuropathy (PN) 8.4% (3.8-17.8) were measured in 626, 668 and 143 pts respectively. Elotuzumab as monotherapy: 1 study (n=34) evaluated the efficacy of elo as single agent in RRMM. The median age, time from diagnosis and number of prior therapies were 64.5 years (y) (46-87), 4.4 y (0.9-12.8) and 4.5 y (2-10) respectively. It produced an ORR of 1.4% (0.1-19.1 95% CI) in 34 evaluable pts. Adverse events recorded were pyrexia and fatigue in 17.6% and 8.8% pts respectively. Elotuzumab in two drug regimen: In RRMM, 2 clinical trials (n=49) evaluated the efficacy (95% CI) of elo, ORR of 25% (4.1-72.3) was calculated. The best PFS (progression free survival) produced was in combination of elo 20 mg with bortezumib (bort) 1.3mg/m2 of 9.46 months as compared to 1.8 months when elo10mg/kg + dexamethasone (dexa) 28mg was used. In our analysis for safety, common G≥ 3 HAE calculated were, thrombocytopenia 8.7% (3.3-21.1) n=49, neutropenia 10.7 % (3.5-28.4) n=28 pts and anemia 7.1% (1.8-24.5) n=28 pts. NHAE included diarrhea 1.7% (0.1-22.3), PN 10.7% (3.5-28.4), pyrexia 1.7% (0.1-22.3) in 28 evaluable pts each. Elotuzumab in three drug regimen: In RRMM, 10 clinical trials including 602 pts evaluated the efficacy of elo as a part of triple drug regimen, producing an ORR of 72.2% (54-76.2). The best results were produced with the combination of elo 10-20mg/kg + lenalidomide (lena) 25mg + dexa 40mg producing a PFS of 32.2 mo and 28.62 mo in its phase I and II cohorts respectively. Based on pooled analysis (95% CI) common HAE calculated were neutropenia 17.5% (7.6-35.4) in n=563, thrombocytopenia 12.7% (8.2-19.4) in n=149 and anemia 13% (8-20.5) in n=531 pts. Common G ≥ 3 NHAE estimated were diarrhea 5.7% (3.7-8.6), PN 6.6% (2-19.2), pyrexia 2.5% (1.5-4.1) in 598, 115 and 640 pts respectively. Elotuzumab based regimen in NDMM: A currently ongoing clinical trial NCT02272803 has produced promising results in NDMM pts. As a part of three drug regimen with dose of elo 10mg/kg-20mg/kg, lena 25mg, dexa 20mg in 40 pts produced an ORR of 87.5% (73.2-95.8) versus control group of lena 25mg plus dexa 40mg in 42 pts with an ORR of 73.8% (58-86.1). The PFS rate recorded at 1 year was 93% (79-98%) and 91% (73-97%) respectively. The HAE G ≥ 3 included, neutropenia 18% and leukopenia 15%. In another study with 41 pts, elo was used in combination with lena, bort and dexa producing an ORR of 100% and greater than grade 3 adverse events including Tcp 15%, PN 2%. Conclusion: Results produced in our study suggest that elotuzumab is highly effective when used in pts with RRMM and NDMM. Combination regimens for elo produces an ORR ranging from 79-83% with elo + lena+ dexa, proving that the best results were produced by three drug regimens. Large prospective studies are required to evaluate efficacy and safety of elotuzumab in combination therapies. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-117209
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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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  • 9
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    Antibody Based Three-Drug Regimens for Multiple Myeloma - a Systematic Review of Phase II and Phase III Clinical Trials
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5546-5546
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5546-5546
    Abstract: Introduction Elotuzumab is monoclonal antibody (mAb) that specifically targets signaling lymphocytic activation molecule family member 7 (SLAMF7) that is present on myeloma cells. It fights myeloma cells by stimulating phagocytic action of NK cells and via ADCC (antibody‐dependent cell‐mediated cytotoxicity) pathway. Daratumumab is an anti-CD38 mAb with dual mechanisms of action i.e. tumoricidal and immunomodulation. The aim of this study is to review the efficacy and toxicity of elotuzumab and daratumumab based 3-drug combinations in patients (pts) with multiple myeloma (MM). Methods A systematic search of PubMed, Embase, Clinicaltrials.gov, Cochrane and Web of Science was performed for elotuzumab and daratumumab based regimen in MM patients from inception to June 12, 2019. Out of 604 studies, 08 phase II and III clinical trials based on 3-drug regimen were finalized. Results Total 2809 patients (pts) were evaluated out of 2879 enrolled pts. 856 were newly diagnosed (ND) and 1953 were relapsed/refractory (R/R). Elotuzumab (E) based 3-drug regimen were evaluated in 560 whereas daratumumab (D) based 3-drug regimen were analyzed in 889 pts. ELOQUENT-3 trial (n=117) in phase II used E + pomalidomide (P) and dexamethasone (d) (EPd) for R/R pts with ≥2 prior therapies. Median (m) progression free survival (PFS) was 10.2 months (mo) in EPd versus (vs) 4.6 mo in Pd arm [Hazard ratio (HR) 0.54 (95% CI: 0.34-0.86; p=0.008)], i.e. 46% lower risk of progression or death in EPd vs Pd arm. ORR (overall response rate) was 53% (complete response [CR] 5% + stringent CR [sCR] 3% + partial response [PR] 33% + very good partial response [VGPR] 12%) in EPd vs 26% in Pd arm (odds ratio [OR] : 3.25 (1.49-7.11). Grade (G) ≥3 adverse events (AEs) were anemia (10%), neutropenia and infections (13% each). (Dimopoulos et al. 2018). Phase II trial by Jakubowiak et al. (2016) observed 1 year (y) PFS of 39% in E-Bortezomib(B)-d vs 33% in Bd arm in 152 R/R pts (HR: 0.72; p = .09) with 28% decrease in progression or death with EBd vs Bd. ORR was 66% (4% CR+ 33% VGPR + 30% PR) vs 63%. OS (overall survival) at 1 y was 85% (EBd) and 74% (Bd) (HR:0.6). G≥3 AEs were infections (21%), thrombocytopenia and peripheral neuropathy (9% each). In phase II trial, ELd (E-Lenalidomide-d) arm yielded ORR of 88% (CR 3% + sCR 5% + PR 43% + VGPR 38%) vs 74% in Ld arm in 82 ND pts. PFS at 1 yr was 93% vs 91%. G≥3 AEs included neutropenia (18%) and leukopenia (15%). (Takezako et al. 2017). Berenson et al. (2017) in phase II trial (n=70) studied G≥3 infusion reactions (IRs) using ELd in ND and R/R pts. ORR was 70% (CR 6% + VGPR 27% + PR 37%). G3 AEs included anemia in 10% pts (no G3 IRs). ELOQUENT-2 trial randomized 646 R/R pts in phase III. PFS at 4 y is 21% vs 14% (HR: 0.71, 0.59-0.86; p= .0004), favoring ELd with 29% reduction in myeloma progression or death. With VGPR of 30%, ORR was 79% vs 66 % (ELd vs Ld) with HR: 0.77; 0.62-0.95; p = 0.0176. OS at 4 y was 50% vs 43% (HR: 0.78; 0.63-0.96). G≥3 AEs included lymphocytopenia (79%), neutropenia (36%), anemia (20%) and thrombocytopenia (21%). (Dimopoulos et al, 2018). POLLUX trial used daratumumab (D)-Ld regimen in 569 R/R patients in phase III. PFS at 3 y was 55% vs 27% (DLd vs Ld) in pts with 1-3 prior therapies. With 56% CR and 80% VGPR; ORR was 93% vs 76%. DLd arm achieved 30% minimal residual disease (MRD)-negative status compared to 5% in Ld arm (p 〈 0.001). OS at 3-yr was 34% vs 42%. G≥3 AEs were neutropenia (55%), anemia (18%), thrombocytopenia (15%) and pneumonia (14%). (Bahlis et al. 2018). CASTOR trial in phase III (n=498) showed 18-mo PFS of 48% vs 7.9% in DBd vs Bd arm in R/R pts (HR: 0.31 (0.24-0.39); p 〈 0.0001). ORR was 83.8% (CR 28.8%+ sCR 8.8% + VGPR 62.1%) vs 63.2% (p 〈 0.001). DBd-treatment led to 11.6% MRD-negative status vs 2.4% in Bd-treated pts (p=0.000034). Thrombocytopenia (45.7%), anemia (15.2%) and neutropenia (13.6%) were G≥3 AEs. (Spencer et al. 2018). A Phase III trial (n=737) observed 30 mo PFS of (66 vs 52) % in ≥75 y old pts [HR 0.63 (0.44-0.92)] with DLd vs Ld arms in ND transplant ineligible pts with ORR of (90 vs 81) % (≥CR 41% + ≥VGPR 77%). MRD- negative rate was (19 vs 8) % in DLd vs Ld arms respectively. G≥3 AEs were neutropenia (60%), lymphopenia (19%), anemia (16%), pneumonia (15%) and leukopenia (12%). 〈 75 y old showed ORR of (95 vs 82) % with 30 mo PFS of (75 vs 58) % in both arms. (Usmani et al 2019). Conclusion: Elotuzumab and daratumumab based 3-drug combinations showing great improvements in ORR, PFS and OS of ND and RR MM patients with favorable toxicity profile. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-121999
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    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 10
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    Efficacy, Toxicity and Targets for Adoptive Cellular Therapy in Multiple Myeloma: A Systematic Review
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5649-5649
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5649-5649
    Abstract: Introduction Advancement in multiple myeloma (MM) has led to the development of adoptive cell transfer (ACT), an immunotherapeutic modality that utilizes body's own effector cells (T cells or Natural killer cells) to kill cancer cells. These include chimeric antigen receptor T cells (CAR-T cells), genetically modified T cell receptors (TCRs), activated Natural Killer (NK) cells and native T cells armed with bispecific antibodies. Potential antigen targets for TCRs in MM include B cell maturation antigen (BCMA), CD19, CD138, NKG2D, Ig kappa, LeY and SLMF7/CS-1, MAGE A3 and NY-ESO-1. The purpose of this review is to summarize various types of cellular therapies which are being tested in early phase clinical trials for treatment of MM. Methods We performed a comprehensive literature search (PubMed, EMBASE, AdisInsight and Clinicaltrials.gov) between January 2008 to December 2017, to identify early phase (I and I/II) trials of cellular therapy for the treatment of MM. We included studies involving cellular therapy, irrespective of the geo-location, age, sex or specific eligibility criteria. Results With initial search yielded 2537 phase I and phase I/II studies. After initial screening by two reviewers and categorization by mechanism of action, 37 clinical trials (CTs) that involved ACT were included. Out of the 37 trials, 18 are active or completed (Table 1) and 19 are recruiting subjects (Table 2). Most explored mechanism of action (21 CTs) in these trials is CAR T-cell therapy directed against B cell maturation antigen (BCMA). Anti-BCMA CART has shown promising efficacy of up to 100% objective response (OR) in a phase I trial (NCT03090659, n=22). In a phase I/II trial by Fan et al. (n=19), 6 (32%) patients showed complete response (CR), 12 (63%) developed near complete response (nCR), 1 (5%) achieved partial response (PR). In phase I trial by Ali et al. (2016, n=12), anti-BCMA CART cells led to stringent complete response (sCR) in 1 (8%) patient, very good partial response (VGPR) in 2 (16%), PR in 1 (8%) and stable disease (SD) in 8 (66%). Grade 3-4 cytokine release syndrome (CRS) was reported in 3 (25%) patients receiving high dose of CAR T cells (9 x 106 / kg in 2 patients and 3 x 106 /kg in 1 patient). Cohen et al., 2017 (n= 24) reported the objective response rate (ORR) defined as ≥PR in 11 (47%) patients. In 75% of patients with grade 3-4 CRS, tocilizumab/siltuximab was used to manage CRS. According to Garfall et al. (2018, n=10), administration of anti-CD19 CART after autologus stem cell transplant (auto-SCT) improved progression free survival (PFS) in 2 (20%) patients compared to PFS due to auto-SCT done earlier in same patients (from 181 to 479 days and 127 to 249 days). Leivas et al. (2016, n=5) showed that infusion of expanded and activated natural killer cells (NKAE) with lenalidomide have shown better response (PR=1, SD=1, SD to PD=1) than NKAE with bortezomib (SD=1, PD=1). In 10 (83%) patients, VGPR or better response was achieved after infusion of allogenic cord blood derived NK cells along with auto-SCT (Shah et al., 2017). Rapoport et al. (2017, n=25) infused CAR T-cells against cancer testes antigens (NY-ESO-1, LAGE-1a) and demonstrated the OR in 19 (76%) patients (1 sCR, 12 VGPR, 6PR) at day 100. Al-Kadhimi et al. (2011, n=9) administered activated autologous T cells armed with bispecific antibodies against CD3 and CD20 (aATC) prior to auto-SCT. Two patients achieved VGPR, two patients achieved CR while five patients developed PR. Fowler et al. (2016, n=20) used type 1 polarized, rapamycin resistant T (T1-Rapa) cells after auto-SCT in high risk myeloma patients. Out of 19 evaluable patients, 5 had ongoing CR (at 733, 787, 847, 926, 1186 days) while 14 patients had disease progression (from 64 to 917 days). No adverse effects or dose limiting toxicity was observed in any of the patients. Conclusion Adoptive cellular therapy has shown excellent clinical activity against myeloma cells in relapsed refractory patients. The adverse events like CRS and infusion reactions are concerning but manageable. The results of trials involving T cells targeting BCMA are very encouraging. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-109944
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    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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