Measurable residual disease (MRD) is being recognised as an optimal method for assessing depth of... more Measurable residual disease (MRD) is being recognised as an optimal method for assessing depth of response, identifying higher risk of relapse, and guiding response-based treatment paradigms for multiple myeloma (MM). Although MRD negativity is increasingly replacing complete response as the surrogate endpoint in clinical trials, its role in real-world practice is less established. We retrospectively analyzed EuroFlow MRD results from patients with newly diagnosed MM (NDMM) who underwent bortezomib, cyclophosphamide and dexamethasone (VCD) induction and high dose melphalan conditioned autologous stem cell transplant (ASCT) at the Alfred Hospital between January 2016 and December 2020. Next generation flow MRD evaluation was performed 3 months following ASCT using the standardised EuroFlow platform. 112 patients with available MRD data were identified to have received VCD induction followed by ASCT. Post ASCT MRD was undetectable in 28.6% of patients. Those who achieved MRD negativit...
Proteasome inhibitors (PIs) are highly active in multiple myeloma (MM) but resistance is commonly... more Proteasome inhibitors (PIs) are highly active in multiple myeloma (MM) but resistance is commonly observed. All clinical stage PIs effectively inhibit chymotrypsin-like (CT-L) activity; one possible mechanism of resistance is compensatory hyperactivation of caspase-like (C-L) and trypsin-like (T-L) subunits, in response to CT-L blockade. Marizomib (MRZ), an irreversible PI that potently inhibits all three 20S proteasome subunits with a specificity distinct from other PIs, is currently in development for treatment of MM and malignant glioma. The pan-proteasome pharmacodynamic activity in packed whole blood and peripheral blood mononuclear cells was measured in two studies in patients with advanced solid tumours and haematological malignancies. Functional inhibition of all proteasome subunits was achieved with once- or twice-weekly MRZ dosing; 100% inhibition of CT-L was frequently achieved within one cycle at therapeutic doses. Concomitantly, C-L and T-L activities were either unaffe...
Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrate... more Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrated that bortezomib combined with pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in patients with relapsed/refractory multiple myeloma who had previously received one or more lines of therapy. Protocol-defined final survival data from that study are provided here. Patients were randomized (1:1) to receive either bortezomib alone (1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of every 21-day cycle) or bortezomib-PLD (bortezomib plus PLD 30 mg/m(2) intravenously on day 4). The primary endpoint was the time to progression. Secondary efficacy endpoints included overall survival (OS), progression-free survival, and the overall response rate. In total, 646 patients (bortezomib-PLD, n = 324; bortezomib alone, n = 322) were randomized between December, 2004, and March, 2006. On the clinical cutoff date (May 16, 2014) for the final survival analysis, at a median fo...
Histone deacetylase inhibitors (HDACi) are novel therapeutics compounds being utilised in multipl... more Histone deacetylase inhibitors (HDACi) are novel therapeutics compounds being utilised in multiple myeloma (MM) clinical trials in combination with approved and investigational agents. While proteasome inhibitors are known to synergise effectively with HDACi, there is a lack of understanding concerning other potential partner drugs. In this report, utilising human myeloma cell lines (HMCL) as a paradigm, gene expression profile was performed to determine if a genetic signature associated with HDACi-resistance could be identified. Nine HMCLs were treated with HDACi (LBH589, SAHA or FK228) and cell death proportion determined after 48 hours through flow cytometric enumeration of propidium iodide staining. Of the nine cell lines, five were sensitive (70-90% cell death), two showed an intermediate response (70-40%) and two were resistant (40-10%) to HDACi. Following the determination of HDACi-response of HMCLs, RNA was extracted from untreated cell lines and gene expression profiling wa...
Histone deacetylase inhibitors (HDACi) are novel chemotherapeutics undergoing evaluation in clini... more Histone deacetylase inhibitors (HDACi) are novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with multiple myeloma (MM). Although HDACi have demonstrable synergy when combined with proteasome inhibitors (PIs), recent evidence indicates that combination of HDACi and PI is beneficial only in a subset of patients with advanced MM, clearly indicating that other rational combinations should be explored. In this context we hypothesized that understanding the molecular signature associated with inherent resistance to HDACi would provide a basis for the identification of therapeutic combinations with improved clinical efficacy. Using human myeloma cell lines (HMCL) categorized as sensitive, intermediate or resistant to HDACi, gene expression profiling (GEP) and gene ontology enrichment analyses were performed to determine if a genetic signature associated with inherent resistance to HDACi-resistance could be identified. Correlation of G...
Multiple myeloma (MM) is a heterogeneous plasma cell disorder characterized by genetic abnormalit... more Multiple myeloma (MM) is a heterogeneous plasma cell disorder characterized by genetic abnormalities, including chromosomal translocations, deletions, duplications and genetic mutations. Translocations involving the immunoglobulin heavy chain region at chromosome 14q32 are observed in approximately 40% of patients with MM. Translocation of oncogenes into this region may lead to their increased expression, contributing to disease initiation, disease progression and therapeutic resistance. The t(4;14) translocation is associated with upregulation of the fibroblast growth factor receptor 3 (FGFR3) and the myeloma SET domain protein. Patients with t(4;14) demonstrate an overall poor prognosis that is only partially mitigated by the use of the novel agents bortezomib and lenalidomide; as such, an unmet medical need remains for patients with this aberration. Preclinical studies of inhibitors of FGFR3 have shown promise in t(4;14) MM, and these studies have led to the initiation of clinica...
Key Points Afuresertib has a favorable safety profile with manageable side effects and demonstrat... more Key Points Afuresertib has a favorable safety profile with manageable side effects and demonstrates single-agent activity against hematologic malignancies. Inhibition of AKT with afuresertib may provide a novel therapeutic strategy for hematologic malignancies, especially for multiple myeloma.
The second most commonly diagnosed hematologic malignancy, multiple myeloma, affects predominantl... more The second most commonly diagnosed hematologic malignancy, multiple myeloma, affects predominantly older patients (>60s) and is characterized by paraprotein in the serum or urine. Clinical manifestations include anemia, hypercalcaemia, progressive renal impairment, and osteolytic bone destruction. Despite promising new therapies, multiple myeloma eventually relapses in almost all patients. HSP are ubiquitous and highly conserved in prokaryotes and eukaryote organisms. Exposure to a broad range of stimuli results in increased HSP protein expression. These chaperone proteins are involved in protein transportation, prevent protein aggregation, and ensure correct folding of nascent and stress-accumulated misfolded proteins. In cancer, HSP expression is dysregulated, resulting in elevated expression, which promotes cancer by preventing programmed cell death and supporting autonomous cells growth, ultimately leading to resistance to heat, chemotherapy, and other stresses. Client protei...
Purpose This phase III international study compared the efficacy and safety of a combination of p... more Purpose This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma. Patients and Methods Six hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m2 on day 4. Results Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant. Median duration of response was increased from 7...
Deacetylases (DACs) are a highly conserved group of enzymes that regulate a myriad of cellular fu... more Deacetylases (DACs) are a highly conserved group of enzymes that regulate a myriad of cellular functions through deacetylation of histones, transcription factors and molecular chaperones. Altered DAC expression is significantly associated with poor prognosis in solid and haematological malignancies, however the expression pattern and correlation of dysregulated expression to patient outcome has not been characterized in multiple myeloma (MM) cells. To address this, quantitative PCR was performed for DAC1-11 on MM (n=60) and normal plasma cells (n=11) purified from bone-marrow (BM) samples. Analyses revealed that median levels of all DACs, with the exception of DAC1 and DAC11, were significantly altered in MM. Interestingly, patients with increased DAC1, 2 and 6 levels had a significantly shorter progression-free survival from diagnosis compared to patients with lower levels. Inhibitors to DACs (DACi) are currently being used in clinical trials of multiple myeloma (MM), either alone ...
Improved therapeutic interventions over the past decade has led to prolonged survival rates of pa... more Improved therapeutic interventions over the past decade has led to prolonged survival rates of patients with multiple myeloma (MM) but unfortunately, the subsequent development of progressive disease is inevitable. As such, the identification of novel compounds and strategies that improve therapeutic response is essential. GSK1120212b, a novel orally bio-available MEK inhibitor, has been shown to inhibit tumour growth and induce cell cycle arrest in some cancer cells. Here we report the efficacy of GSK1120212b in human myeloma cell lines (HMCL) and primary myeloma cells when used as a single agent and in combination with conventional and novel anti-myeloma therapies. HMCL response to variable doses of GSK1120212b (10nM-5µM) was determined by MTS assay. FACS and cell cycle analysis were used to evaluate the profiles of the cells post-MEK inhibition. Mechanistic studies using Western analysis with antibodies against p-MEK, MEK, p-ERK and ERK were performed. Subsequently, the anti-MM a...
Measurable residual disease (MRD) is being recognised as an optimal method for assessing depth of... more Measurable residual disease (MRD) is being recognised as an optimal method for assessing depth of response, identifying higher risk of relapse, and guiding response-based treatment paradigms for multiple myeloma (MM). Although MRD negativity is increasingly replacing complete response as the surrogate endpoint in clinical trials, its role in real-world practice is less established. We retrospectively analyzed EuroFlow MRD results from patients with newly diagnosed MM (NDMM) who underwent bortezomib, cyclophosphamide and dexamethasone (VCD) induction and high dose melphalan conditioned autologous stem cell transplant (ASCT) at the Alfred Hospital between January 2016 and December 2020. Next generation flow MRD evaluation was performed 3 months following ASCT using the standardised EuroFlow platform. 112 patients with available MRD data were identified to have received VCD induction followed by ASCT. Post ASCT MRD was undetectable in 28.6% of patients. Those who achieved MRD negativit...
Proteasome inhibitors (PIs) are highly active in multiple myeloma (MM) but resistance is commonly... more Proteasome inhibitors (PIs) are highly active in multiple myeloma (MM) but resistance is commonly observed. All clinical stage PIs effectively inhibit chymotrypsin-like (CT-L) activity; one possible mechanism of resistance is compensatory hyperactivation of caspase-like (C-L) and trypsin-like (T-L) subunits, in response to CT-L blockade. Marizomib (MRZ), an irreversible PI that potently inhibits all three 20S proteasome subunits with a specificity distinct from other PIs, is currently in development for treatment of MM and malignant glioma. The pan-proteasome pharmacodynamic activity in packed whole blood and peripheral blood mononuclear cells was measured in two studies in patients with advanced solid tumours and haematological malignancies. Functional inhibition of all proteasome subunits was achieved with once- or twice-weekly MRZ dosing; 100% inhibition of CT-L was frequently achieved within one cycle at therapeutic doses. Concomitantly, C-L and T-L activities were either unaffe...
Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrate... more Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrated that bortezomib combined with pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in patients with relapsed/refractory multiple myeloma who had previously received one or more lines of therapy. Protocol-defined final survival data from that study are provided here. Patients were randomized (1:1) to receive either bortezomib alone (1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of every 21-day cycle) or bortezomib-PLD (bortezomib plus PLD 30 mg/m(2) intravenously on day 4). The primary endpoint was the time to progression. Secondary efficacy endpoints included overall survival (OS), progression-free survival, and the overall response rate. In total, 646 patients (bortezomib-PLD, n = 324; bortezomib alone, n = 322) were randomized between December, 2004, and March, 2006. On the clinical cutoff date (May 16, 2014) for the final survival analysis, at a median fo...
Histone deacetylase inhibitors (HDACi) are novel therapeutics compounds being utilised in multipl... more Histone deacetylase inhibitors (HDACi) are novel therapeutics compounds being utilised in multiple myeloma (MM) clinical trials in combination with approved and investigational agents. While proteasome inhibitors are known to synergise effectively with HDACi, there is a lack of understanding concerning other potential partner drugs. In this report, utilising human myeloma cell lines (HMCL) as a paradigm, gene expression profile was performed to determine if a genetic signature associated with HDACi-resistance could be identified. Nine HMCLs were treated with HDACi (LBH589, SAHA or FK228) and cell death proportion determined after 48 hours through flow cytometric enumeration of propidium iodide staining. Of the nine cell lines, five were sensitive (70-90% cell death), two showed an intermediate response (70-40%) and two were resistant (40-10%) to HDACi. Following the determination of HDACi-response of HMCLs, RNA was extracted from untreated cell lines and gene expression profiling wa...
Histone deacetylase inhibitors (HDACi) are novel chemotherapeutics undergoing evaluation in clini... more Histone deacetylase inhibitors (HDACi) are novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with multiple myeloma (MM). Although HDACi have demonstrable synergy when combined with proteasome inhibitors (PIs), recent evidence indicates that combination of HDACi and PI is beneficial only in a subset of patients with advanced MM, clearly indicating that other rational combinations should be explored. In this context we hypothesized that understanding the molecular signature associated with inherent resistance to HDACi would provide a basis for the identification of therapeutic combinations with improved clinical efficacy. Using human myeloma cell lines (HMCL) categorized as sensitive, intermediate or resistant to HDACi, gene expression profiling (GEP) and gene ontology enrichment analyses were performed to determine if a genetic signature associated with inherent resistance to HDACi-resistance could be identified. Correlation of G...
Multiple myeloma (MM) is a heterogeneous plasma cell disorder characterized by genetic abnormalit... more Multiple myeloma (MM) is a heterogeneous plasma cell disorder characterized by genetic abnormalities, including chromosomal translocations, deletions, duplications and genetic mutations. Translocations involving the immunoglobulin heavy chain region at chromosome 14q32 are observed in approximately 40% of patients with MM. Translocation of oncogenes into this region may lead to their increased expression, contributing to disease initiation, disease progression and therapeutic resistance. The t(4;14) translocation is associated with upregulation of the fibroblast growth factor receptor 3 (FGFR3) and the myeloma SET domain protein. Patients with t(4;14) demonstrate an overall poor prognosis that is only partially mitigated by the use of the novel agents bortezomib and lenalidomide; as such, an unmet medical need remains for patients with this aberration. Preclinical studies of inhibitors of FGFR3 have shown promise in t(4;14) MM, and these studies have led to the initiation of clinica...
Key Points Afuresertib has a favorable safety profile with manageable side effects and demonstrat... more Key Points Afuresertib has a favorable safety profile with manageable side effects and demonstrates single-agent activity against hematologic malignancies. Inhibition of AKT with afuresertib may provide a novel therapeutic strategy for hematologic malignancies, especially for multiple myeloma.
The second most commonly diagnosed hematologic malignancy, multiple myeloma, affects predominantl... more The second most commonly diagnosed hematologic malignancy, multiple myeloma, affects predominantly older patients (>60s) and is characterized by paraprotein in the serum or urine. Clinical manifestations include anemia, hypercalcaemia, progressive renal impairment, and osteolytic bone destruction. Despite promising new therapies, multiple myeloma eventually relapses in almost all patients. HSP are ubiquitous and highly conserved in prokaryotes and eukaryote organisms. Exposure to a broad range of stimuli results in increased HSP protein expression. These chaperone proteins are involved in protein transportation, prevent protein aggregation, and ensure correct folding of nascent and stress-accumulated misfolded proteins. In cancer, HSP expression is dysregulated, resulting in elevated expression, which promotes cancer by preventing programmed cell death and supporting autonomous cells growth, ultimately leading to resistance to heat, chemotherapy, and other stresses. Client protei...
Purpose This phase III international study compared the efficacy and safety of a combination of p... more Purpose This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma. Patients and Methods Six hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m2 on day 4. Results Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant. Median duration of response was increased from 7...
Deacetylases (DACs) are a highly conserved group of enzymes that regulate a myriad of cellular fu... more Deacetylases (DACs) are a highly conserved group of enzymes that regulate a myriad of cellular functions through deacetylation of histones, transcription factors and molecular chaperones. Altered DAC expression is significantly associated with poor prognosis in solid and haematological malignancies, however the expression pattern and correlation of dysregulated expression to patient outcome has not been characterized in multiple myeloma (MM) cells. To address this, quantitative PCR was performed for DAC1-11 on MM (n=60) and normal plasma cells (n=11) purified from bone-marrow (BM) samples. Analyses revealed that median levels of all DACs, with the exception of DAC1 and DAC11, were significantly altered in MM. Interestingly, patients with increased DAC1, 2 and 6 levels had a significantly shorter progression-free survival from diagnosis compared to patients with lower levels. Inhibitors to DACs (DACi) are currently being used in clinical trials of multiple myeloma (MM), either alone ...
Improved therapeutic interventions over the past decade has led to prolonged survival rates of pa... more Improved therapeutic interventions over the past decade has led to prolonged survival rates of patients with multiple myeloma (MM) but unfortunately, the subsequent development of progressive disease is inevitable. As such, the identification of novel compounds and strategies that improve therapeutic response is essential. GSK1120212b, a novel orally bio-available MEK inhibitor, has been shown to inhibit tumour growth and induce cell cycle arrest in some cancer cells. Here we report the efficacy of GSK1120212b in human myeloma cell lines (HMCL) and primary myeloma cells when used as a single agent and in combination with conventional and novel anti-myeloma therapies. HMCL response to variable doses of GSK1120212b (10nM-5µM) was determined by MTS assay. FACS and cell cycle analysis were used to evaluate the profiles of the cells post-MEK inhibition. Mechanistic studies using Western analysis with antibodies against p-MEK, MEK, p-ERK and ERK were performed. Subsequently, the anti-MM a...
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