There is a strong need to better predict the survival of patients with newly diagnosed multiple myeloma (MM). As gene expression profiles (GEPs) reflect the biology of MM in individual patients, we ...built a prognostic signature based on GEPs. GEPs obtained from newly diagnosed MM patients included in the HOVON65/GMMG-HD4 trial (n=290) were used as training data. Using this set, a prognostic signature of 92 genes (EMC-92-gene signature) was generated by supervised principal component analysis combined with simulated annealing. Performance of the EMC-92-gene signature was confirmed in independent validation sets of newly diagnosed (total therapy (TT)2, n=351; TT3, n=142; MRC-IX, n=247) and relapsed patients (APEX, n=264). In all the sets, patients defined as high-risk by the EMC-92-gene signature show a clearly reduced overall survival (OS) with a hazard ratio (HR) of 3.40 (95% confidence interval (CI): 2.19-5.29) for the TT2 study, 5.23 (95% CI: 2.46-11.13) for the TT3 study, 2.38 (95% CI: 1.65-3.43) for the MRC-IX study and 3.01 (95% CI: 2.06-4.39) for the APEX study (P<0.0001 in all studies). In multivariate analyses this signature was proven to be independent of the currently used prognostic factors. The EMC-92-gene signature is better or comparable to previously published signatures. This signature contributes to risk assessment in clinical trials and could provide a tool for treatment choices in high-risk MM patients.
While clinical benefit of the proteasome inhibitor (PI) bortezomib (BTZ) for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term ...utility. The E3 ubiquitin ligase Skp1-Cullin-1-Skp2 (SCF
) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCF
activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B. Here we observed higher CUL1, COMMD1 and SKP2 mRNA levels in CD138
cells isolated from BTZ-resistant MM patients. Higher CUL1, COMMD1, SKP2 and CKS1B mRNA levels in patient CD138
cells correlated with decreased progression-free and overall survival. Genetic knockdown of CUL1, COMMD1 or SKP2 disrupted the SCF
complex, stabilized p27 and increased the number of annexin-V-positive cells after BTZ treatment. Chemical library screens identified a novel compound, designated DT204, that reduced Skp2 binding to Cullin-1 and Commd1, and synergistically enhanced BTZ-induced apoptosis. DT204 co-treatment with BTZ overcame drug resistance and reduced the in vivo growth of myeloma tumors in murine models with survival benefit. Taken together, the results provide proof of concept for rationally designed drug combinations that incorporate SCF
inhibitors to treat BTZ resistant disease.
With advent of several treatment options in multiple myeloma (MM), a selection of effective regimen has become an important issue. Use of gene expression profile (GEP) is considered an important tool ...in predicting outcome; however, it is unclear whether such genomic analysis alone can adequately predict therapeutic response. We evaluated the ability of GEP to predict complete response (CR) in MM. GEP from pretreatment MM cells from 136 uniformly treated MM patients with response data on an IFM, France led study were analyzed. To evaluate variability in predictive power due to microarray platform or treatment types, additional data sets from three different studies (n=511) were analyzed using same methods. We used several machine learning methods to derive a prediction model using training and test subsets of the original four data sets. Among all methods employed for GEP-based CR predictive capability, we got accuracy range of 56-78% in test data sets and no significant difference with regard to GEP platforms, treatment regimens or in newly diagnosed or relapsed patients. Importantly, permuted P-value showed no statistically significant CR predictive information in GEP data. This analysis suggests that GEP-based signature has limited power to predict CR in MM, highlighting the need to develop comprehensive predictive model using integrated genomics approach.
In multiple myeloma, expression of cancer testis antigens may provide prognostic markers and potential targets for immunotherapy. Expression at relapse has not yet been evaluated for a large panel of ...cancer testis antigens which can be classified by varying expression in normal tissue: restricted to testis, expressed in testis and brain and not restricted but selectively expressed in testis.
Evaluation of cancer testis antigen expression was made in newly diagnosed multiple myeloma cases (HOVON-65/GMMG-HD4 trial; n = 320) and in relapse cases (APEX, SUMMIT, CREST trials; n = 264). Presence of expression using Affymetrix GeneChips was determined for 123 cancer testis antigens. Of these 87 had a frequency of more than 5% in the newly diagnosed and relapsed patients, and were evaluated in detail.
Tissue restriction was known for 58 out of 87 cancer testis antigens. A significantly lower frequency of presence calls in the relapsed compared to newly diagnosed cases was found for 3 out of 13 testis restricted genes, 2 out of 7 testis/brain restricted genes, and 17 out of 38 testis selective genes. MAGEC1, MAGEB2 and SSX1 were the most frequent testis-restricted cancer testis antigens in both data sets. Multivariate analysis demonstrated that presence of MAGEA6 and CDCA1 were clearly associated with shorter progression free survival, and presence of MAGEA9 with shorter overall survival in the set of newly diagnosed cases. In the set of relapse cases, presence of CTAG2 was associated with shorter progression free survival and presence of SSX1 with shorter overall survival.
Relapsed multiple myeloma reveals extensive cancer testis antigen expression. Cancer testis antigens are confirmed as useful prognostic markers in newly diagnosed multiple myeloma patients and in relapsed multiple myeloma patients. The HOVON-65/GMMG-HD4 trial is registered under Dutch trial register n. NTR-213. CREST, SUMMIT and APEX trials were registered under ns. M34100-024, M34100-025 and NCT00049478/NCT00048230, respectively.
Introduction
A triplet combination including a proteasome inhibitor (PI) and an IMiD has shown significant efficacy in the setting of newly diagnosed multiple myeloma (NDMM). In addition, a role for ...maintenance therapy with the PI bortezomib has been suggested in non-head to head comparisons. However, in elderly patients especially non-hematological toxicity is a concern and an oral drug is preferred as maintenance therapy. Therefore, we investigated the efficacy and feasibility of an oral regimen including induction therapy with the PI ixazomib in combination with thalidomide, followed by a randomization between maintenance therapy with either ixazomib or placebo in elderly non-transplant eligible (nte) NDMM. We here report the efficacy and toxicity of the induction therapy of the first 120 patients, with subgroup analyses based on frailty and cytogenetic risk. The study is currently ongoing and results with longer follow up and the maintenance part will be reported at future meetings. This trial was registered at www.trialregister.nl as NTR4910.
Methods
In this prospective multicenter phase II trial nte-NDMM patients were treated with nine 28 day-cycles consisting of ixazomib 4mg (day 1, 8, 15), thalidomide 100 mg (day 1-28) and dexamethasone 40 mg (day 1, 8, 15, 22) followed by randomisation between either ixazomib or placebo (both day 1, 8, 15 every 28 days) until progression. Primary objectives were comparison of progression free survival (PFS) between maintenance therapy with ixazomib or placebo and to determine the overall response rate of induction therapy.
Frailty was assessed by a modification of the IMWG frailty index based on age, the Charlson Comorbidity Index (retrospectively retrieved from the list of comorbidities that were present at entry) and the WHO performance as a proxy for (instrumental) Activities of Daily Living (scoring WHO 0 as 0 points, WHO 1 as 1 point, and WHO 2-3 as 2 points).
High risk cytogenetics was defined as del17p, t(4;14) or t(14;16).
Results
Patient characteristics are presented in table 1. The median follow up is 17.0 months (range 0.9-28.1 months). Following induction treatment overall response rate (ORR, i.e. ≥PR) was 81% (95% confidence interval (CI) 73-87%), 44% (95% CI 35-54%) of patients reached ≥ VGPR and 10% (95% CI 5-17%) ≥ CR. ORR was 85% in patients ≤75 years versus 73% in ≥76 years (p=0.15), while for ≥VGPR these were 45% vs 42% (p=0.85) and for ≥CR 13% vs 4% (p=0.21). In responding patients, the median time to response was 1.1 month.
Using the revised IMWG Frailty Index 47% of patients were frail, 28% unfit and 21% fit (4% unknown). Frailty status did not affect the efficacy of induction therapy with ITd with ORR 75%, ≥ VGPR 43% and ≥ CR 9% in frail versus 85%, 53% and 9% in unfit and 88%, 36% and 16% in fit patients (p=0.34, p=0.43 and p=0.62, respectively).
At the time of this analysis cytogenetic risk could be determined in 77/120 (64%) patients, with 23% of high risk patients. Response rates were comparable in high versus standard risk patients: ORR 14/18 (78%) versus 50/59 (85%), ≥ VGPR 7/18 (39%) versus 25/59 (42%) and ≥ CR 1/18 (6%) and 4/59 (7%) (p=0.49, p=1.0 and p=1.0).
Toxicity is presented in table 2. The incidence of severe neuropathy was low; 3% grade 3 and no grade 4. During induction 18/120 (15%) patients discontinued therapy due to toxicity; 6 neurotoxicity, 3 infection, 2 dermatological toxicity, 2 gastro-intestinal toxicity and 5 other toxicity. Discontinuation was comparable in patients ≥76 versus age ≤75, however none of the 10 patients > 80 years reached maintenance therapy, of whom 6/10 due to toxicity. Early mortality was higher in patients ≥76; 4/45 (9%) versus 1/75 (1%) in patients ≤75, mainly due to infections (4/5). The discontinuation rate due to toxicity was 1/25 (4%), 5/34 (15%) and 9/56 (16%)(p=0.34) in fit, unfit and frail patients respectively.
Conclusion
Induction treatment with ITd in NDMM results in high overall response rate of 81%, with 44% ≥ VGPR. Median time to response was 1.1 month. In frail and high risk cytogenetic patients induction therapy with ITd was equally effective with respect to response. Therapy was found to be feasible with limited toxicity and a low resulting discontinuation rate of 15%, although in patients >80 years toxicity was higher.
Display omitted
Zweegman:Janssen: Other: advisory board participation, Research Funding; Celgene: Other: advisory board participation, Research Funding; Amgen: Other: advisory board participation; Takeda: Other: advisory board participation, Research Funding. Waage:Celgene, Takeda: Honoraria. Sonneveld:Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria. Abildgaard:Takeda: Research Funding.
PDF
