Chr t(14;20)

P1/2, N=20, Active, not recruiting, Ciusss de L'Est de l'Île de Montréal | Trial primary completion date: Sep 2021 --> Oct 2023

P2, N=40, Completed, Maisonneuve-Rosemont Hospital | Active, not recruiting --> Completed

No superior outcomes were observed in patients with HRMM who received bortezomib monotherapy or (to a lesser extent) in those who received bortezomib in combination as maintenance compared with lenalidomide alone. Until prospective data from randomized clinical trials are available, post-transplant therapy should be tailored to each patient with consideration for treating patients in clinical trials that target novel therapeutic strategies for HRMM, and lenalidomide should remain a cornerstone of treatment.

In contrast to FISH, conventional karyotyping could detect MM-related aberrations in 50% cases , of which 44% revealed highly complex karyotype with common aberrations of chromosome 1q. Overall FISH was found to be novel , easy approach with high success rate and capability of detection of all cytogenetic abnormalities that add valid information for the risk stratification of disease which in future in combination with mutation profile and Gene expression profile will help in further refinement of disease & identification of actionable targets.

On the other hand, in our population, ISS, CRAB symptoms, cytogenetic data, immunophenotypic features and treatment was not shown to have an impact on clinical course of the disease or survival. This study has limitations, particularly attributable to its retrospective nature, small number of patients within a single institution and lack of detailed information regarding imaging techniques, and comorbidities.

Methods MASTER is a prospective, multi-center clinical trial utilizing daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, AHCT (Melphalan conditioning), followed by MRD response-adapted Dara-KRd consolidation with planned enrichment for pts with high-risk chromosome abnormalities (HRCA). The greatest impact is afforded to the highest risk disease subset elucidating the biologic underpinnings of the impact of AHCT in MM. At this time, AHCT should remain an integral part of therapy for fit, NDMM patients, particularly those with the high-risk disease and those who remain MRD positive after induction.

This study aimed to evaluate the association between cytogenetic abnormalities and clinicohaematological characteristics at diagnosis, and retrospectively compare the overall response rate to 2 triple drug combinations comprised of bortezomib, cyclophosphamide, and dexamethasone (VCd) versus thalidomide, cyclophosphamide, and dexamethasone (VRd) in transplant eligible patients with untreated MM. The key differences in baseline characteristics at presentation compared to Western population could be attributed to ethnic diversity. Triplet induction therapy VRd was superior as regards to response rates compared to VCd arm.

"Methods MASTER is a prospective, multi-center clinical trial utilizing daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, AHCT (Melphalan conditioning), followed by MRD response-adapted Dara-KRd consolidation with planned enrichment for patients with high-risk chromosome abnormalities (HRCA). At this time, AHCT should remain an integral part of therapy for fit, NDMM patients, particularly those with the high-risk disease and those who remain MRD positive after induction. Future studies exploring AHCT deferral in NDMM should be focused on patients who are MRD negative post optimal induction."

Immunofixation: lambda IgA. 24-hour monoclonal urinary component: 430 mg. Urinary immunofixation: lambda. Imaging exams (cranial X-ray, CT and MRI) multiple lytic lesions in skull, iliac and vertebral fractures of T9, L4, T12, pathological fractures and extra-osseous soft tissue components in the 4th costal arch on the right and lesion in the right sacral wing . Myelogram with 76.4% of plasma cells with plasmablast morphology. Immunophenotyping with 8.8% plasma cells (CD38+, CD138+, CD45+, CD56 -, CD117 -, lambda +). Bone marrow biopsy: 80 and 90% anaplastic plasma cells. Hyperdiploid complex karyotype with several numerical and structural changes. FISH panel with selected CD138+ cells: Amplification of the CKS1B gene (5 to 7 copies of chromosome 1q), gain of the genes CDKN2C (chromosome 1p), FGFR3 (chromosome 4p), CCND1 (chromosome 11q), MAF (chromosome 16q), region D17Z1 (chromosome 17) and atypical IGH/MAFB t(14;20) gene fusion in approximately 95% of the analyzed nuclei. Diagnosis of double hit multiple myeloma (MM) (mSMART 3.0), IgA lambda, R-ISS: III. The patient started treatment with cyclophosphamide, thalidomide and dexamethasone. Discussion and Conclusion MM is a disease with a heterogeneous course and cytogenetic abnormalities are important to explain the biological behavior of this pathology. The most common genetic abnormalities in MM present in 40-50% of cases are chromosomal translocations involving the IGH gene and copy number variation in chromosomal regions. Translocations involving the IGH gene are primary alterations in the pathology and can be composed of at least 30 partner genes: CCND1 (11q13) 15%, FGFR3 (4p16) 15%, MAF (16q23) 5%, CCND3 (6p21) 2%, 2% MAFB (20q12), MAFA (8q24) 1%. MAFB, C-MAF and MAFA belong to the MAF family, are zipper leucine transcription factors and have gene transactivation and transrepression functions. Studies with a prognostic value of t(14;20) suggest that this finding is a rare event, is correlated with increased regulation of cyclin D2 and resistant to proteosome inhibitors, configuring an unfavorable prognosis and short survival time.

Furthermore, our results provide a roadmap for immunotherapy of MM by unbiasedly comparing the expression of top MM cell surface targets in patient data and normal cells and suggest that the genetic landscape of MM may predict the expression of specific targets for precision immunotherapy. The quest for novel MM targets for immunotherapies remains open, and CAR target discovery driven by specific genetic events remains an active area of investigation.

Briefly, the patients accepted bortezomib or thalidomide-based induction therapy...Subsequently, unless intolerance, patients received either thalidomide-based or lenalidomide-based maintenance therapy for two years... Age is an important prognostic factor in MM. With age, the risk of MM progression or death steadily grows. Cytogenetic abnormalities are equally important in every age group.

The 1L Tx pattern was consistent across cytogenetic cohorts with bortezomib (V), lenalidomide (R), dexamethasone (d) as the most common Tx (>42%)...The use of regimens containing carfilzomib (K) and daratumumab (D) was emerging in 2L: KRd in 8% of t(11;14)+ and HR and 5% in SR; Kd 5% in all groups; DRd in 4% of t(11;14)+ and 3% in SR and HR (Figure 1)...While TTNT did not differ by age across lines of Tx, OS was superior in pts <70 yrs across all 3 cytogenetic risk cohorts. This study sets the benchmark for novel treatment options, such as BCL-2 pathway inhibitors, primarily wherever available biomarker-driven therapy is considered appropriate.