Significance of Modified Risk Stratification Msmart 3.0 and Autologous Stem Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma

Abstract

Background The risk-stratification systems are repeatedly updated in accordance with the emergence of new information about the prognostic impact of anomalies and other factors. The most extensive and modern system in this time is mSMART risk stratification involving many parameters such as genetic anomalies, albumin, beta-2-microglobulin, LDH, Plasma Cell S-phase and GEP levels. It is possible to use risk-adapted treatment programs with or without ASCT. Nevertheless, the role of complex karyotype, combination of genetic abnormalities and ASCT remains unclear. Aims To estimate the genetic abnormalities in patients with newly diagnosed multiple myeloma and define the role of risk-stratification and ASCT in prognosis of disease. Methods The study included 159 patients (median age 63 years, range 28 - 83; male: female ratio - 1:1.37) with NDMM. Metaphase cytogenetics on bone marrow samples was done by standard GTG-method. FISH analyses were performed according to the manufacturer's protocol for detection primary IgH translocations, 13q (13q14/13q34) deletion, 1p32/1q21 amplification/deletion, P53/cen 17 deletion (MetaSystems DNA probes). We additional searched the t(4;14), t(6;14), t(11;14), t(14;16) and t(14;20) in patients with IgH translocation. All patient was treated by bortezomib-based programs (VD, CVD, VMP, PAD). ASCT was performed at 42% patients. Results The frequency of genetic abnormalities in NDMM patients was 49% (78/159). IgH translocation was detected in 26.4% (42/159) patients: t(11;14) - 16.3% (26/159), t(4;14) - 5.0% (8/159); TP53/del17p - 5.6% (9/159); 1p32/1q21 amp/del - 12% (19/159); hypodiploidy - 3.1% (5/159); hyperdiploidy - 1.25% (2/159); del5q - 0,6% (1/159); other - not found. Combination two aberrations was discovered in 11.9% (19/159) patients, complex abnormalities (>3 aberrations) - in 4.4% (7/159) patients. The median OS in "two aberration" and "complex abnormalities" groups were lower than in standard-risk mSMART 3.0 (normal, t(11;14), hypodiploidy, hyperdiploidy and other): 49 months, 26 months and was not reached, respectively (p=.00015). The median PFS for these groups was 12 months, 11 months and 30 months, respectively (p=.011). Differences between "two aberration" and "complex abnormalities" groups were not find (p> .05). We modified high-risk (gain 1q, p53 mutation, del 17p deletion, t(4;14), t(14;16), t(14;20), R-ISS stage III, double and triple hit myeloma) mSMART 3.0 by adding "two aberration" and "complex abnormalities" groups on based the OS and PFS results. The final analysis was based on the results of the complex examination of 87 patients: 53 patients in standard-risk group and 34 patients in high-risk group. The median OS in standard-risk mSMART 3.0 was not reached, in high-risk mSMART 3.0mod - 48 months; 5-years OS was 62% and 38%, respectively (p=0.0073). The median PFS was 43 and 29 months, respectively (p=.09). The best results of OS and PFS were reach in both groups of patient who performed ASCT. The median OS in standard-risk mSMART 3.0 with ASCT (n=37) was not reached, in high-risk mSMART 3.0mod with ASCT - 48 months (n=20); standard-risk mSMART 3.0 without ASCT - 40 months (n=16); in high-risk mSMART 3.0mod without ASCT - 22 months (n=14); 5-years OS was 81%, 60%, 33% and 28%, respectively (p=0.0015). The median PFS was not reached, 46, 22 and 19 months, respectively (p=.017). Conclusions The combination of two aberrations and complex abnormalities is unfavorable prognostic markers. The median OS and PFS was higher in standard-risk than high-risk group according mSMART 3.0mod. The ASCT can improve treatment's outcomes and life expectancy especially in patients with high-risk. It can be useful for update risk stratification in a future. Disclosures Shuvaev: Novartis: Consultancy; Pfize: Honoraria; Fusion Pharma: Consultancy; BMS: Consultancy.

Proposed risk‐scoring model for estimating the prognostic impact of 1q gain in patients with newly diagnosed multiple myeloma

“…However, the impact of CA concurrence varied among different HRCAs, in which concurrence of t(14;16) or del(17p), rather than t(4;14), markedly exacerbated the outcomes of patients with +1q. While these observations support the definition of double‐hit MM described in the mSMART 3.0, 38 they also raise a consideration that it may be important to know which concurrent HRCAs are exactly involved. Interestingly, concurrence of some non‐HRCAs (e.g., del(1p) and del(13q)) might also influence the outcomes of patients with +1q 36,39 .…”

The R2-ISS in a Multicenter Cohort of Chinese Patients With Newly Diagnosed Multiple Myeloma

“…In this context, the international staging system (ISS) was developed to predict the prognosis of MM patients in 2005, 4 which was later updated and named revised ISS (R‐ISS) in 2015 5 . Although the R‐ISS has widely been used as a powerful tool to guide daily practice till present, some considerable limitations (eg, a large proportion of R‐ISS II patients with varied outcomes, not reflecting the significance of 1q gain/amplification and concurrent high‐risk cytogenetic abnormalities [HRCAs]) have been emerging 6–9 . In this context, several new prognostic scoring systems have been reported, 10,11 the most recent of which is the second revision of ISS (R2‐ISS) updated by the European Myeloma Network (EMN) 12 …”

“…5 Although the R-ISS has widely been used as a powerful tool to guide daily practice till present, some considerable limitations (eg, a large proportion of R-ISS II patients with varied outcomes, not reflecting the significance of 1q gain/amplification and concurrent high-risk cytogenetic abnormalities [HRCAs]) have been emerging. [6][7][8][9] In this context, several new prognostic scoring systems have been reported, 10,11 the most recent of which is the second revision of ISS (R2-ISS) updated by the European Myeloma Network (EMN). 12 In the R2-ISS, 12 5 risk variates with the highest impact on both progression-free survival (PFS) and overall survival (OS) were weighted according to their OS impact, including ISS III 1.5, ISS II 1.0, del(17p) 1.0, lactate dehydrogenase high 1.0, t(4;14) 1.0, and 1q+ (either 1q gain or amplification) 0.5.…”

Current Main Topics in Multiple Myeloma

“…A recent retrospective experience confirmed the greater role of the association of high risk feature rather than a single one, but also the size of high risk clone influenced prognosis [ 26 ]. M-Smart MM risk stratification guideline by Mayo Clinic proposed an innovative concept, with patients possessing two of the high risk genetic abnormalities defined as “double hit” and having any three as “triple hit” MM [ 27 ]. Both phenotypes were considered ultra-high-risk disease characteristics, having observed that they correlated with aggressive clinical presentations, high early mortality and poor outcomes even in real life settings [ 9 , 28 , 29 , 30 ].…”