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000291411 041__ $$aEnglish
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000291411 1001_ $$00000-0002-2771-712X$$aSeckinger, Anja$$b0
000291411 245__ $$aMolecular Long-Term Analysis of the GMMG-HD4 Trial in Multiple Myeloma-Patterns of Association of Chromosomal Aberrations with Response and Proliferation Determining Survival in Selecting Treatments in View of Limited Resources in Low- and Middle-Income Countries.
000291411 260__ $$aBasel$$bMolecular Diversity Preservation International$$c2024
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000291411 520__ $$aBased on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; n = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront 'novel agents' in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization (n = 354) and gene expression profiling (n = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an adverse response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent better response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with 'conventional' (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly better median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to 'outdated' treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront 'novel agents'.
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000291411 650_7 $$2Other$$aLMIC
000291411 650_7 $$2Other$$amolecular profiling
000291411 650_7 $$2Other$$amultiple myeloma
000291411 650_7 $$2Other$$aproliferation
000291411 650_7 $$2Other$$aresponse
000291411 650_7 $$2Other$$asurvival
000291411 650_7 $$07S5I7G3JQL$$2NLM Chemicals$$aDexamethasone
000291411 650_7 $$069G8BD63PP$$2NLM Chemicals$$aBortezomib
000291411 650_7 $$04Z8R6ORS6L$$2NLM Chemicals$$aThalidomide
000291411 650_2 $$2MeSH$$aHumans
000291411 650_2 $$2MeSH$$aMultiple Myeloma: genetics
000291411 650_2 $$2MeSH$$aMultiple Myeloma: drug therapy
000291411 650_2 $$2MeSH$$aMultiple Myeloma: mortality
000291411 650_2 $$2MeSH$$aMultiple Myeloma: pathology
000291411 650_2 $$2MeSH$$aChromosome Aberrations
000291411 650_2 $$2MeSH$$aFemale
000291411 650_2 $$2MeSH$$aMale
000291411 650_2 $$2MeSH$$aMiddle Aged
000291411 650_2 $$2MeSH$$aAged
000291411 650_2 $$2MeSH$$aAntineoplastic Combined Chemotherapy Protocols: therapeutic use
000291411 650_2 $$2MeSH$$aCell Proliferation: drug effects
000291411 650_2 $$2MeSH$$aPrognosis
000291411 650_2 $$2MeSH$$aAdult
000291411 650_2 $$2MeSH$$aDeveloping Countries
000291411 650_2 $$2MeSH$$aDexamethasone: therapeutic use
000291411 650_2 $$2MeSH$$aDexamethasone: pharmacology
000291411 650_2 $$2MeSH$$aBortezomib: therapeutic use
000291411 650_2 $$2MeSH$$aBortezomib: pharmacology
000291411 650_2 $$2MeSH$$aThalidomide: therapeutic use
000291411 7001_ $$aSalwender, Hans$$b1
000291411 7001_ $$aMartin, Hans$$b2
000291411 7001_ $$00009-0007-6539-226X$$aScheid, Christof$$b3
000291411 7001_ $$0P:(DE-He78)743a4a82daab55306a2c88b9f6bf8c2f$$aHielscher, Thomas$$b4$$udkfz
000291411 7001_ $$00000-0001-5584-3951$$aBertsch, Uta$$b5
000291411 7001_ $$0P:(DE-He78)fae4f3c76bbbd2fc21dd920b46945d42$$aHummel, Manuela$$b6
000291411 7001_ $$aJauch, Anna$$b7
000291411 7001_ $$aKnauf, Wolfgang$$b8
000291411 7001_ $$aEmde-Rajaratnam, Martina$$b9
000291411 7001_ $$aBeck, Susanne$$b10
000291411 7001_ $$00000-0003-1311-8107$$aNeben, Kai$$b11
000291411 7001_ $$aDührig, Jan$$b12
000291411 7001_ $$aLindemann, Walter$$b13
000291411 7001_ $$00000-0002-5655-0867$$aSchmidt-Wolf, Ingo G H$$b14
000291411 7001_ $$aHänel, Mathias$$b15
000291411 7001_ $$aBlau, Igor W$$b16
000291411 7001_ $$aWeisel, Katja$$b17
000291411 7001_ $$aWeinhold, Niels$$b18
000291411 7001_ $$aRaab, Marc S$$b19
000291411 7001_ $$aGoldschmidt, Hartmut$$b20
000291411 7001_ $$aChoon-Quinones, Mimi$$b21
000291411 7001_ $$aHose, Dirk$$b22
000291411 773__ $$0PERI:(DE-600)2019364-6$$a10.3390/ijms25126431$$gVol. 25, no. 12, p. 6431 -$$n12$$p6431$$tInternational journal of molecular sciences$$v25$$x1422-0067$$y2024
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