Outcome of Patients with Multiple Myeloma Treated with Autologous Stem Cell Transplantation in the Era of Novel Therapies

Abstract Abstract 1865 Poster Board I-890 Background: The incorporation of novel therapies, including thalidomide, bortezomib, and lenalidomide, in the treatment of multiple myeloma as induction, maintenance, or salvage therapy, along with autologous stem cell transplantation (ASCT) is expected to result in improved outcome. The impact of a single regimen or drug on Progression Free Survival (PFS) or overall survival (OS) is difficult to determine because, even within a single institution, these drugs and treatment modalities are used in varying sequences among patients. The goal of this retrospective analysis is to determine the PFS and OS of patients with multiple myeloma treated with ASCT at a single institution, in the era of novel therapeutic agents and to validate the significance of established prognostic factors. Methods: We performed a retrospective analysis of all patients with multiple myeloma who were eligible to undergo ASCT at MSKCC between 2000 and 2007 and received novel therapies including thalidomide, bortezomib, and lenalidomide during the course of their disease. During this period of time, 274 patients were transplanted and were analyzed for overall survival. Among them, a subset of 116 patients who received induction therapy, ASCT, and long term follow up at MSKCC, on whom baseline data and response analysis at all stages of disease was available, was used to analyze prognostic factors. Log-rank test was performed to assess the difference of OS and PFS among subgroups of patients stratified by baseline variables. A time-dependent Cox model was used to assess the effect of post treatment parameters on OS and PFS. Landmark analysis at 6 months after first ASCT was performed to assess the association between post-transplant response and survival endpoints. Results: For the entire study population of MM patients (n=274), with a median follow up of 4 years, the median OS measured from the time of transplant is 7 years [95% CI (6, not reached)]. For the subset of 116 patients treated exclusively at MSKCC, with a median follow up of 5 years, the median OS measured from initial treatment has not been reached and median PFS is 3 years =95% CI (2,4)] Using the subset of 116 patients treated exclusively at MSKCC, several baseline characteristics were analyzed as prognostic factors for OS and PFS including age =median age 57 (32 to 72)] gender =M 73, F 43] type of M-spike =IgGK 49, IgGL 21, FKLC 17, IgAK 13, FLLC 10, IgAL 5, IgMK 1] kappa to lambda ratio at diagnosis =Normal 15, Abnormal 75, Not available 26] ISS stage =I 50, II 49, III 16] and cytogenetic risk =standard 95, high 14, N/A 7] As reported by others, the type of monoclonal protein had a significant impact on OS (P = 0.02) with FKLC and IgAK having the worse prognosis. Other baseline characteristics including age, gender and K/L ratio did not influence OS and none affected the PFS. Several post treatment parameters were also analyzed including response to initial therapy =CR 15, nCR 18, VGPR 20, PR 42, SD 15, POD 5] response to ASCT =CR 73, VGPR 14, PR 29] response conversion =based on response before and after first ASCT: ≥VGPR - ≥ VGPR 51; < VGPR - ≥ VGPR 34, and < VGPR - < 0.0001, and P < 0.0001, respectively). Conclusion: This retrospective study confirms the marked improvement in OS for patients who undergo ASCT in the era of novel anti-myeloma therapies. It is difficult to ascribe this improvement to a specific regimen but rather probably to the abundance of successive options available to myeloma patients in the current era. Interestingly, we find no prognostic value to the response status to initial therapy or to ASCT for overall survival in contrast to PFS. Disclosures: Comenzo: Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees

The structure, function and evolution of a complete human chromosome 8

The complete assembly of each human chromosome is essential for understanding human biology and evolution(1,)(2). Here we use complementary long-read sequencing technologies to complete the linear assembly of human chromosome 8. Our assembly resolves the sequence of five previously long-standing gaps, including a 2.08-Mb centromeric alpha-satellite array, a 644-kb copy number polymorphism in the beta-defensin gene cluster that is important for disease risk, and an 863-kb variable number tandem repeat at chromosome 8q21.2 that can function as a neocentromere. We show that the centromeric alpha-satellite array is generally methylated except for a 73-kb hypomethylated region of diverse higher-order alpha-satellites enriched with CENP-A nucleosomes, consistent with the location of the kinetochore. In addition, we confirm the overall organization and methylation pattern of the centromere in a diploid human genome. Using a dual long-read sequencing approach, we complete high-quality draft assemblies of the orthologous centromere from chromosome 8 in chimpanzee, orangutan and macaque to reconstruct its evolutionary history. Comparative and phylogenetic analyses show that the higher-order alpha-satellite structure evolved in the great ape ancestor with a layered symmetry, in which more ancient higher-order repeats locate peripherally to monomeric alpha-satellites. We estimate that the mutation rate of centromeric satellite DNA is accelerated by more than 2.2-fold compared to the unique portions of the genome, and this acceleration extends into the flanking sequence

The complete sequence of a human genome.

Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion-base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies

The complete sequence of a human genome.

Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion-base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies