J. Sawyer

Unique role of cytogenetics in the prognosis of patients with myeloma receiving high-dose therapy and autotransplants.

PURPOSE Although important predictors of survival in myeloma patients have been identified, it is well recognized that better prognostic factors for this disease are needed. Because cytogenetics play a dominant role in the outcome of patients with acute leukemia, their prognostic value was evaluated in a large group of newly diagnosed and previously treated myeloma patients receiving autotransplants. METHODS A total of 427 either newly diagnosed (26%) or previously treated patients (74%) received tandem transplants, supported by mobilized peripheral-blood stem cells. Numerous variables, including cytogenetics, were analyzed for their impact on complete remission, event-free survival (EFS), and overall survival (OS). RESULTS Abnormal karyotypes were detected in 37% of our patients and were very complex, irrespective of the duration of standard therapy before the first autotransplant. In addition to previously recognized unfavorable implications of partial or complete deletion of chromosome 13 and 11q abnormalities, we now observed that the presence of any translocation likewise portended poor outcome (unfavorable karyotypes). On multivariate analysis, the absence of an unfavorable karyotype was the most favorable variable for both EFS (P = .0001) and OS (P = .0001). Other favorable factors were duration of standard therapy and a low beta-2 microglobulin (B2M) level before the first autotransplant. A risk-based classification system was developed according to the number of these favorable variables present, showing highly significant differences in event-free and overall survival. CONCLUSION Cytogenetics play a dominant role in myeloma and were independent of previously recognized important prognostic factors, such as B2M and duration of prior standard therapy.

MDS-type abnormalities within myeloma signature karyotype (MM-MDS): only 13% 1-year survival despite tandem transplants

Summary. Cytogenetic abnormalities (CA), especially of chromosome 13, have been used to identify a subgroup of previously untreated multiple myeloma (MM) patients with very poor prognosis despite high‐dose therapy (HDT). We examined the prognostic implications of CA in 1000 MM patients receiving melphalan‐based tandem autotransplants (median follow‐up, 5 years). Negative consequences for both overall survival (OS) and event‐free survival (EFS) in the presence of any CA were confirmed, especially when detected within 3 months of HDT. In the context of standard prognostic factors (SPF), ‘MM‐MDS’ (MM karyotype that contains, in addition, CA typical of MDS) imparted a poor OS and EFS, after adjusting for any CA and all individual CA. One‐year mortality was also high, especially for the MM‐MDS subgroup with trisomy 8 within a MM signature karyotype (87%vs 34% in its absence, P < 0·001). No patient remained event free 5 years post transplant in the presence of these baseline high‐risk CA. However, certain trisomies (e.g. chromosomes 7 and 9) and del 20 had favourable clinical consequences. The higher risk that is associated with CA compared with SPF justifies routine cytogenetic studies in all patients with MM at diagnosis and whenever additional treatment decisions are considered, such as in planning HDT either for initial response consolidation, at the time of primary unresponsiveness to induction therapy, or at relapse.

The role of cytogenetics in myeloma

Multiple myeloma is a slowly proliferating disease of ‘mature B cells’, involving mainly the bone marrow. Active myeloma is often preceded by an indolent phase of monoclonal gammopathy of undetermined significance or smoldering myeloma. Although patients at this stage do not require therapy, genetically, the plasma cells are already very abnormal with the large majority of such patients having an aneuploid DNA content and abnormal cytogenetics by fluorescence in situ hybridization (FISH), including deletion of chromosome 13, t(11;14), t(4;14), t(6;14), t(14;16) and t(14;20), although the latter three translocations are uncommon. In patients with active myeloma, more than 90% have abnormal cytogenetics by FISH if tested for hyperdiploidy and for the common translocations involving 14q32. In contrast, using metaphase cytogenetics, only one-third of patients will show an abnormal karyotype, which is usually complex and on an average 11 chromosomes are involved. The other two-thirds will have normal metaphase cytogenetics. These normal metaphases are not derived from the myeloma cells, but from the remaining normal hematopoietic cells. The reason for failure to have informative mitoses is the low proliferative capacity of the myeloma cells. It is the failure to obtain informative cytogenetics in the majority of patients that has led to a shift away from metaphase cytogenetics to interphase FISH. Deletion of chromosome 13 and hypodiploidy by metaphase cytogenetics are associated with a poor outcome. Based on these findings, it has been assumed that deletion of chromosome 13 by FISH would have a similar poor prognosis as the metaphase abnormality. In fact, in the IFM 99 study, poor prognosis was defined as a combination of deletion 13 by FISH and elevated B2 microglobulin level. Unfortunately, mixing results of metaphase cytogenetics with those obtained by FISH has resulted in confusion and statements that deletion of chromosome 13 (as determined by FISH) was not a poor prognostic factor. Patients with inferior outcome as analyzed by FISH were those with t(4;14), t(14;16) and gene deletion of p53. Also, it was claimed that on metaphase cytogenetics not deletion 13, but hypodiploidy was associated with poor outcome. It is clear that often there is an association between hypodiploidy and deletion of chromosome 13. However, our work has shown that both hypodiploidy without deletion of chromosome 13 and deletion of chromosome 13 without hypodiploidy are associated with a poor prognosis. When analyzing outcome of patients with or without FISH deletion 13, those with deletion 13 (approximately 50% of all patients) as a group have an inferior outcome (Figure 1), but if we divide patients with deletion 13 by FISH into those with normal versus abnormal metaphase karyotypes, it becomes evident that the inferior prognosis of patients with FISH deletion 13 is entirely due to the one-third of those patients (17% of the overall patient population) with abnormal metaphase cytogenetics, whereas those with normal metaphase cytogenetics and deletion 13 by FISH have an outcome similar to those without FISH deletion 13 (Figure 2). In the context of the ongoing confusion of the prognostic value of metaphase versus FISH cytogenetics, the paper in this issue by Laura Chiecchio et al. is very relevant. The authors compared results obtained by FISH, not only for deletion of chromosome 13, but also for hyperdiploidy, p53, t(14;16), t(14;20), t(6;14) and t(4;14), with those obtained by metaphase cytogenetics. This was a large multicenter study including 794 patients, with 78% of these patients studied at the time of diagnosis. A weakness of the study is that the treatment approach was not uniform and that it is unknown whether the knowledge of cytogenetic results had an impact on the type of therapy given to patients. In addition, the median follow-up was a short 22 months. Their findings confirm our data that abnormal metaphase cytogenetics are associated with a poor outcome and that patients with FISH deletion 13 but without abnormal metaphase cytogenetics had similar outcomes to those with no

Dose-dense and less dose-intense Total Therapy 5 for gene expression profiling-defined high-risk multiple myeloma

Multiple myeloma (MM) is a heterogeneous disease with high-risk patients progressing rapidly despite treatment. Various definitions of high-risk MM are used and we reported that gene expression profile (GEP)-defined high risk was a major predictor of relapse. In spite of our best efforts, the majority of GEP70 high-risk patients relapse and we have noted higher relapse rates during drug-free intervals. This prompted us to explore the concept of less intense drug dosing with shorter intervals between courses with the aim of preventing inter-course relapse. Here we report the outcome of the Total Therapy 5 trial, where this concept was tested. This regimen effectively reduced early mortality and relapse but failed to improve progression-free survival and overall survival due to relapse early during maintenance.

Hyperhaploidy is a novel high-risk cytogenetic subgroup in multiple myeloma

Hyperhaploid clones (24–34 chromosomes) were identified in 33 patients with multiple myeloma (MM), demonstrating a novel numerical cytogenetic subgroup. Strikingly, all hyperhaploid karyotypes were found to harbor monosomy 17p, the single most important risk stratification lesion in MM. A catastrophic loss of nearly a haploid set of chromosomes results in disomies of chromosomes 3, 5, 7, 9, 11, 15, 18, 19 and 21, the same basic set of odd-numbered chromosomes found in trisomy in hyperdiploid myeloma. All other autosomes are found in monosomy, resulting in additional clinically relevant monosomies of 1p, 6q, 13q and 16q. Hypotriploid subclones (58–68 chromosomes) were also identified in 11 of the 33 patients and represent a duplication of the hyperhaploid clone. Analysis of clones utilizing interphase fluorescence in situ hybridization (iFISH), metaphase FISH and spectral karyotyping identified either monosomy 17 or del17p in all patients. Amplification of 1q21 was identified in eight patients, demonstrating an additional high-risk marker. Importantly, our findings indicate that current iFISH strategies may be uninformative or ambiguous in the detection of these clones, suggesting this patient subgroup maybe underreported. Overall survival for patients with hyperhaploid clones was poor, with a 5-year survival rate of 23.1%. These findings identify a distinct numerical subgroup with cytogenetically defined high-risk disease.