by Charles Bankhead
Staff Writer, MedPage Today
Action Points
Staging for newly diagnosed myeloma improved significantly with the addition of genomics information and a simple lab test to the standard staging criteria.
Note that the new system combines chromosomal abnormalities and serum lactate dehydrogenase with the International Staging System.
Staging for newly diagnosed myeloma improved significantly with the addition of genomics information and a simple lab test to the standard staging criteria, according to the International Myeloma Working Group (IMWG).
By the revised criteria, favorable-risk patients had a 5-year overall survival of 82%, declining to 62% for those with intermediate risk, and 40% among patients with unfavorable characteristics. Similar between-group differences resulted from an analysis of progression-free survival (PFS). The new system classified a majority of patients as intermediate risk as opposed to low risk, according to Antonio Palumbo, MD, of the Azienda Ospedaliero-Universitaria Citta della Salute e della Scienza di Torin, and colleagues on an IMWG panel.
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Combining chromosomal abnormalities and serum lactate dehydrogenase (LDH) with the International Staging System (ISS), the revised criteria offer a “simple and powerful prognostic staging system” that should be used to evaluate patients with newly diagnosed myeloma, they wrote online in the Journal of Clinical Oncology.
“I think this is of interest not just to researchers, but to anybody who is taking care of a myeloma patient,” co-author Robert Z. Orlowski, MD, PhD, of MD Anderson Cancer Center in Houston, told MedPage Today. “One of the reasons for this revised version is that the older versions did not take into account the results of chromosome studies and things like the LDH levels, which we know have an impact on prognosis. The current revised system includes that information. As a result, healthcare providers, whether it be research or standard of care, will be able to give patients a more accurate prognosis.”
“This study suggests that up to a quarter of patients were mis-staged with the old system,” he added.
Better Treatment, Better Outcomes
Myeloma has long been recognized as a heterogeneous disease, associated with survival ranging from a few months to a decade or more. Improved staging precision is an essential first step toward better treatment and outcomes, the IMWG authors noted.
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Since 2005 the ISS has represented standard diagnostic criteria for multiple myeloma. The system defines risk on the basis of information derived from two parameters: serum Beta2-microglobulin (reflecting tumor mass and renal function) and serum albumin (affected by inflammatory cytokine production in the myeloma microenvironment).
The ISS identifies three categories of risk. As shown in a validation study, patients with ISS stage I myeloma had a median overall survival (OS) of 62 months, declining to 44 months for those with ISS stage II, and 29 months for ISS stage III.
Chromosomal abnormalities identified by interphase fluorescent in situ hybridization (iFISH) provide key information about biologic features of myeloma, according to the IMWG authors. Standard risk is defined by absence of del(17p), translocation t(4;14)(p16;q32), and translocation t(14;16)(q32;q23) and has been associated with a median survival of 50.5 months. Presence of any of the abnormalities defines high risk, which has been associated with about a 50% reduction in median survival.
Serum LDH that is elevated beyond the upper limit of normal reflects increased disease aggressiveness and suggests increased proliferation or tumor mass, particularly extramedullary and extraosseous disease. High serum LDH is associated with shorter OS, initially established prior to the development of novel agents and subsequently confirmed since the agents became available.
Preliminary studies combining ISS with chromosomal abnormalities identified three risk categories (low, intermediate, and high) and associated survival ranges. A study that combined ISS, chromosomal abnormalities, and serum LDH identified four categories of risk, ranging from very low to very high.
“These data strongly suggest the need for combining these prognostic factors to better stratify patients into homogeneous survival subgroups,” according to the IMWG authors.
Study Details
IMWG investigators evaluated the revised staging criteria in patients with newly diagnosed myeloma from 11 international, multicenter clinical trials during 2005 to 2012. All of the trials have been completed and results reported. All patients received new drugs (immunomodulators or proteasome inhibitors) in association with conventional myeloma therapies. Of 4,445 patients enrolled in the trials, 3,060 had complete information related to ISS, chromosomal abnormalities, and LDH.
Investigators estimated OS and PFS for the following risk factors: age at diagnosis, sex, iFISH high risk versus standard risk, LDH, ISS stage, and revised ISS risk categories. Initially, the role of each predictor was evaluated in all 4,445 patients, who had a median follow-up of 46 months
ISS stage I was associated with a 5-year survival of 77%, decreasing to 62% for stage II, and 47% for stage III (P<0.001). The 5-year PFS was 49% for ISS stage I, 36% for stage II, and 30% for stage III (P<0.001). Standard-risk chromosomal status (n=2,718) was associated with a 5-year survival of 69% versus 50% (P<0.001) in the high-risk group (N=851), and 5-year PFS was 42% and 31%, respectively (P<0.001). The 3,443 patients with normal serum LDH had a 5-year survival of 68% compared with 47% for 530 patients with high LDH levels (P<0.001). The 5-year PFS was 42% and 31%, respectively, for patients with normal and high serum LDH (P=0.004). For the 3,060 patients with complete data, K-adaptive partitioning identified three risk categories for the revised-ISS staging criteria: Stage I-ISS stage I, no chromosomal abnormalities, normal LDH (n=871, 28%) Stage III-ISS stage III plus high-risk chromosomal abnormalities or elevated LDH (n=295, 10%) Stage II-All other combinations of ISS, chromosomal abnormalities, and LDH (n=1,894, 62%) The combined criteria stratified patients into groups that differed significantly with respect to 5-year overall survival (P<0.001) and 5-year PFS (55%, 36%, 24%, P<0.001). The median OS was not reached in the stage I group, as compared with medians of 83 and 43 months for stage II and stage III, respectively. The median PFS was 66 months for stage I, 42 months for stage II, and 29 months for stage III. In a multivariable analysis, the risk of death was significantly increased in patients with revised ISS stage II versus stage I (HR 3.59, 95% CI 2.68-4.80, P<0.001) and stage III versus stage I (HR 9.64, 95% CI 6.24-14.88, P<0.001). The PFS hazard also was significantly increased for stage II versus stage I (HR 1.99, 95% CI 1.61-2.37, P<0.001) and stage III versus stage I (HR 3.37, 95% CI 2.54-4.56, P<0.001). In earlier studies of different prognostic tools, a majority of patients fell into the low-risk category (42% to 58%), the authors noted. In the current study, 62% of patients were classified as intermediate risk by the revised criteria. Additionally, 95% of patients included in the IMWG analysis received novel agents, which have been shown to improve survival, an impact reflected in results obtained with the revised system. The study had some limitations. The authors only included patients enrolled in trials who were and the majority were younger than age 65. Some patients without baseline data were excluded from the ?nal analysis. Also, the authors "did not include host-related prognostic factors such as age, performance status, and comorbidities, which still play an important role in de?ning patient prognosis," they explained. Palumbo