The incidence of multiple myeloma (MM) is known to be variable according to ethnicity. However, the differences in clinical characteristics between ethnic groups are not well-defined. In Asian countries, although the incidence of MM has been lower than that of Western countries, there is growing evidence that MM is increasing rapidly. The Asian Myeloma Network decided to initiate the first multinational project to describe the clinical characteristics of MM and the clinical practices in Asia. Data were retrospectively collected from 23 centers in 7 countries and regions. The clinical characteristics at diagnosis, survival rates and initial treatment of 3,405 symptomatic MM patients were described. Median age was 62 years (range, 19–106), with 55.6% of being male. Median overall survival (OS) was 47 months (95% CI 44.0–50.0). Stem cell transplantation was performed in 666 patients who showed better survival rates (79 vs. 41 months, P < 0.001). The first-line treatments of 2,970 patients were analyzed. The overall response rate was 71% including very good partial response or better in 31% of the 2,660 patients those were able to be evaluated. New drugs including bortezomib, thalidomide, and lenalidomide were used in 36% of 2,970 patients and affected OS when used as a first-line treatment. Am. J. Hematol. 89:751–756, 2014. © 2014 Wiley Periodicals, Inc.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.23731

Clinical profiles of multiple myeloma in Asia-An Asian Myeloma Network study.

Survival in multiple myeloma (MM) is variable, ranging from several months to more than 15 years. While survival has recently improved with the use of novel therapy, approximately 25% of patients have a median survival of 2 years or less. Accurate identification of high-risk patients, and risk stratification, are crucial in improving outcomes for all patients. In the first part of this two part series, we review the currently identified prognostic factors characterized by disease burden (Durie-Salmon staging system, International Staging System, magnetic resonance imaging, (18F) fluorodeoxyglucose positron emission tomography, presence of extramedullary disease or plasma-cell leukemia), host factors (age, performance status, and renal function), tumor biology (proliferation rate, conventional cytogenetics, interphase fluorescence in situ hybridization, and gene expression profiling), and depth of response to therapy. Efforts have been made to identify ultra-high-risk patients by combining all the identified variables into a unifying comprehensive model. In the second part of this series, we will discuss the significance of these factors in the context of currently available therapies for MM, distinguishing between treatments that only improve outcomes of high-risk patients when compared with previous therapies, versus those that overcome high-risk status, thereby reclassifying these patients as standard risk.

Risk stratification in multiple myeloma, part 1: characterization of high-risk disease.

BACKGROUND The prognostic value of 1q21 gain in newly diagnosed multiple myeloma (NDMM) remains controversial. Our aim was to investigate the prognostic value of 1q21 gain in a Chinese population. MATERIALS AND METHODS We retrospectively identified 565 patients with NDMM from multiple centers in China. RESULTS We detected 1q21 gain in 222 (39.3%) patients, among whom 144 had three copies of 1q21, 57 had four copies of 1q21, and 21 had at least five copies of 1q21. Copy number variation did not show any effect on the disease outcome. Multivariate analysis indicated that 1q21 gain was an independent factor for poor prognosis, but we found that 1q21 gain was strongly associated with other high-risk factors, such as del(17p), t(4;14), t(14;16), lactate dehydrogenase (LDH) level >300 U/L and International Scoring System (ISS) stage II-III (p < .001). Further analysis revealed that in the absence of other high-risk factors, isolated 1q21 gain resulted in similar progression-free survival (PFS; 52.0 vs. 52.8 months, p = .810) and overall survival (OS; not reached vs. not reached, p = .833); additionally, when present with other high-risk cytogenetic abnormalities or increased LDH levels, 1q21 gain lost its prognostic power. However, the presence of 1q21 gain increased the adverse impact of ISS stage. Furthermore, 1q21 gain predicted poor PFS and OS in patients who received bortezomib-based regimens. Moreover, autologous stem cell transplantation reversed the poor prognosis in patients with 1q21 gain. CONCLUSION Our results show that heterogeneity exists among patients with 1q21 gain and suggest that we should assess the impact of 1q21 gain on prognosis according to different treatment regimens and accompanying high-risk factors. IMPLICATIONS FOR PRACTICE 1q21 gain is one of the most common chromosomal aberrations in multiple myeloma (MM); however, the prognostic value of 1q21 gain remains controversial. This study investigated the prognostic value of 1q21 gain in a Chinese population with newly diagnosed MM. The results showed that heterogeneity exists among patients with 1q21 gain and suggested that the impact of 1q21 gain on prognosis should be assessed according to different treatment regimens and accompanying high-risk factors. These results could help stratify risk in patients with MM and guide treatment decisions.

1q21 Gain Combined with High-Risk Factors Is a Heterogeneous Prognostic Factor in Newly Diagnosed Multiple Myeloma: A Multicenter Study in China

Background The cut-off value for gain/amplification of 1q21(1q21+) was 20% according to the recommendations of the European Myeloma Network and there were limited studies concerning less than 20%. Meanwhile, the copy number variation of 1q21+ remains controversial. Our purpose was to evaluate the significance of clone size and copy numbers of 1q21+ in Chinese newly diagnosed multiple myeloma (NDMM). Patients and methods We retrospectively analyzed 161 consecutive NDMM patients who were tested for common cytogenetic abnormalities at diagnosis by fluorescence in-situ hybridization and 5% was set for the threshold for 1q21+ by a comparative study. Results Ninety-six (59.6%) patients were determined for 1q21+ by fluorescence in-situ hybridization including 38 had ≥4 copies. In clone size analyses, the 2-year progression-free survival (PFS) in <5% group was superior in comparison with 5% to 20% (65.2% vs. 47.0%, P = .041) and >20% group (65.2% vs. 37.5%, P < .001), whereas there was no significant difference between the 2 latter groups. Patients with ≥ 4 copies of 1q21 had inferior 2-year PFS compared to patients with 3 copies (23.3% vs. 50.6%, P = .028) and 2 copies (23.3% vs. 65.2%, P < .001). Bortezomib-based treatment might benefit the PFS for patients with 3 copies but could not improve the adverse effect of ≥ 4 copies. 1q21+ was an independent risk factor for inferior PFS and OS in multivariate analysis (P < .001 and P = .028). Conclusion Our results demonstrated that 5% was a reliable cut-off value for 1q21+, and 1q21+ was an adverse prognostic factor in NDMM, especially when ≥ 4 copies were present. 

The Importance of FISH Signal Cut-off Value and Copy Number Variation for 1q21 in Newly Diagnosed Multiple Myeloma: Is it Underestimated?

Cytogenetic abnormalities are important prognostic markers in plasma cell myeloma (PCM) and detection is routinely performed by interphase fluorescence in-situ hybridization (FISH) with a panel of probes after enrichment of the plasma cells in the bone marrow specimen. Cell sorting by immunomagnetic beads and concurrent labeling of the cytoplasmic immunoglobulin are the usual enrichment methods. We present an alternative method of plasma cell enrichment termed Target FISH, which is an automated system that combines the images of May-Grunwald- Giemsa (MGG) staining and FISH study on the same plasma cell for analysis. Our experience of Target FISH on 40 PCM patients was described. Briefly, plasma cells were MGG stained, image captured, de-stained, FISH probe hybridized and finally relocated for simultaneous analysis of morphology and FISH signal pattern. The FISH probe panel was TP53/CEP17, t(4;14) IGH/FGFR3, t(14;16) IGH/MAF and CKS1B(1q21)/CDKN2C(P18). Gain of 1q21 was the most common abnormality detected in 18 patients (45 %), to be followed by t(4;14) IGH/FGFR3 detected in 11 patients (27.5 %). Of note, 10 patients showed coexistence of both t(4;14) and 1q21 gain. Two patients showed del(17p)/TP53, one in association with t(4;14) and 1q gain while the other was stand alone. None of this patient cohort showed t(14;16) IGH/MAF. Using the critical binomial function, the normal cutoff FISH positive value for del(17p)/TP53 was 3.4 %, t(4;14) IGH/FGFR3 was 6.8 %, t(14;16) IGH/MAF was 5.6 % and +1q21 was 5.7 %. The equipment cost notwithstanding, when compared with cell sorting, the total reagent cost was around 10 % lower in Target FISH. The total processing time was longer for Target FISH but manual fluorescence microscopy was no longer necessary. The main advantage of Target FISH was the complete certainty that the cytogenetic abnormality was detected in the cells of interest, and hence a more stringent analytical cutoff value might be considered. Optimization of the cell collection and slide preparation process upfront was required to accrue adequate target cells on each slide for analysis. Our experience suggested that Target FISH was applicable as a routine method of plasma cell enrichment in clinical diagnostic laboratories.

/pdf/target-fluorescence-in-situ-hybridization-target-fish-for-26cz1dyzts.pdf

Target fluorescence in-situ hybridization (Target FISH) for plasma cell enrichment in myeloma

Background Chromosomal abnormalities have been shown to play an important prognostic role in multiple myeloma (MM). Interphase fluorescence in situ hybridization (i-FISH) has been much more effective to identify cytogenetic aberrations in MM than conventional cytogenetic technique (CC). To clearly determine the cytogenetic features of Chinese MM patients and identify their prognostic implications, we designed a multicenter study based on i-FISH including 672 patients from 52 hospitals in China. Methods All 672 patients were systematically screened for the following genomic aberrations: del(13q), IgH rearrangement, del(p53) and 1q21 amplifications. Results The analysis showed that the chromosomal changes were detected in 22.1% patients by CC and in 82.3% patients by i-FISH. The most common abnormalities by CC were chromosome 1 aberrations (48.4%), -13/13q- (37.6%), hyperdiploidy (36.6%), hypodiploidy (30.1%) and IgH rearrangements (23.7%). The most frequent abnormalities by FISH was del(13q), which was found in 60.4% patients, whereas IgH rearrangement, 1q21 amplification and p53 deletions were detected in 57.6%, 49.0% and 34.7% cases, respectively. By statistical analysis, -13/13q- by CC was associated with low level of platelet (P=0.015), hyperdiploidy was associated with low level of serum albumin (P=0.028), and IgH rearrangement by FISH was associated with high level of 82 microglobulin (P=0.019). Moreover, 1q21 amplification and del(p53) by FISH conferred a high incidence of progressive disease (PD) after initial therapy. Metaphase detection of IgH rearrangements and chromosome 1 aberrations concurrently was associated with a short progression free survival (PFS) (P=0.036). No significant prognostic implications of other cytogenetic abnormalities were found associated with overall survival and PFS. Conclusions Chinese MM patients had similar cytogenetic abnormalities compared with the previous reported studies. However, the prognostic significance of FISH aberrations were not clearly determined and further study is required. Chin Med J 2012;125(15):2663-2670

Prognostic power of abnormal cytogenetics for multiple myeloma: a multicenter study in China.

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Prognostic power of abnormal cytogenetics for multiple myeloma: a multicenter study in China.