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Plasmablastic Morphology Is an Independent Predictor of Poor Survival After Autologous Stem-Cell Transplantation for Multiple Myeloma

From the Division of Hematology and Internal Medicine and the Section of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, MN.

Address reprint requests to Philip R. Greipp, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; email greipp.philip{at}mayo.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To study the prognostic value of plasmablastic morphology after autologous stem-cell transplantation for relapsed or primary refractory myeloma.

PATIENTS AND METHODS: Seventy-five patients were studied. Investigators blinded to the clinical details of the individual cases reviewed bone marrow aspirate slides to determine plasmablastic classification. Plasmablasts were defined using strict, well-described criteria. Plasmablastic morphology was considered to be present (plasmablastic myeloma) when 2% or more plasmablasts were present in the plasma-cell population.

RESULTS: Patients underwent transplantation 5 to 88 months (median, 20 months) after the initial diagnosis of myeloma. Twenty-eight percent of patients had plasmablastic morphology. A significantly greater proportion of patients with plasmablastic morphology had abnormal cytogenetics compared with those with nonplasmablastic classification (73% v 31%, respectively; P = .003). The overall survival rate measured from the time of transplantation was significantly worse in patients with plasmablastic morphology compared with those without (median survival time, 5 months v 24 months, respectively; P < .001). Progression-free survival time was shortened also, with a median time of 4 months compared with 12 months, respectively (P < .001). In the multivariate analysis, plasmablastic classification was the most powerful prognostic factor after transplantation for both overall (P = .001) and progression-free survival rates (P < .001). We also identified three risk groups based on plasmablastic morphology: plasma-cell labeling index, lactate dehydrogenase, and cytogenetics. The median overall survival time was 38 months when none of these factors was abnormal, 17 months with one abnormal factor, and 8 months with two or more abnormal factors (P < .001).

CONCLUSION: Plasmablastic morphology is a powerful independent predictor of poor survival rate after autologous stem-cell transplantation for relapsed or primary refractory myeloma.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
MULTIPLE MYELOMA is a clonal plasma-cell proliferative disorder that accounts for 1% of all malignancies and 10% of malignant hematologic neoplasms.^1,2 It was estimated that in 1998 approximately 13,800 new cases of myeloma would be diagnosed and over 11,000 would die of the disease in the United States (US). The median survival time in patients treated with conventional chemotherapy is approximately 3 years, although 3% live longer than 10 years.³ High-dose therapy before autologous stem-cell transplantation improves survival time in selected patients, but it is not a cure.^4-6

Morphologic features on bone marrow examination, such as infiltration pattern, presence of fibrosis, and mitotic index, have been described and have prognostic value in myeloma.⁷ In addition, using well-defined morphologic criteria, it is possible to identify a subgroup of patients with myeloma who have plasmablastic features on bone marrow examination.⁸ Earlier studies suggest that the presence of a plasmablastic morphology has prognostic significance.^8-12 Subsequently, a large study by the Eastern Cooperative Oncology Group on newly diagnosed myeloma has recently confirmed that plasmablastic morphology is a powerful independent adverse prognostic factor for survival.¹³

The prognostic value of the plasmablastic classification in relapsed and refractory myeloma is unclear. It is also not known whether plasmablastic morphology is a useful prognostic factor for patients who undergo stem-cell transplantation for myeloma. The purpose of this study was to investigate the prevalence and prognostic value of plasmablastic morphology in patients who undergo autologous stem-cell transplantation for relapsed and refractory myeloma.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients and Data Collection
Seventy-five patients underwent high-dose therapy and stem-cell transplantation for refractory or relapsed myeloma at the Mayo Clinic, Rochester, MN, between June 1989 and February 1998. Data from transplant recipients are collected prospectively and entered into a comprehensive computerized database. Response to therapy, relapse, and survival data are updated continuously. Information on prognostic factors, including beta 2-microglobulin (ß-2M) (all patients), bone marrow plasma-cell percentage (all patients), plasma cell–labeling index (PCLI) (74 patients), cytogenetic analysis (70 patients), lactate dehydrogenase (LDH) (58 patients), and C-reactive protein (CRP) (58 patients), collected just before transplantation were used for this study. Bone marrow samples were available for assessment of plasmablastic morphology in 69 patients.

Stem cells were harvested in most patients after initial chemotherapy with vincristine, doxorubicin, and dexamethasone chemotherapy. The conditioning regimen (high-dose therapy) consisted of melphalan (140 mg/m²) and total-body irradiation (12 Gy) in 57 patients. Eleven patients received melphalan, cyclophosphamide, and total-body irradiation and three received melphalan (200 mg/m²) alone. Four patients received other regimens. All patients had stem cells reinfused after high-dose therapy except for one patient (included in the analysis) who died of sepsis 1 day before stem-cell infusion.

No patients were lost to follow-up. All patients gave written informed consent for research bone marrow and blood samples and again before stem-cell mobilization. Approval of the protocol by the Mayo Clinic Institutional Review Board was obtained in accordance with US federal regulations and the Declaration of Helsinki.

Assessment of Plasmablastic Morphology
Bone marrow aspirates obtained before transplantation and prepared with the Wright-Giemsa stain or Wright stain were examined simultaneously by two investigators (S.V.R. and P.R.G.) using a two-headed microscope (Mayo Medical Laboratories, Rochester, MN). Both investigators were blinded to the diagnosis and clinical details of all samples being studied. Initially, areas of the aspirate slide that possessed a good spread of cells and high quality of staining, sufficient to identify critical features of the plasma cells, including nuclear chromatin pattern, nuclear size, nucleolar size, and cytoplasmic distribution, were identified for evaluation. Plasmablasts were characterized as follows: fine reticular chromatin pattern in the nucleus (no or minimal chromatin clumping); large nucleus (estimated to be > 10 µm) or a large nucleolus (estimated to be > 2 µm); no or minimal hof region in the cytoplasm; and less-abundant cytoplasm (< one half the nuclear area).¹³ About 500 plasma cells were identified and the percentage of plasmablasts was estimated. Plasmablastic morphology was considered to be present (plasmablastic myeloma) when 2% or more plasmablasts were present in the plasma-cell population.⁸ When the percentage of plasmablasts was close to 2%, another 500 plasma cells were assessed. Because of morphologic heterogeneity, the reviewers thoroughly reviewed the entire area of a well-spread slide before they concluded whether the case exhibited plasmablastic morphology in any area of the slide. Figure 1A and 1B illustrate the differences between mature plasma cells and the plasmablastic morphology.

View larger version (68K): [in this window] [in a new window]   Fig 1. (A) Mature plasma cell (MPC). Note clumped chromatin, eccentric nucleus, and perinuclear hof; (B) Plasmablast (PB). Note fine chromatin, large nucleus, scanty cytoplasm, and no perinuclear hof. Also note immature plasma cell (IMM) with nucleus resembling plasmablasts, but abundant cytoplasm. Magnification x100.

Response and Survival
A complete response was defined as a lack of detectable monoclonal protein in serum and urine by immunoelectrophoresis and immunofixation. A partial response was defined as a reduction of serum monoclonal protein and 24-hour urinary light-chain excretion by at least 50%, accompanied by a similar reduction of soft tissue plasmacytomas if present. Disease progression was defined as 50% increase in the serum monoclonal protein or 24-hour urinary monoclonal protein excretion over the lowest remission level. An increase in the size of existing lytic bony lesions or soft tissue plasmacytomas or the appearance of new lytic bony lesions constituted progression. In those with complete response, any detectable monoclonal protein by immunofixation constituted progression. Overall survival time was measured both from the date of transplantation and from the date myeloma was initially diagnosed to the date of death or last follow-up. Progression-free survival (PFS) was defined as time from transplantation to disease progression or death.

Labeling Index and Cytogenetics
Bone marrow PCLI, cytogenetics, and other laboratory parameters were assessed before transplant. The PCLI, a reflection of the proliferative activity, was determined using a slide-based immunofluorescence method on bone marrow samples, as described elsewhere.^9,14 A PCLI of 1% or greater was classified as high. For cytogenetic analysis, bone marrow specimens were processed by both direct and short-term culture techniques, as described previously.^15,16

Statistical Analysis
Survival analysis was done using the method described by Kaplan and Meier.¹⁷ Differences between survival curves were tested for statistical significance using the two-tailed log-rank test. The following prognostic factors for posttransplant overall survival and PFS rates were tested in a univariate analysis: age, sex, ß-2M, LDH, CRP, response to previous chemotherapy, PCLI, bone marrow plasma-cell percentage, bone marrow cytogenetics, and plasmablastic morphology. Factors that significantly predicted survival rate in the univariate model were then studied in a multivariate analysis using Cox's proportional hazards model.¹⁸ The ² and Fisher's exact tests were used to compare differences in nominal variables; the rank sum test was used for continuous variables.

	RESULTS

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Fifty men and 25 women ranging in age from 33 to 68 years (median, 53 years) were studied. Patient characteristics are listed in Table 1. All patients had received chemotherapy previously, and 87% had received two or more regimens. Sixty-three patients received transplants for relapsed disease; 30 had relapsed while off chemotherapy and 33 while still receiving standard-dose chemotherapy. Twelve patients underwent transplantation for primary chemotherapy-refractory myeloma.

Patients underwent transplantation 5 to 88 months (median, 23 months) after the initial diagnosis of myeloma. The serum monoclonal protein was immunoglobulin (Ig) G in 54%, IgA in 21%, IgD in 3%, and light chain only in 22%. Thirty (43%) of 70 patients had abnormal marrow cytogenetics and most abnormalities (93%) were complex ( three abnormalities). Cytogenetic abnormalities most frequently involved chromosomes 1, 11, 13, and 14. Numeric or structural abnormalities of chromosomes 13 or 11 were present in 87% of patients with abnormal cytogenetics. Translocations were present in 16 patients. Abnormalities of 14q were found in nine patients, comprising 33% of patients with a chromosomally abnormal clone. This included five patients with a t(11;14)(q13;q32), two patients with structural abnormalities that involved 14q32, and one patient each with t(11;14)(q13;q24) and t(12;14)(p11.2;q11.2). In 97% of patients with an abnormal karyotype, cytogenetic abnormalities involved chromosomes 1, 11, and 12, which house the N-ras, H-ras, and K-ras genes, respectively.

Incidence of Plasmablastic Morphology and Correlation With Cytogenetics and Other Prognostic Factors
Plasmablastic morphology was present in 19 (28%) of 69 patients. A significantly greater proportion of patients with plasmablastic morphology had abnormal cytogenetics compared with those with nonplasmablastic classification (73% v 31%, respectively; P = .003). There were no significant differences in age or sex distribution, stage, monoclonal protein type or level, bone marrow plasma-cell percentage, PCLI, or disease status at the time of transplantation between those who had a plasmablastic morphology and those who did not. Serum levels of LDH, CRP, serum creatinine, and ß-2M were likewise similar between the two groups.

Response and Survival Analysis
There was no significant difference in overall or complete response rates between those who had plasmablastic myeloma compared with those with nonplasmablastic morphology (Table 2).

Forty-five patients have died. Recurrent myeloma was the cause of death in 35 patients; seven patients died of complications related to transplantation and one patient each died of intracranial bleed, acute myeloid leukemia, and suicide. Most deaths related to transplantation occurred during the early years of our transplantation program. The median survival time from the time myeloma was first diagnosed was 53 months. The median survival time from the date of transplantation was 18 months for the cohort; PFS was 9 months.

Univariate Analysis
Univariate survival comparisons for overall survival and PFS rates are listed in Table 3. Age, sex, ß-2M, CRP, and time from initial diagnosis and response to previous chemotherapy were not predictive indicators of survival or progression rate. Overall survival time after blood cell transplantation was significantly shorter in patients with plasmablastic morphology compared with those without, with median survival times of 5 and 24 months, respectively (P < .001; Fig 2A). PFS was also significantly shorter, with median times of 4 and 12 months, respectively (P < .001; Fig 2B). Other predictors on univariate analysis were abnormal cytogenetics, PCLI, and LDH (Table 3). ß-2M was not a significant predictor (P > .5) for overall survival or PFS times, even when a cutoff value of 4.0 mg/L was used in the analysis.

View larger version (24K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimation of (A) overall survival time, and (B) PFS time for patients with plasmablastic versus nonplasmablastic morphology who undergo autologous transplantation for myeloma

Using plasmablastic morphology, PCLI, and LDH, we were able to identify three risk groups. The median overall survival time was 38 months when none of the factors were abnormal (n = 29), 12 months when any one factor was abnormal (n = 31), and 3 months when two or more factors were abnormal (n = 15) (P < .001). PFS was also significantly different (P < .001), with median times of 15, 7, and 3 months, respectively.

Multivariate Analysis
Plasmablastic classification was highly prognostic in the multivariate analysis. In a model that included cytogenetics, PCLI, and LDH, plasmablastic classification was highly prognostic for overall survival (P = .003). PCLI was not prognostic independently for overall survival rate (Table 4). Plasmablastic morphology was an independent adverse prognostic factor for PFS time as well (P < .001; Table 4). PCLI and LDH were additional prognostic factors for PFS time in the multivariate model (Table 4). Abnormal cytogenetics was not predictive of poor overall survival or PFS rate in this model, which included plasmablastic morphology.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Almost all patients with myeloma, including those who undergo transplantation, eventually relapse, and there is no plateau in the survival curves.⁴ Important prognostic factors are ß-2M, PCLI, cytogenetic analysis, LDH, and CRP.^9,19

Plasmablastic morphology has major prognostic value in newly diagnosed myeloma. This study demonstrates for the first time that plasmablastic morphology has important prognostic value in patients with relapsed and primary refractory myeloma who undergo transplantation. Although there is no difference in response rates to high-dose therapy, both overall survival and PFS rates are significantly shorter in patients with plasmablastic myeloma. We also show that by combining important prognostic factors, patients can be classified into different risk groups. This will aid therapeutic decision making by identifying patients with relapsed myeloma and plasmablastic morphology as poor candidates for autologous stem-cell transplantation in whom alternative approaches need to be discussed and pursued.

The prevalence of plasmablastic morphology in patients with newly diagnosed myeloma is approximately 10%. Because our cohort consisted of patients with relapsed or refractory myeloma, it was not surprising that a relatively high percentage (28%) of patients had plasmablastic morphology. It has been shown that if clearly defined criteria are used, the diagnosis of plasmablastic morphology on bone marrow aspirate examination is easy to perform and highly reproducible.¹³ No special stains are required. We are now planning further studies to examine the time course to the development of plasmablastic morphology and to assess the occurrence and importance of a plasmablastic transformation in myeloma.

Waldron et al⁷ have studied other bone marrow morphologic features consisting of mitotic index, Bartl stage and grade, infiltration pattern, and presence of fibrosis in 201 patients undergoing tandem transplantation for myeloma. They found that such features have prognostic value, independent of cytogenetic abnormalities, for both overall and event-free survival rates. These findings further establish the need for careful morphologic interpretation of bone marrow biopsy results in myeloma.

A high LDH was an independent prognostic factor for both overall survival and PFS rates, although the utility of this finding is limited because only a small percentage (13%) of patients had a high LDH. Although PCLI had independent prognostic value for PFS time, it was not a statistically significant indicator for overall survival time. This may be a reflection of inadequate sample size. The lack of prognostic value for ß-2M may also reflect sample size issues. Although other studies have found a minor degree of correlation between the presence of plasmablastic morphology and adverse prognostic factors such as high PCLI, LDH, and ß-2M, such an association was not seen in this study.^8,13

Abnormal cytogenetics did not add further prognostic information in the multivariate model, and this may be related to the finding that plasmablastic morphology was strongly associated with the presence of chromosomal abnormalities. This result is common in multivariate analysis when two highly associated variables are entered in the same model. In this situation, it would require a much larger sample size to demonstrate the prognostic value of cytogenetic abnormalities, independent of plasmablastic morphology. The association between cytogenetic abnormalities and plasmablastic morphology is nevertheless an interesting finding and raises the hypothesis that the presence of chromosomal abnormalities may confer the plasmablastic phenotype in many patients. Because the chromosomal abnormalities in myeloma are complex and because of the limited sample size in this study, it was not possible to determine whether one or more chromosomal abnormalities had a specific association with plasmablastic myeloma. However, earlier studies have shown that mutations of ras oncogenes are associated with a higher frequency of plasmablastic morphology.²⁰ There is also an association with higher serum levels of soluble interleukin-6 (IL-6) receptor, an important cytokine in the pathogenesis of myeloma.¹³ It is not clear why the plasmablastic phenotype is associated with an extremely poor outcome that is independent of other prognostic factors. One hypothesis is that the plasmablastic morphology is partly a result of activating ras mutations that potentiate myeloma cell growth. These mutations may lead to increased soluble IL-6 receptor levels, resulting in an enhanced proliferative response of myeloma cells to IL-6. The plasmablastic morphology and the associated poor prognosis are then a manifestation of this IL-6–mediated amplification of myeloma cell proliferation.¹³

Although posttransplant survival time in this study (median, 18 months after transplantation) seems lower than in other studies,^21-23 this is clearly attributable to patient selection because we only studied patients with relapsed or refractory myeloma. Moreover, 47% of patients in our study had a high (> 1%) PCLI and 43% had abnormal cytogenetics, which are adverse prognostic factors (Table 1). We also used a strategy of delayed transplantation, and the median time from initial diagnosis of myeloma to transplantation was 20 months. Although these differences in patient selection, referral pattern, and time from initial diagnosis to transplantation contribute to the poorer survival rates reported in our series, comparing results across various nonrandomized studies is still difficult and biased because of numerous unknown variables. The posttransplantation survival rate in our study is similar to that of a cohort of patients with advanced myeloma studied by Alexanian et al.²⁴ The median survival rate measured from the initial diagnosis of myeloma in the patients we studied was 53 months and is similar to results reported by other investigators.²⁵

One of the concerns that arises with any prognostic factor that includes histologic interpretation is interobserver variation. In a study of 453 patients with newly diagnosed myeloma, the concordance rate between two histologic reviewers was 85% (386 of 453 cases were correctly classified).¹³ Because only 8% of the total cases were of the plasmablastic phenotype, agreement between the two reviewers after excluding nonplasmablastic cases was only 50%. However, patients classified as plasmablastic by either of the two reviewers had a poor prognosis, not statistically different from the patients classified as plasmablastic by both reviewers.¹³ This suggests that the prognostic value of plasmablastic morphology is high and able to overcome any misclassification that results from interobserver variation. Nevertheless, significant expertise may be needed to make an accurate classification of plasmablastic morphology in clinical practice. This underscores the need for more confirmatory and collaborative studies in this area. We are currently attempting to confirm the significance of the plasmablastic morphology in a collaborative effort with the Southwest Oncology Group. We are also studying the utility of flow cytometry in defining the plasmablastic phenotype, which may greatly aid in the clinical diagnosis of this entity.

Because patients with plasmablastic morphology do poorly with transplantation, other therapeutic options need to be identified. Alternative options for these patients may include modifications of the conditioning regimen to improve complete response rates, trials using novel agents, and perhaps allogenic transplantation in selected patients. Patients being considered for transplantation in whom a plasmablastic morphology is discovered should be counseled on the limitations of such therapy in their situation.

	ACKNOWLEDGMENTS

 
Supported by program project grant no. CA 62242 from the National Cancer Institute, National Institutes of Health, Bethesda, MD.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted August 31, 1998; accepted January 7, 1999.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rajkumar, S. V. Articles by Greipp, P. R. Search for Related Content PubMed PubMed Citation Articles by Rajkumar, S. V. Articles by Greipp, P. R. Social Bookmarking                            What's this?