Abstract
Risk stratification of multiple myeloma (MM) at diagnosis is critical. We examined the ability of hematopoietic indices including mean corpuscular volume (MCV), hemoglobin (Hgb), and platelet (Plt) to predict outcomes. This was a retrospective study of patients treated at Mayo Clinic between January 2004 and April 2018. We incorporated three variables (Hgb < 10 g/dL, Plt < 150 × 109/L, and MCV > 96 fL), assigning a score of 1 to each. We identified 1540 newly diagnosed MM patients, of whom 707 (46%) had a score of 0, 513 (33%) had a score of 1, 260 (17%) had a score of 2, and 60 (4%) had a score of 3. The score risk stratified patients into four groups with differing survivals. The median PFS was 32.3 months for score 0, 24.8 months for score 1, 21.7 months for score 2, and 18.3 months for score 3, for P < .001. The median OS was 80.7 months for score 0, 59.9 months for score 1, 51.7 months for score 2, and 31.3 months for score 3, P < .0001. Predictors of OS on the multivariable analysis were age ≥ 65 (HR, 1.93; P < .0001), R-ISS stage (1-2 vs 3) (HR, 0.48; P < .0001), and hematopoietic score (0-2 vs 3) (HR, 0.51; P = .006). A hematopoietic score can predict survival in newly diagnosed myeloma patients.
1 ∣. INTRODUCTION
Multiple myeloma (MM) constitutes around 1% of all cancers and approximately 10% of all hematological malignancies.1 Risk stratification at diagnosis allows us to prognosticate and tailor therapy better in this heterogeneous disease. Previously, the Durie-Salmon Staging2 was utilized. Currently the International staging system (ISS) and the Revised International staging system (R-ISS) are routinely used to stage patients at diagnosis.3,4 The ISS and R-ISS use a combination of serum albumin, beta 2 microglobulin, lactate dehydrogenase (LDH) and cytogenetic abnormalities to risk stratify patients. However, other hematopoietic parameters have also been shown to impact prognosis.
Anemia is the most common cytopenia seen in patients with myeloma, with leukopenia and thrombocytopenia being less common. Anemia is a prognostic marker used in the Durie-Salmon Staging system2 and has been associated with worse survival.5 Vitamin B12 deficiency can be found in patients with plasma cell disorders and ranges from 13%-20%,6,7 but it is not solely the cause of anemia. Thrombocytopenia is also known to be predictive of worse outcomes.5 The precise mechanism for hematopoietic suppression is not well understood yet, but is thought to go beyond simple marrow infiltration and replacement.8 Malignant plasma cells are known to alter the cellular and extracellular compartments of the bone marrow microenvironment to promote survival of the malignant cells and suppress normal hemopoiesis.9,10 Red blood cell distribution width (RDW) has previously been investigated as a predictor of progression-free (PFS) and overall survival (OS)11-13 and increased RDW predicted lower treatment responses and worse survival.
We hypothesized that the hematopoietic indices including mean corpuscular volume (MCV) level, hemoglobin (Hgb) level, and platelet (Plt) count may reflect the impact of the tumor cells on the marrow microenvironment, and examined its ability to predict outcomes of patients with newly diagnosed MM.
2 ∣. METHODS
We conducted a retrospective study of 1540 patients with newly diagnosed MM seen at Mayo Clinic, Rochester between January 2, 2004 and April 6, 2018. The IMWG diagnostic criteria were used to identify patients with active MM.1,14 Data was extracted from a prospectively maintained database and chart review conducted to ensure accuracy of the data. The study was approved by the Mayo Clinic Institutional Review Board. We evaluated the prognostic impact of the hematopoietic indices from the complete blood count (CBC) examination, such as Hgb level, white blood cell (WBC) count, Plt count, and MCV level. Based on univariable analysis, we incorporated three variables (Hgb < 10 g/dL, Plt < 150 × 109/L, and MCV > 96 fL), into a hematopoietic score assigning a score of 1 to each variable. Patients were categorized into four groups based on the total score (group 1: score of 0, group 2: score of 1, group 3: score of 2, and group 4: score of 3). We used the cutoffs of Hgb < 10 g/dL and Plt < 150 × 109/L, as these were previously found to be prognostic.5 For MCV, we choose >96 fL, as this reflected the upper quartile of MCV within our population. We then examined the impact of this index in the context of other prognostic factors in myeloma. Patients were considered to have high-risk abnormalities if they had any of the following findings on marrow plasma cell fluorescence in situ hybridization (FISH): t(4;14), t(14;16), t(14;20), and del(17p).4,15 The PFS was calculated from the time of diagnosis to disease progression or death from any cause. The OS was calculated from the time of diagnosis to death from any cause. Chi-square test was used to compare categorical variables. The PFS and OS analysis were performed using the Kaplan-Meier method. All statistical tests were two-sided and P-values of <.050 were considered to be significant. Univariate analysis (for PFS and OS) using the Cox proportional hazards model was performed for age, FISH risk, ISS, R-ISS, hematopoietic score, plasma cell percentage, levels of creatinine (Cr) and LDH, and values of the WBC, Hgb, Plt, and MCV. The hazard ratio (HR) and 95% confidence intervals (CI) were reported. Only statistically significant factors on univariable analysis were included in the multivariable models. Statistical analysis was performed on JMP Pro software version 14.0 (SAS, Cary, NC).
3 ∣. RESULTS
The study cohort included 1540 patients with newly diagnosed MM. Relevant baseline characteristics are displayed in Table 1. The median age at diagnosis was 66.5 (56-73.6). 462 (28%) had an MCV > 96 fL, 502 (33%) had Hgb < 10 g/dL, and 285(19%) had Plt < 150 × 109/L. Vitamin B12 was available in only 227 patients with 17 patients having deficiency. Overall, 707 (46%) had a score of 0, 513 (33%) had a score of 1, 260 (17%) had a score of 2, and 60 (4%) had a score of 3.
TABLE 1.
Baseline characteristics of all patients
| N = 1540 | |
|---|---|
| Age (years), median, (IQR) | 66.5 (56-73.6) |
| Male, n (%) | 918 (60%) |
| ISS, n (%) | |
| 1 | 307 (26%) |
| 2 | 473 (39%) |
| 3 | 415 (35%) |
| R-ISS, n (%) | |
| 1 | 165 (17%) |
| 2 | 668 (67%) |
| 3 | 163 (16%) |
| FISH, n (%) | |
| Standard risk | 668 (78%) |
| High-riska | 186 (22%) |
| Hgb (g/dL),median, (IQR) | 10.9 (9.6-12.3) |
| Plt,median, (IQR) | 214 × 109/L (165-265) |
| WBC,median, (IQR) | 5.4 × 109/L (4.1-7) |
| MCV (fL), median, (IQR) | 93 (90-97) |
| Vitamin B12 deficiency, n (%) | 17 (7%) |
| Hematopoietic score, n (%) | |
| 0 | 707 (46%) |
| 1 | 513 (33%) |
| 2 | 260 (17%) |
| 3 | 60 (4%) |
| 0–1 | 194 (13%) |
| 0–2 | 1480 (96%) |
| LDH (u/L), median, (IQR) | 164 (136-199) |
| Cr (mg/dL), median, (IQR) | 1.1 (0.9-1.4) |
| Bone marrow plasma cells %, median, (IQR) | 50 (25-70) |
| Therapy received, n (%) | |
| ASCT | 512 (35%) |
| IMiD only | 425 (29%) |
| PI only | 70 (5%) |
| Alkylator only | 62 (4%) |
| Steroids only | 61 (4%) |
| IMiD+PI | 145 (10%) |
| PI+alylator | 182 (12%) |
| No treatment | 15 (1%) |
High-risk FISH abnormalities included: t(4;14), t(14;16), t(14;20), and del(17p).
Abbreviations: IQR, interquartile range; ISS, International staging system; R-ISS, Revised International staging system; FISH, fluorescence in situ hybridization; Hgb, hemoglobin; Plt, platelet; WBC, white blood cell; MCV, mean corpuscular volume; LDH, lactate dehydrogenase; Cr, creatinine.
Therapy for the cohort consisted of autologous stem cell transplant (ASCT) in 35% following induction therapy, immunomodulatory drugs (IMiD) only in 29%, proteasome inhibitor (PI) only in 5%, alkylator only in 4%, steroids only in 4%, combination of an IMiD with a PI in 10%, and combination of an alkylator with a PI in 12%.
The median PFS and OS for all patients were 27.7 and 66 months respectively. Anemia with a Hgb < 10 g/dL was predictive for PFS and OS (median PFS 22.6 months for Hgb < 10 g/dL vs 30 months for Hgb≥10 g/dL, P < .0001; median OS 50 months for Hgb < 10 g/dL vs 75.4 months for Hgb≥10 g/dL, P < .0001). Thrombocytopenia (Plt < 150 × 109/L) predicted PFS and OS (median PFS 20.1 months for Plt < 150 × 109/L vs 29.9 months for Plt≥150 × 109/L, P < .0001; median OS 42.4 months for Plt < 150 × 109/L vs 70.5 for Plt≥150 × 109/L, P < .0001) (all summarized in Table S1). Patients with macrocytosis (MCV > 96 fL) were more likely to be older, have high-risk FISH, have advanced ISS, R-ISS staging, anemia, thrombocytopenia, abnormal LDH, and > 50% bone marrow plasma cells than patients without macrocytosis (Table S2). They also had lower median PFS and OS (median PFS 24.4for MCV > 96 fL vs 28.2 months for MCV≤96 fL, P = .034, and median OS 56 months for MCV > 96 fL vs months for MCV≤96 fL, P = .0006). The overall score risk stratified patients into four groups with differing survival (median PFS was 32.3 months for score 0, 24.8 months for score 1, 21.7 months for score 2, and 18.3 months for score 3, P < .0001; median OS was 80.7 months for score 0, 59.9 months for score 1, 51.7 months for score 2, and 31.3 months for score 3, P < .0001) (Figure 1).
FIGURE 1.
Progression-free survival (A) and overall survival (B) based on the hematopoietic score. PFS, progression-free survival; OS, overall survival
On univariable analysis, increasing age, ISS stage, R-ISS stage, high-risk FISH, anemia, thrombocytopenia, macrocytosis, increased LDH, increased percentage of plasma cells, increased serum Cr, and advanced hematopoietic score were predictive of PFS (Table 2). Specifically, the HRs and P values for anemia (Hgb < 10 g/dL), thrombocytopenia (Plt < 150 × 109 L, macrocytosis (MCV > 96 fL), and the hematopoietic score (0-2 vs 3) were (HR, 1.43; P < .0001), (HR,1.65; P < .0001), (HR, 1.17; P = .037), and (HR, 0.58; P = .001) respectively. On the multivariable analysis, predictors for PFS were age ≥ 65 (HR, 1.31; P = .001), R-ISS stage (1-2 vs 3) (HR, 0.56; P < .0001), and > 50% plasma cells in the bone marrow (HR, 1.23; P = .015) (Table 2). The hematopoietic score (0-2 vs 3) showed a trend towards shorter PFS (HR:0.66, confidence interval:0.44-1.002, P = .051). Predictors of OS on univariable analysis included increasing age, ISS stage, R-ISS stage, high-risk FISH, anemia, thrombocytopenia, macrocytosis, increased LDH, increased percentage of plasma cells, increased Cr, and advanced hematopoietic score (Table 3). Specifically, the HRs and P values for anemia (Hgb < 10 g/dL), thrombocytopenia (Plt < 150 × 109 L, macrocytosis (MCV > 96 fL), and the hematopoietic score (0-2 vs 3) were (HR, 1.68; P < .0001), (HR,1.69; P < .0001), (HR, 1.35; P = .037), and (HR, 0.43; P < .0001) respectively. Predictors of OS on the multivariable analysis were age ≥ 65 (HR, 1.93; P < .0001), R-ISS stage (1-2 vs 3) (HR, 0.48; P < .0001), and hematopoietic score (0-2 vs 3) (HR, 0.51; P = .006)(Table 3).
TABLE 2.
Univariable and multivariable analysis for PFS
| Univariable analysis |
Multivariable analysis |
||||
|---|---|---|---|---|---|
| Variable | HR(95%CI) | P value | Variable | HR(95% CI) | P value |
| Age ≥ 65 years | 1.3 (1.14-1.48) | <.0001 | Age ≥ 65 years | 1.31 (1.11-1.54) | .001 |
| R-ISS (1–2 vs 3) | 0.53 (0.43-0.65) | <.0001 | R-ISS (1-2 vs 3) | 0.56 (0.43-0.72) | <.0001 |
| Hematopoietic score (0-2 vs 3) | 0.58 (0.422-0.81) | .001 | Hematopoietic score (0-2 vs 3) | 0.66 (0.44-1.002) | .051 |
| Plasma cells >50% | 1.42 (1.25-1.62) | <.0001 | Plasma cells >50% | 1.23 (1.04-1.45) | .015 |
| Cr > 2 mg/dL | 1.39 (1.15-1.68) | .0004 | Cr > 2 mg/dL | 0.86 (0.64-1.16) | .330 |
| LDH > 222 u/L | 1.79 (1.48-2.16) | <.0001 | |||
| WBC <4 × 109/L | 1.13 (0.97-1.33) | .112 | |||
| ISS (1–2 vs 3) | 0.65 (0.56-0.76) | <.0001 | |||
| Hgb < 10 g/dL | 1.43 (1.24-1.64) | <.0001 | |||
| Plt < 150 × 109/L | 1.65 (1.4-1.94) | <.0001 | |||
| MCV > 96 fL | 1.17 (1.01-1.33) | .037 | |||
| FISH (high-risk vs standard risk) | 1.74 (1.45-2.09) | <.0001 | |||
Note: Bold values indicate statistically significant P values.
Abbreviations: HR, hazard ratio; CI, confidence interval; R-ISS, Revised International staging system; Cr, creatinine; LDH, lactate dehydrogenase; WBC, white blood cell; ISS, International staging system; Hgb, hemoglobin; Plt, platelet; MCV, mean corpuscular volume; FISH, fluorescence in situ hybridization.
TABLE 3.
Univariable and multivariable analysis for OS
| Univariable analysis |
Multivariable analysis |
||||
|---|---|---|---|---|---|
| Variable | HR (95%CI) | P value | Variable | HR (95%CI) | P value |
| Age ≥ 65 years | 1.9 (1.64-2.26) | <.0001 | Age ≥ 65 years | 1.93 (1.58-2.36 | <.0001 |
| R-ISS (1–2 vs 3) | 0.42 (0.33-0.53 | <.0001 | R-ISS (1–2 vs 3) | 0.48 (0.37-0.63) | <.0001 |
| Hematopoietic score (0–2 vs 3) | 0.43 (0.31-0.61) | <.0001 | Hematopoietic score (0-2 vs 3) | 0.51 (0.33-0.79) | .006 |
| Plasma cells >50% | 1.35 (1.16-1.57) | .0002 | Plasma cells >50% | 1.18 (0.97-1.44) | .088 |
| Cr > 2 mg/dL | 1.65 (1.34-2.03) | <.0001 | Cr > 2 mg/dL | 1.1 (0.8-1.51) | .53 |
| LDH > 222 u/L | 2.4 (1.99-3.01) | <.0001 | |||
| WBC <4 × 109/l | 1.04 (0.86-1.25) | .63 | |||
| ISS (1–2 vs 3) | 0.47 (0.43-0.61) | <.0001 | |||
| Hgb < 10 g/dL | 1.68 (1.44-1.97) | <.0001 | |||
| Plt < 150 × 109/L | 1.69 (1.41-2.03) | <.0001 | |||
| MCV > 96 fL | 1.35 (1.14-1.59) | .0006 | |||
| FISH (high-risk vs standard risk) | 1.99 (1.59-2.48) | <.0001 | |||
Note: Bold values indicate statistically significant P values.
Abbreviations: HR, hazard ratio; CI, confidence interval; R-ISS, Revised International staging system; Cr, creatinine; LDH, lactate dehydrogenase; WBC, white blood cell; ISS, International staging system; Hgb, hemoglobin; Plt, platelet; MCV, mean corpuscular volume; FISH, fluorescence in situ hybridization.
4 ∣. DISCUSSION
We have shown that the hematopoietic score, which incorporated commonly available variables from a CBC, was able to predict overall survival in patients with newly diagnosed MM. The anemia in MM patients is multifactorial: plasma cells infiltrate the bone marrow causing direct destruction of erythroblasts, alternation of the bone marrow microenvironment, involvement of the kidneys leading to decreased erythropoietin production, and inflammation and cytokine release which affect the production of healthy and functional RBCs. The Durie-Salmon Staging system2 used Hgb > 10 g/dL for stage one, and patients with Hgb < 8.5 g/dL had worse outcomes. Also, in an analysis of 1027 patients seen at Mayo Clinic between 1985 and 1988, having a Hgb < 10 g/dL and Plt < 150 × 109/L were predictive of worse outcomes in a univariable analysis.5
Macrocytosis is more common in elderly patients, and the increased MCV could be reflected by the shorter lifespan of the red blood cells (RBCs) necessitating increased production of younger cells (reticulocytes), leading to the macrocytosis.16 It can also reflect an advanced and aggressive disease biology in MM. Hata et al,17 described the survival of 60 MM patients according to the MCV. Patients with MCV > 97 fL had a non-significant better survival. However, in their study the Durie-Salmon’s stage was used to risk stratify patients, and the other currently used prognostic factors in MM were not available. Stage III Durie-Salmon patients had similar rates of death and the MCV was not helpful. Also, the hemoglobin level did not differ between the two groups. This may suggest that other biological factors were implicated in the poor outcomes. Although vitamin B12 deficiency can be found in patients with plasma cell disorders,6,7 it does not always cause macrocytosis and even patients with low MCV can have vitamin B12 deficiency.7 In our study, the level of vitamin B12 was not available in most patients, but it is unlikely to be the sole cause for the increased MCV.
Alteration of the bone marrow microenvironment is critical for the survival and growth of malignant plasma cells. The interaction is complex, as the clonal plasma cells can use factors, that are normally required for maintaining normal hematopoiesis, for their own growth and survival, as well as, express other factors that can inhibit normal hematopoiesis.18 For example, osteopontin and angiopoietin-1 are required for the normal maintenance of hematopoiesis, and are also involved in enhancing the activities of osteoclast and angiogenesis in MM.18 On the other hand, Notch signaling can result in more production of interleukin 6 and vascular endothelial growth factor that enhance plasma cell survival, but inhibit hematopoietic stem cell differentiation.18 Preclinical data suggests that cytokine mediated alterations in pro- and anti-apoptotic pathway dependence may impact the sensitivity of myeloma cells to certain therapies.19 These changes in the microenvironment have also been shown to impact hematopoiesis. One study found a significant reduction of hematopoietic stem and progenitor cells, in particular of megakaryocyte-erythrocyte progenitors. They were functionally impaired with regard to clonogenic and long-term self-renewal capacity, as well as proliferative activity.8 This suggests that the marrow suppression seen in myeloma is due to both a quantitative and qualitative deficiency of hematopoietic stem cell progenitors, driven by changes in the microenvironment.20 In our study, the hematopoietic score, utilizing commonly available indices from the CBC, is likely to reflect these changes heralding a more aggressive disease that is resistant to therapy. This score could be used in addition to the R-ISS and could be valuable in situations where FISH could not be done, especially if resources are not available. All patients with MM have a CBC done, which can be used to calculate the score and risk-stratify patients.
Our study is limited by the biases of a retrospective review. Incomplete data on ISS and the R-ISS staging system may have impacted our results. Vitamin B12 was not measured in most patients to determine if vitamin B12 deficiency played a role in macrocytosis. Also, PFS data was not available for all patients and the treatment for MM has changed over the years, which could affect the outcomes of our patients. In summary, hematopoietic parameters available on a CBC can be incorporated in to a scoring system that predicts survival in patients with newly diagnosed myeloma. This is likely to reflect alterations in the bone marrow microenvironment of patients with myeloma that reflects the aggressiveness of the disease. This scoring system needs to be validated in other cohorts to confirm its prognostic value.
Supplementary Material
Footnotes
CONFLICT OF INTEREST
The authors report no relevant financial conflicts of interest.
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section at the end of this article.
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