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. Author manuscript; available in PMC: 2020 Dec 9.
Published in final edited form as: Am J Hematol. 2020 Jan 8;95(3):310–315. doi: 10.1002/ajh.25709

Enhancing the R-ISS Classification of Newly Diagnosed Multiple Myeloma by Quantifying Circulating Clonal Plasma Cells

Wilson I Gonsalves 1, Dragan Jevremovic 2, Bharat Nandakumar 1, Angela Dispenzieri 1, Francis K Buadi 1, David Dingli 1, Martha Q Lacy 1, Suzanne R Hayman 1, Prashant Kapoor 1, Nelson Leung 1,3, Amie Fonder 1, Miriam Hobbs 1, Yi Lisa Hwa 1, Eli Muchtar 1, Rahma Warsame 1, Taxiarchis V Kourelis 1, Stephen Russell 1, John A Lust 1, Yi Lin 1, Ronald S Go 1, Mustaqeem A Siddiqui 1, Robert A Kyle 1, Morie A Gertz 1, S Vincent Rajkumar 1, Shaji K Kumar 1
PMCID: PMC7724649  NIHMSID: NIHMS1644809  PMID: 31867775

Abstract

Our prior studies identified the prognostic significance of quantifying cPCs by multiparametric flow cytometry (MFC) in newly diagnosed multiple myeloma (NDMM) patients. We evaluated if a similar quantification of cPCs could add prognostic value to the current R-ISS classification of 556 consecutive NDMM patients seen at the Mayo Clinic, Rochester from 2009-2017. Those patients that had ≥ 5 cPCs/μL and either R-ISS stage I or stage II disease were re-classified as R-ISS IIB stage for the purposes of this study. The median time to next therapy (TTNT) and overall survival (OS) for patients with ≥ 5 cPCs/μL at diagnosis was as follows: R-ISS I (N = 110) – 40 months and not reached; R-ISS II (N = 69) – 30 and 72 months; R-ISS IIB (N = 96) – 21 and 45 months and R-ISS III (N = 281) – 20 and 47 months respectively. Finally, ≥ 5 cPCs/μL retained its adverse prognostic significance in a multivariable model for TTNT and OS. Hence, quantifying cPCs by MFC can potentially enhance the R-ISS classification of a subset of NDMM patients with stage I and II disease by identifying those patients with a worse than expected survival outcome.

INTRODUCTION

Multiple myeloma (MM) is a plasma cell disorder resulting in more than 13,000 deaths annually in the United States.[1] In the last two decades, the incorporation of therapeutic agents such as immunomodulators, proteasome inhibitors and high dose chemotherapy followed by stem cell rescue (i.e. autologous stem cell transplantation (ASCT)) has led to significant improvements in the survival of MM patients.[2, 3] However, MM is also biologically heterogeneous leading to significant variations in disease phenotype among its patients such as their clinical presentation, disease course and overall survival (OS). Several prognostic variables that affect survival outcomes have been identified and incorporated into clinical practice such as the International Staging System (ISS)[4] and more advanced genomic characterizations of the clonal plasma cells[5–8] The revised ISS (R-ISS) classification was designed to improve the prognostic ability of the original ISS classification by including genomic features and LDH levels at diagnosis.[9] This has led to a more robust discrimination of NDMM patients with good and poor prognosis being categorized as R-ISS stage I and III respectively. However, as a result, this system lends itself to categorize a larger cohort of NDMM patients as R-ISS stage II. Prior studies have demonstrated the independent prognostic significance of quantifying circulating clonal plasma cells (cPCs) by multiparametric flow cytometry (MFC) in NDMM patients.[10, 11] Thus, we determined if a similar quantification of cPCs using MFC at diagnosis could add further prognostic value to the current R-ISS classification of NDMM patients by identifying those R-ISS stage I and II patients that would have a worse than expected disease course and survival outcome.

METHODS:

We retrospectively evaluated all NDMM patients seen at the Mayo Clinic, Rochester from January 2009 to December 2017 who had their peripheral blood samples evaluated by flow cytometry prior to beginning therapy. Any patient who had 5% or more plasma cells and/or an absolute count greater than 0.5 × 109/l plasma cells on a peripheral blood smear at diagnosis were excluded for the purposes of this study as they could have had primary plasma cell leukemia (pPCL) by the re-defined criteria.[12] Approval for this study was obtained from the Mayo Clinic IRB in accordance with the federal regulations and the principles of the Declaration of Helsinki.

A 6-color multiparametric flow cytometry assessment was performed on the mononuclear cells from the peripheral blood samples that were isolated by Ficoll gradient. These cells were stained with antibodies to CD45, CD19, CD38, CD138 and cytoplasmic Kappa and Lambda immunoglobulin light chains. The data was collected using A Becton Dickinson FacsCanto II instrument was used to analyze 150,000 events of the aforementioned mononuclear cells. The flow cytometry data obtained was analyzed using the BDFacs DIVA Software. The expression of CD38, CD138, and cytoplasmic immunoglobulin light chains was used to identify all plasma cells in the specimen. The cPCs were then discriminated from polyclonal/normal plasma cells based on differential expression of CD19 and CD45. The final number of cPCs detected in each sample was reported as the number of cPCs/150,000 collected total events. We also calculated the absolute number of cPCs/μL using the following equation: cPCs/μL = Number of cPCs x (Absolute lymphocyte count + Absolute monocyte count) / 150,000 (The 150,000 represents the mononuclear cell fraction of the peripheral blood sample that consists of lymphocytes, monocytes and plasma cells). The absolute lymphocyte count and absolute monocyte count were collected from a complete blood count panel at the time of the blood draw for cPC MFC assessment.

Patients who had fluorescent in situ hybridization (FISH) analysis performed on their bone marrow aspirate at diagnosis were categorized as having high risk cytogenetics if they had any of the following abnormalities detected: t(4;14), t(14;16), t(14;20) and del17p. The various host and disease variables at diagnosis that were recorded and examined for prognostic significance included: age, bone marrow plasma cell percentage (BMPC%), presence of high-risk cytogenetics by FISH, serum albumin, β2-microglobulin, plasma cell labeling index (PCLI), serum M spike, urine M spike, hemoglobin, creatinine and LDH. The primary end-points of the study were time to next therapy (TTNT) and OS. TTNT was determined from the day of diagnosis to the day of initiating the next therapy due to a documented relapse or progression of disease, with those who are alive or dead but relapse free being censored at the day of last follow up. OS was measured from the day of diagnosis to death from any cause, with censoring performed at the date of last contact if alive.

Statistical analysis was performed using the SAS biostatistical software JMP 13.0.1 (SAS Institute Inc., Cary, NC). Differences between sub-groups were compared by using either the Chi-square test or Fisher exact test. Data points were graphically compared between different sub-groups in this analysis using GraphPad Prism version 7.00 for Windows, GraphPad Software, La Jolla California USA, www.graphpad.com. A Kaplan-Meier analysis was used to analyze and create the OS and TTNT curves, and log rank test was used to compare these curves. Finally, a multivariable analysis was performed using the Cox proportions hazards model to assess the influence of various prognostic factors on OS and TTNT found to be of significance in univariate analyses.

RESULTS:

The cohort included in this study comprised of 566 consecutive patients with NDMM. The clinical and pathologic characteristics of this entire cohort are detailed in Supplementary Table 1. The median age was 66 years (range: 27 - 95) of which 20% were 75 years of age or older and 60% of this entire cohort were male. At presentation, 8% of the patient cohort had a serum creatinine level of 2 mg/dL or greater and 5% had serum calcium levels of 11 mg/dL or greater. A total of 541 (96%) patients had molecular cytogenetics results by FISH at diagnosis of which a total of 131 patients (24%) had high risk cytogenetics. All but two patients underwent induction therapy containing novel agents such as PIs or IMiDs. More than half (57%) underwent an upfront ASCT as part of consolidation after their induction therapy. The stage distribution of patients included in this cohort is as follows: ISS → Stage I- 174 (31%) patients, Stage II- 237 (42%) patients and Stage III- 155 (27%) patients; R-ISS → Stage I- 128 (23%) patients, Stage II- 369 (65%) patients and Stage III- 69 (12%) patients.

There were 383 (67%) patients who had detectable cPCs in their peripheral blood. The clinical and pathologic characteristics of this cohort based on the presence or absence of cPCs are detailed in Supplementary Table 1. For the entire cohort, the median number of cPCs per 150,000 events analyzed was 67 (range: 0 - 46,413) and the median absolute number of cPCs per microliter was 0.74 (range 0 – 10,454) (available for calculation in only 556 patients due to presence of a complete blood count result at the time of MFC assessment). Of the patients with detectable cPCs, the median number of cPCs per 150,000 events analyzed was 212 (range: 5 - 46,413) and the median absolute number of cPCs per microliter was 2.5 (range 0.05 – 10,454). The correlation between the levels of cPCs/150,000 events analyzed and absolute number of cPCs/μL is demonstrated in Supplementary Figure 1 and showed a non-parametric spearman correlation coefficient (r) of 0.99 (p < 0.001). The level of cPCs/150,000 events analyzed and absolute number of cPCs/μL detected in these patients based on their molecular cytogenetics at the time of diagnosis is depicted in Figures 1A and 1B.

FIGURE 1:

FIGURE 1:

FIGURE 1:

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Levels of cPCs detected based on the primary molecular cytogenetics at the time of diagnosis: A) the levels of cPCs/150,000 events analyzed between hyperdiploid vs. sub-types of non-hyperdiploid, B) the absolute number of cPCs/μL between hyperdiploid vs. sub-types of non-hyperdiploid. (****, Mann Whitney = P < 0.001)

The median TTNT and OS for patients based on presence or absence of cPCs at diagnosis was 43 months vs. 25 months (P < 0.001; Supplementary Figure 2A) and 89 months vs. 54 months (P < 0.001; Supplementary Figure 2B) respectively. The median TTNT for patients based on R-ISS stage at diagnosis was as follows: R-ISS I: 39 months; R-ISS II: 28 months and R-ISS III: 20 months (Supplementary Figure 2C). The median OS for patients based on R-ISS stage at diagnosis was as follows: R-ISS I: not reached; R-ISS II: 64 months and R-ISS III: 47 months (Supplementary Figure 2D).

Optimal cutoffs for levels of cPCs per 150,000 events analyzed and absolute number of cPCs per microliter that could predict worse OS was based on the hazard ratio (HR) as seen in Supplementary Figure 3A and Figure 3B. As a result, ≥ 400 cPCs/150,000 events analyzed and ≥ 5 cPCs/μL were selected as the optimal cutoffs with significant overlap in the two cohorts being noted in 94% of the patients. A receiver operating curve (ROC) demonstrated that the cutoff of ≥ 5 cPCs/μL predicted for the presence of ≥ 400 cPCs/150,000 events analyzed with a sensitivity of 93% and specificity of 98%. There were 140 (25%) patients and 142 (26%) patients with ≥ 400 cPCs/150,000 events analyzed and ≥ 5 cPCs/μL respectively. Significant predictors for the presence of ≥ 5 cPCs/μL at diagnosis were the presence of high-risk cytogenetics, the presence of highly proliferative disease with a PCLI > 2%, elevated LDH level and BMPC ≥ 50%. The median TTNT and OS for patients based on the cutoff of ≥ 5 cPCs/μL at diagnosis was as follows: a) TTNT: No cPCs - 43 months; < 5 cPCs/μL - 28 months and ≥ 5 cPCs/μL - 21 months (Figure 2A); b) OS: No cPCs - 89 months; < 5 cPCs/μL - 76 months and ≥ 5 cPCs/μL - 46 months (Figure 2B).

FIGURE 3:

FIGURE 3:

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Distribution of patients based on ISS, R-ISS and mR-ISS classification schemes. (* results are the same using either cutoffs by cPCs/150,000 events analyzed or absolute number of cPCs/μL).

FIGURE 2:

FIGURE 2:

FIGURE 2:

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Kapan Meir curves comparing the (A) TTNT and (B) OS for patients based on the absolute number of cPCs/μL.

There were 17 (13%) patients with R-ISS I disease, 79 (22%) patients with R-ISS II and 46 (68%) patients with R-ISS III at diagnosis that had the presence of ≥ 5 cPCs/μL. All patients with R-ISS I and II disease that had the presence of ≥ 5 cPCs/μL at diagnosis where classified as R-ISS IIB as part of a modified R-ISS (mR-ISS) classification scheme which led to an upstaging of the R-ISS system as seen in Figure 3 where more patients were being classified as mR-ISS IIB. Thus, the effect of this mR-ISS classification on the median TTNT and OS for patients based on incorporating the cutoff of ≥ 5 cPCs/μL at diagnosis was as follows: a) TTNT: R-ISS I - 40 months; R-ISS II - 30 months, R-ISS IIB – 21 months and R-ISS III - 20 months (Figure 4A); b) OS: R-ISS I – not reached; R-ISS II - 72 months; R-ISS IIB – 45 months and R-ISS III - 47 months (Figure 4B).

FIGURE 4:

FIGURE 4:

FIGURE 4:

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Kapan Meir curves comparing the (A) TTNT and (B) OS for patients with a mR-ISS classification based on the absolute number of cPCs/μL.

The following variables were assessed in a univariate and multivariate analysis to determine their effects on TTNT and OS (Supplementary Table 2): presence of ≥5 cPCs/μL, age ≥ 75 years, β2-microglobulin > 5.5 mcg/dL, albumin < 3.5 g/dL, elevated LDH level, BMPC ≥ 50% and HR FISH status. In a univariate model, all of the aforementioned variables adversely affected TTNT and OS except for the elevated LDH in OS. However, in a multivariable model, only the presence of ≥5 cPCs/μL, age ≥ 75 years and HR FISH status were associated with worse TTNT and OS. Although plasma cell proliferation also serves as a marker of high-risk biology, it was not included in either multivariable as the methodology for measurement transitioned during this time period to a flow-based method which was not directly comparable to the antecedent slide-based method. Furthermore, this was available only in 332 (59%) patients in this cohort.

DISCUSSION:

The prognostic significance of cPCs when measured by MFC has been well established across the spectrum of plasma cell disorders such as MGUS[13], smoldering myeloma[14], MM[10, 11] and AL amyloidosis[15] at the time of diagnosis. It has also been established as a prognostic marker in MM patients undergoing ASCT by predicting for early relapse.[16–18] The current R-ISS classification places emphasis on not only the MM disease burden and severity of renal dysfunction in NDMM patients by incorporating the original ISS model but it also integrates the biology of clonal plasma cells by taking into account their molecular cytogenetics characteristics by FISH and their serum LDH levels.[9] However, while providing a more robust discrimination of NDMM patients with good and poor prognosis, it has also led to more patients (>50%) being classified as having R-ISS II disease that have significant heterogeneity in their clinical outcomes. This study demonstrates that incorporating the number of cPCs detected by MFC can add prognostic value to the current R-ISS classification system of NDMM patients treated with novel agent induction therapy. More specifically, it demonstrates that the presence of ≥ 5 cPCs/μL by MFC can potentially upstage the R-ISS classification of a subset of NDMM patients with stage I and II disease to a similar outcome in terms of TTNT and OS as expected in stage III disease.

The MFC protocol utilized in this study is performed on peripheral blood mononuclear cells obtained by Ficoll gradient. Thus, the results reported as number of cPCs per 150,000 events or mononuclear cells analyzed is rather a relative and not an absolute quantification of cPCs in whole blood. Nevertheless, we were able to calculate the absolute number of cPCs/μL of whole blood in 556 (98%) of patients in this study cohort as they had concurrent complete blood count assays measured at the time of their peripheral blood MFC assessment. There appeared to be a very strong correlation between the number of cPCs / 150,000 events analyzed and the absolute number of cPCs/μL of whole blood (Supplementary Figure 1). Furthermore, there was significant overlap in the patients (94% of cohort) who had both ≥ 400 cPCs/150,000 events analyzed and ≥ 5 cPCs/μL or both < 400 cPCs/150,000 events analyzed and < 5 cPCs/μL. This allows the absolute number of cPCs/μL cutoff determined in this study to be potentially applicable as a reference for other MFC methodologies used in the future to measure and validate the prognostic significant of cPCs in the clinic.

Despite the presence of high levels of cPCs in this study being associated with traditional adverse prognostic factors such as high risk cytogenetics, PCLI > 2%, elevated LDH levels and BMPC ≥ 50%, it is an independent prognostic factor in the multivariable model outlined in Supplementary Table 2. Pre-clinical models have suggested the importance of interactions between clonal plasma cells in MM and the bone marrow microenvironment as a requirement for growth, proliferation[19] and resistance mechanism to treatment.[20] Thus, the presence of cPCs has suggested a more aggressive disease biology by their independence from their bone marrow microenvironment. This is confirmed clinically by the fact that NDMM patients who meet criteria for having pPCL have the worst survival outcomes even when compared to NDMM patients with high risk cytogenetics.[12] In addition, this study demonstrated an association of higher levels of cPCs in patients with t(11;14), t(14;16) and deletion 17p when compared to patients with hyperdiploid disease (Figures 1A and 1B) which is not surprising given that patients with pPCL also have a higher than expected predisposition towards similar primary cytogenetic abnormalities compared to NDMM patients.[21] However, the exact biologic mechanisms for these associations remain elusive. The results from a similar study also demonstrate the association of high levels of cPCs with high risk cytogenetics and gene expression profiles suggesting that NDMM patients with high levels of cPCs may be in a transitional phase between MM and plasma cell leukemia.[22] Finally, recent work has suggested that cPCs in patients with MM contain a mostly concordant mutational landscape when compared to their corresponding paired clonal bone marrow plasma cells, however, there can exist mutations exclusive to cPCs alone.[23, 24]

There are several limitations to our study, the first being its retrospective nature. Secondly, the cutoff of ≥ 400 cPCs/150,000 events analyzed and ≥ 5 cPCs/μL is based on our single institution data and needs to be validated across other institutions. Nevertheless, this study suggests that the quantitative estimation of cPCs in patients with NDMM is a powerful predictor of early relapse from therapy and shorter OS. Finally, the EuroFlow next generation flow (NGF-MM) minimal residual disease (MRD) panel has been standardized for the detection of MRD in the bone marrow aspirates of MM patients and is currently the gold standard for MRD detection.[25] This NGF-MM approach analyzes between 2 to 15 million events per whole blood sample compared to 150,000 events of mononuclear cells per sample in this study, making the former approach more sensitive but time consuming than our approach in this study. This NGF-MM approach has been utilized for the high sensitive detection of cPCs and detects them in every NDMM patient with a median absolute number of cPCs of 2.01 cPCs/μl (range: 0.043–103.8 cPCs/μl) and a median percentage of cPCs at 0.0033% (range: 0.00064% – 1.05%).[13] In contrast, in our study, only 383 (68%) of the NDMM patients had cPCs due to a lower sensitivity of our MFC methodology in detecting cPCs. Nevertheless, similar studies evaluating the utility of the NGF-MM methodology in quantifying cPCs in NDMM patients to validate our proposed cutoff of ≥ 5 cPCs/μL as a predictor of worse TTNT and OS should be undertaken in the future. Application of this measure holds several important clinical implications in the future such as being able to refine the selection criteria for patients enrolling on clinical trials so as to adapt better risk-adapted therapy strategies and by providing more appropriate comparisons of survival outcomes amongst patients with R-ISS I and II disease across clinical trials and treatment regimens.

Supplementary Material

supplementary

SUPPLEMENTARY FIGURE 1: The correlation between the levels of cPCs/150,000 events analyzed and absolute number of cPCs/μL.

SUPPLEMENTARY FIGURE 2: Kapan Meir curves comparing the (A) TTNT and (B) OS for patients based on presence or absence of cPCs at diagnosis and the (C) TTNT and (D) OS for patients based on their R-ISS classification.

SUPPLEMENTARY FIGURE 3: Hazard ratio plots evaluating the impact of different cPC level cutoff on OS based on A) the levels of cPCs/150,000 events analyzed and B) the absolute number of cPCs/μL.

ACKNOWLEDGEMENTS

Research reported in this publication was supported by Mayo Clinic Hematological Malignancies Program and in part by grants from the National Cancer Institute of the National Institutes of Health under Award Number K23CA218742 and P50CA186781. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Finally, this research is also supported in part by the Marion Schwartz Foundation for Multiple Myeloma.

Footnotes

Conflict-of-interest disclosure:

These authors declare no competing financial interests.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supplementary

SUPPLEMENTARY FIGURE 1: The correlation between the levels of cPCs/150,000 events analyzed and absolute number of cPCs/μL.

SUPPLEMENTARY FIGURE 2: Kapan Meir curves comparing the (A) TTNT and (B) OS for patients based on presence or absence of cPCs at diagnosis and the (C) TTNT and (D) OS for patients based on their R-ISS classification.

SUPPLEMENTARY FIGURE 3: Hazard ratio plots evaluating the impact of different cPC level cutoff on OS based on A) the levels of cPCs/150,000 events analyzed and B) the absolute number of cPCs/μL.

NIHMS1644809-supplement-supplementary.docx (310.6KB, docx)

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