The Impact of Focal Lesions on Overall and Progression-free Survival in Multiple Myeloma

Introduction

Multiple myeloma (MM) is a disease caused by malignantly differentiated plasma cells, with the bone marrow being the primary site where these malignant plasma cells reside.[1] However, these malignant plasma cells can migrate beyond the bone marrow and form tumors in neighboring bones, defined as focal lesions (FLs).[2,3] The extension of life expectancy in MM has been achieved with the introduction of new therapeutic agents and better definition and understanding of the disease’s biology, as well as diagnostic and prognostic markers. However, a subgroup of patients has a poorer response to treatment and survival and, so, studies to characterize this group are ongoing. Despite the existence of available prognostic models for MM, such as the International Staging System (ISS), the Revised-ISS (R-ISS) and genetic risk assessment, patients with these poor outcomes should have additional prognostic markers for re-evaluation.[4,5] As a result of this need, when imaging techniques were adapted to the evaluations, the number of FLs indicating tumor burden (especially when greater than 3) was found to be an independent prognostic marker of poor overall and progression-free survival (PFS) in studies.[6,7] Studies have shown that ¹⁸F-fluorodeoxyglucose positron emission tomography/computerized tomography (¹⁸F-FDG PET/CT) is a sensitive and specific imaging technique for detecting bone lesions in MM, and that the number of FLs is a useful predictor of prognosis at the time of MM diagnosis.[8910] In line with these results, the International Myeloma Working Group (IMWG) recommended, in its 2019 guideline, that ¹⁸F-FDG PET/CT can be used in the initial evaluation of the disease, providing level 4 evidence.[11] In clinical practice, the use of ¹⁸F-FDG PET/CT for initial assessment of MM is increasing; however, there are some unclear answers and unanswered questions regarding the relationship between mortality and the number of FLs, as well as the prognostic value of FLs in patients who are not suitable for autologous transplantation.

Therefore, we aimed to reveal the incidence of ≥3 FLs in our newly diagnosed transplant-eligible and -ineligible MM patients, analyzing overall survival (OS) and PFS in patients according to whether they had ≥3 FLs. In addition, we aimed to evaluate predictive factors for mortality and PFS in this patient group.

Materials and Methods

A total of 89 consecutive symptomatic newly diagnosed MM (NDMM) patients with ¹⁸F-FDG PET/CT imaging at the time of diagnosis between January 2015 and December 2022 were included in this retrospective study. The study was approved by the Institutional Ethical Committee of Trakya University (TUTF- GOBAEK 2022/69). Patients with other malignancy diagnoses, monoclonal gammopathy of undetermined significance (MGUS), smoldering MM, solitary plasmacytoma, amyloidosis, and active infection that could lead to misinterpretation of PET/CT findings were excluded. All data were collected from the patients’ medical files and electronic medical records, including the patients’ age, gender, subtype of the disease, laboratory and genetic test results at diagnosis, frontline treatment, response status to frontline treatment, history of autologous hematopoietic cell transplantation (ASCT), relapse or progression of the disease, outcome of disease, and number of FLs in ¹⁸F-FDG PET/CT. Patients were followed throughout the study period until their last hospital admission or death.

Symptomatic MM, response status and clinical relapse were defined according to the IMWG criteria.[12] The definitions of the IMWG response criteria are as follows:[12]

• Complete response (CR): Negative immunofixation on the serum and urine, and disappearance of any soft-tissue plasmacytomas and <5% plasma cells in bone marrow aspirates

• Stringent CR (sCR): In addition to the CR criteria, normal-free light chain (FLC) ratio and absence of clonal cells in bone marrow biopsy through immunohistochemistry

• Very good partial response (VGPR): Serum and urine M-protein detectable by means of immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus a urine M-protein level of <100 mg per 24 h

• Partial response: A ≥50% reduction in serum M-protein plus a reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h. If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, a ≥50% reduction in plasma cells is required in place of M-protein, provided that the baseline bone marrow plasma cell percentage is ≥30%. In addition to these criteria, if present at baseline, a ≥50% reduction in the sum of the products of the maximal perpendicular diameters of measured lesions (SPD) of soft-tissue plasmacytomas is also required

• Minimal response: A ≥25% but ≤49% reduction in serum M-protein and reduction in 24-h urine M-protein by 50%–89%. In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the SPD of soft-tissue plasmacytomas is also required

• Stable disease: Not meeting criteria for CR, VGPR, partial response, minimal response, or progressive disease.

• Progressive disease: One or more of any of the following criteria

An increase of 25% from lowest confirmed response value in one or more of the following criteria: serum M-protein (absolute increase must be ≥0.5 g/dL) or serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL or urine M-protein (absolute increase must be ≥200 mg/24 h) or, in patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL) or, in patients without measurable serum and urine M-protein levels and without measurable involved FLC levels, bone marrow plasma-cell percentage regardless of baseline status (absolute increase must be ≥10%);

The appearance of a new lesion (s), ≥50% increase from nadir in SPD of >1 lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm in short axis;

A ≥50% increase in circulating plasma cells (minimum of 200 cells per microL), if this is the only measure of disease.

• Clinical relapse: One or more of the following criteria

Direct indicators of increasing disease and/or end-organ dysfunction (CRAB features) related to the underlying clonal plasma-cell proliferative disorder. It is not used in calculation of time to progression or PFS, but is listed as a factor that can be reported optionally, for use in clinical practice, the development of new soft-tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression), or definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and ≥1 cm) increase, as measured serially by the SPD of the measurable lesion or hypercalcemia (>11 mg/dL), a decrease in hemoglobin of ≥2 g/dL not related to therapy or other non-myeloma-related conditions, or an increase in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable to myeloma or hyperviscosity related to serum paraprotein.

Patients who had sCR or CR were categorized as CR. The definition of a FL (FL) was that the FDG uptake in the bone or bone marrow was focally higher than the physiological uptake in the bone marrow or liver.[8] Prognostic staging of patients was performed according to the ISS and Revised-ISS (R-ISS), according to the levels of serum β2 microglobulin, albumin, lactate dehydrogenase, and chromosomal abnormalities by means of (FISH) (Fluorescent in Situ Hybridization).[4,5] High-risk genetics were defined as the presence of any of the following in FISH or cytogenetic analyses: t (4;14), t (14;16), t (14;20), 17p deletion, p53 mutation, gain (1q21) and del (1p32).[13] OS is defined as the time from diagnosis to last follow-up or death from any cause. PFS is defined as the time from diagnosis to the progression (according to the progressive disease definition of the IMWG) of the disease or death. The choice of treatment was based on the reimbursement conditions in our country during the study.

PET/CT imaging was performed using a combined whole-body PET/CT system (Discovery STE; GE Medical Systems, Milwaukee, WI). All patients fasted with oral contrast hydration for at least 6 h (blood glucose level <200 mg/dL) prior to imaging, which was started approximately 60 min after intravenous injection of 370–555 MBq (10–15 mCi) of FDG. After a low-dose CT study for attenuation correction and precise anatomical localization without contrast enhancement, patients were examined from the top of the skull to the upper thigh using a three-dimensional mode with a 3 min acquisition and six or seven bed positions.

The images of the patients were re-examined as defined according to the literature and analyzed by two different nuclear medicine specialists. F-18 FDG accumulation was analyzed semi-quantitatively by calculating the maximum standardized uptake value (SUVmax) in the regions of interest placed over the suspected lesions.

The Statistical Package for the Social Sciences (SPSS) SPSS Version 26 (IBM Corp. Released 2019. IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp) was used for all statistical analyses. For the continuous variables, we calculated the mean and the median while, for the descriptive variables, we calculated the proportions. Mann–Whitney–Wilcoxon or t-tests were utilized to compare continuous variables, while the χ² test or Fisher’s exact test was utilized to compare categorical variables, as appropriate. We conducted Kaplan–Meier analysis for OS, PFS and group comparisons. We performed univariate and multivariate Cox regression analysis to identify predictors of OS and PFS.

Results

A total of 89 patients were analyzed, with a median age of 62 years and 55.1% female patients. The most common subtype of disease was IgG κ, in 42.7% of patients. In the frontline setting, 71.9% of patients received the bortezomib–cyclophosphamide and dexamethasone (VCD) protocol. Almost half of the patients were stage 1, according to the ISS and R-ISS. Of the 84 patients for whom genetic testing was available, 23.6% (21 patients) had at least one high-risk genetic test. The partial and better than partial response rate was 75.3% for all patients treated with frontline therapy, of whom 47.2% achieved a CR. ASCT was performed in 52.8% of the patients. Furthermore, 57.3% of the patients had ≥3 FLs, while 20.2% (18 patients) had no FL. The median follow-up time was 39 months. During the follow-up, 48.3% of the patients had relapse and the mortality rate was 50.6%. The median OS and median PFS were 55 and 43 months (95% confidence interval [CI]), respectively. The distribution of the patients is detailed in Table 1.

When patients were divided into groups with ≥3 or <3 FLs, the distribution of gender, age, frontline treatment and disease subtype showed statistically significant differences between patients. However, the genetic risk profile, disease stage, response/progression/relapse status and mortality rate did not statistically differ between the groups. Detailed analyses are shown in Table 2.

Regarding survival analyses, the mortality rate was 57.9% in patients with ≥3 FLs and 43.1% in the <3 FLs group. The median OS in patients with ≥3 FLs was 49 months (95% CI) while, in patients with <3 FLs, the median survival time was 101 months (95% CI). In the Kaplan–Meier log-rank analysis, this difference was statistically significant with a P = 0.049 [Figure 1]. When the survival time was analyzed based on whether ASCT was performed or not, the median survival for patients without ASCT was 21 months (95% CI) for those with ≥3 FLs and 35 months (95% CI) for those with <3 FLs; meanwhile, for patients with ASCT, the median survival was 67 months (95% CI) for those with ≥3 FLs and 101 months (95% CI) for those with <3 FLs. This difference was statistically significant between the groups (P = 0.011). This significant result may be attributed to the statistically significant difference in survival time within the non-ASCT group between those with ≥3 FLs and those with <3 FLs (P = 0.005), whereas this difference was not statistically significant within the ASCT group in the log-rank analysis [Table 3].

Close

Figure 1 Kaplan–Meier (log rank) analysis of overall survival according to the number of focal lesions

Export to PPT

The progression of the disease was observed in 60.8% of patients in the ≥3 FLs group, compared to 42.1% of patients in the <3 FLs group. When PFS was compared, the median duration was 34 months (95% CI) in patients with ≥3 FLs and 67 months (95% CI) in patients with <3 FLs. In the log-rank analysis, this difference was statistically significant (P = 0.026) [Figure 2].

Close

Figure 2 Kaplan–Meier (log rank) analysis of progression-free survival according to the number of focal lesions

Export to PPT

Regarding the predictors of all causes of mortality, in the univariate Cox regression analysis, ≥3 FLs, shorter PFS, not receiving ASCT, <PR status with frontline treatment and worse ISS staging were found to be predictors of mortality (P = 0.054, <0.001, 0.003, 0.007, 0.003 and 0.022, respectively). In the multivariate Cox regression analysis, the number of FLs lost its effect on mortality, while stage 3 ISS, no ASCT and shorter PFS were independent risk factors for mortality (P = 0.006, 0.026 and <0.001, respectively). In terms of the predictors of PFS, in the Cox regression univariate analysis, ≥3 FLs, subtype of disease, and worse than PR status with frontline therapy were found to be predictors of shorter PFS (P = 0.030, 0.051 and 0.058, respectively). When these factors were included in the multivariate analysis, only ≥3 FLs remained a predictor of shorter PFS (P = 0.021), although it was not a predictor of mortality.

Discussion

The evaluation of prognostic markers and the definition of high-risk patients in the initial assessment is critical in the context of MM, which has a heterogeneous aspect due to the biology of the disease, comprising stages of remission and relapse.[1] Due to the ability of the disease to spread to bone or migrate to other organs or tissues, imaging techniques such as CT, magnetic resonance imaging and ¹⁸F-FDG PET/CT have become prominent and highly recommended by myeloma expert groups. ¹⁸F-FDG PET/CT is recognized as a sensitive and specific technique for detecting FLs, which helps to demonstrate the disease burden and predict disease prognosis in symptomatic MM patients.[11,14]

The role of ¹⁸F-FDG PET/CT in MM in diagnostic and prognostic aspects has been revealed in the literature. Previous prospective studies by Zamagni et al. and Bartel et al. showed that ≥3 FLs and >3 FLs were associated with worse PFS and OS in transplant-eligible NDMM patients, respectively.[15,16] Real-world retrospective data also support these findings, and a study in 167 transplant-eligible and-ineligible NDMM patients indicated worse PFS and OS with >3 FLs.[17] In addition, Cho et al. found that only PFS was 2.3 times worse in patients with >3 FLs in their study in 380 NDMM patients, 34.5% of whom had undergone ASCT.[18] Alonso et al. reported that ≥3 FLs was associated with shorter OS and PFS in 103 NDMM patients, 73% of whom underwent ASCT in 2019; however, they could not demonstrate its impact on mortality or PFS in regression models.[19] A meta-analysis study in 1670 NDMM transplant-eligible or -ineligible patients revealed that >3 FLs was an independent risk factor for mortality and disease progression, while another, larger meta-analysis study in more than 2500 patients showed that more FLs was a poor prognostic factor for OS and PFS.[6,7]

In the 2017 recommendations of the IMWG, the prognostic value of FDG PET/CT in the initial assessment of the disease is mentioned at level 2C evidence.[20] However, in their 2019 recommendations, the group underscored the position of FDG PET/CT in baseline work-up for response assessment in clinical trials when it is impossible to perform whole-body CT or whole-body MR/spine–pelvis MR, due to patient factors, providing level 4 evidence.[11]

According to the literature, >3 FLs detected by means of ¹⁸F-FDG PET/CT is accepted as a reliable poor prognostic factor; however, its influence is less accurate in transplant-ineligible patients compared to transplant-eligible patients. In contrast, the meta-analysis study conducted by Han et al. indicated that the prognostic value of FL did not statistically differ, according to transplantation eligibility, in the meta-regression analysis.[3,6,7]

In our study, we demonstrated that patients with ≥3 FLs had significantly worse OS and PFS. Notably, ≥3 FLs was the only predictive factor for shorter PFS. While disease stage, response to frontline treatment, genetic risk, disease progression, and ASCT rates did not differ statistically between the groups with ≥3 or <3 FLs, OS was significantly shorter in patients with ≥3 FLs. In addition, patients with ≥3 FLs who did not undergo ASCT had significantly shorter survival. In the univariate analysis, ≥3 FLs were found to increase mortality; however, it was not a predictor of mortality in the multivariate regression analysis. This suggests that the negative impact of the number of FLs on mortality may have been mitigated by ASCT in subsequent steps.

The limitations of the study include its retrospective design, the small number of patients, the exclusion of laboratory parameters, and the inclusion of patients who underwent PET/CT at the time of diagnosis during the study, which may have introduced bias. However, the study was a single-center study, and the same PET/CT imaging techniques and equipment were used for all patients during the study and the PET/CT images were re-evaluated by two different nuclear medicine specialists experienced in PET/CT.

Conclusion

Despite some recommendations limiting the necessity and prognostic value of ¹⁸F-FDG PET/CT, we believe that this imaging technique is a reliable tool for initial assessment. According to the results of our study, consolidation with ASCT should be attempted in the group of patients with ≥3 FLs on PET/CT, who are likely to have shorter PFS and OS. Understanding the biology of the disease, better differentiation of the risk profile through the addition of available assessment tools and individualized treatment approaches can be expected to lead to survival-related benefits in MM patients.

Author contributions

T. A. K.: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, and Writing – review and editing;

O. K.: Conceptualization, Formal analysis, Methodology, Visualization, Supervision, Writing – original draft, and Writing – review and editing;

S. S.: Data curation, Formal analysis, Investigation, Visualization, Validation, and Writing – review and editing;

E. G. U.: Visualization, Formal analysis, and Writing – review and editing;

F. U.: Data curation, Formal analysis, Investigation, Visualization, Validation, Supervision, and Writing – review and editing;

A. M. D.: Visualization, Formal analysis, Supervision, and Writing – review and editing.