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In recent years, despite advances in the treatment of multiple myeloma (MM), high-risk patients still face the challenges
of early recurrence and short survival.
Many risk factors such as albumin and beta2-microglobulin abnormalities, elevated lactate dehydrogenase (LDH), and cytogenetic abnormalities (CA) can lead to adverse outcomes
for MM.
Bone marrow plasma cells (BMPCs) ≥ 60% were included in the criteria for starting MM therapy (even if no end-organ damage occurred).
However, BMPC has a limited role in assessing the prognosis of patients with MM (which may be due to patchy bone disease).
Plasma cell leukemia is the advanced stage of MM, myeloma cells infiltrate from the bone marrow into the peripheral blood, ≥ the number of plasma cells in the leukocytes (or >2000/μL) is defined as plasma cell leukemia (there is evidence that this threshold can be reduced to 5%), circulating tumor plasma cells (CTCs) are its unique diagnostic markers, which can be detected
by blood cell counts and blood smears in peripheral blood.
In addition, lower levels of CTCs detected using a more sensitive technique, i.
e.
, flow cytometry [FC], have also been shown to be associated
with shorter progression-free survival (PFS) and overall survival (OS).
In MM, most published retrospective or prospective studies have explored the prognostic value of CTC observationally, and there is currently no data from clinical trials and large cohorts of MM patients receiving novel and highly effective therapies, and there is no universally recommended cut-off value
in clinical practice.
Based on this, the investigators conducted a randomized clinical trial designed to adopt multiparametric FC (MFC; Sensitivity of 10-4) to determine the optimal CTC cut-off value to predict PFS
in patients receiving newly diagnosed MM (NDMM) receiving novel drug therapy.
A phase II multicenter randomized FORTE trial of NDMM patients aged < 65 years eligible for autologous hematopoietic stem cell transplantation (ASCT) was included in the study and prospectively evaluated for the presence of CTC<b10> at diagnosis.
Patients were randomly assigned (R1) to 3 groups at diagnosis: carfilzomib-lenalidomide-dexamethasone (KRd)-ASCT (4 KRd induction cycles, melphalan 200 mg/m2 [MEL200]-ASCT, 4 KRd consolidation cycles), KRd 12 groups (12 KRd cycles), carfilzomib-cyclophosphamide-dexamethasone (KCd)-ASCT (4 KCd induction cycles, MEL200-ASCT).
, 4 KCd consolidation cycles).
Patients are then randomly assigned (R2) to two maintenance treatment groups: KR or R, until disease progression or intolerance
.
The study protocol is detailed in Figure 1
.
Figure 1
The investigators analyzed different CTC cut-off values in a multivariate (MV) Cox proportional hazards regression model for PFS outcomes and selected values
that maximized Harrell's C statistics.
MV Cox proportional hazards regression analyses were also performed on treatment and prognostic factors [ISS, LDH, CA, R-ISS, plasmacytoma and amp(1q)] in the R1 stage to compare the effects of CTC and BMPC on prognosis and to assess the effect
of CTC on PFS and OS and early recurrence rates at 18 months.
01CTC Testing
A total of 401 patients
with available baseline CTC data were included.
Median follow-up was 50 months
.
269/401 patients (67%) had CTC detected by MFC
at diagnosis.
The investigators observed a modest correlation
between CTC and BMPC.
As a continuous value, an increase in CTC levels is associated
with poorer PFS.
In different models incorporating traditional risk factors (ISS, LDH, CA, R-ISS), CTC as a continuous variable increases the prognostic impact
of these factors on PFS.
02 OPTIMAL CTC CUT-OFF VALUE
The investigators performed a Cox-proportional hazard regression analysis of PFS for known risk factors (ISS, LDH, and CA) and determined an optimal prognostic cut-off of 0.
07% for CTC (highest C index [0.
64], approximately 5 cells/microliter; 95% CI, 0.
02%-0.
33%, standard error 0.
20%)
.
Two segments of the population were determined using this cut-off value: patients with CTC > 0.
07% (high-level CTC, n=130,32%) and CTC≤0.
07% (low-level CTC, n=271,68%)
.
Notably, CTC is undetectable in half of patients with low-level CTC (n=132, 33% of the population), with a sensitivity of 4×10-5
.
In patients with high-level CTC, adverse prognostic factors are more
present.
However, about 27% of patients considered standard risk also developed high levels of CTC
.
Patients with high-level CTC had lower MRD-negative rates in the pre-maintenance intention-to-treat population and lower ≥ complete response rates before maintenance therapy compared with low-level CTC patients (Table 1).
Table 1
In univariate analysis, PFS rates (4-year PFS rate: 38 versus 69 percent) and OS rates (4-year OS rate: 68 versus 92 percent) were significantly reduced in patients with high-level CTC compared with patients with low-level CTC (Figure 2).
In patients with low-level CTC, there was no significant difference in PFS and OS between those detected and those without CTC (Figure 3).
Figure 2
Figure 3
03 COMPREHENSIVE RISK ASSESSMENT: CTC, BASELINE RISK CHARACTERISTICS, DEPTH OF RESPONSE, AND TREATMENT
In MV analysis that included CTC and BMPC as continuous variables, only the former predicted PFS and OS
.
In MV analysis including baseline features and treatment (Table 2), high levels of CTC were one of the most significant factors associated with poorer PFS [also included elevated LDH, amp(1q)] and one of
the most significant factors independently associated with poorer OS [including elevated LDH, amp(1q), high-risk CA].
In addition, CTC has a potential role
in identifying patients at high risk of early recurrence.
Achieving MRD-negative prior to maintenance therapy significantly reduces the risk of progression/death and death, regardless of the treatment received in stage R1 (Table 2).
Table 2
Poor PFS and OS were associated
with high levels of CTC in all baseline risk subgroups.
In fact, patients with high levels of CTC with another baseline risk factor (high-risk CA, elevated LDH, or amp(1q)) have worse
survival.
The only factor that interferes with the CTC level on the prognosis of PFS is MRD-negative (PFS: interaction P = 0.
039).
In the OS analysis, MRD-negative patients had better HR compared with MRD-positive patients, but the interaction was not significant with a p-value (P=0.
311), possibly due to the lower number of events in the OS analysis or being influenced
by post-relapse outcomes.
A subgroup analysis of PFS and OS in patients with high-level CTC versus low-level CTC is shown in
Figure 4.
Figure 4
In landmark analysis at 12 months post-diagnosis, a combined evaluation of baseline CTC and pre-treatment MRD status showed the best prognosis in patients with low-level CTC MRD (PFS rate 78% at 4 years post-diagnosis; OS rate was 96% at 4 years after diagnosis), while patients with high levels of CTC MRD had poor outcomes (4-year PFS rate 37%; 4-year OS rate is 66%)
.
Interestingly, survival rates were similar in patients with high-level CTC MRD-negative and low-level CTC MRD-positive patients (Figure 5).
Figure 5
The researchers also explored whether intensive treatments could improve survival in
patients with high-level CTC.
Although poor overall outcomes were observed in patients with high levels of CTC, KRd-ASCT treatment prolonged PFS compared with KRd12 and KCd-ASCT (4-year PFS: 58% vs 29% in the KCd-ASCT group versus 34% in the KRd-ASCT group).
Among all baseline features, high levels of CTC are one of the most significant adverse prognostic factors, and MRD negative obtained after high-potency anti-MM therapy can affect its prognostic value
.
The investigators believe that the study data is expected to make CTC more widely included in the clinic for routine diagnosis
of MM patients.
Future analysis of larger cohorts (including transplant-ineligible patients, patients receiving anti-CD38 monoclonal antibody therapy, real-world patients) will help overcome the discrepancies between this study and its companion studies to determine a clear cut-off value
.
The next step will be to evaluate CTC
in a comprehensive staging system and risk-adaptive therapy.
References:
Bertamini L, Oliva S, Rota-Scalabrini D, et al.
High Levels of Circulating Tumor Plasma Cells as a Key Hallmark of Aggressive Disease in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma.
J Clin Oncol.
2022 Sep 20; 40(27):3120-3131.
doi: 10.
1200/JCO.
21.
01393.
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