Comprehensive evaluation of the revised international staging system in multiple myeloma patients treated with novel agents as a primary therapy

Abstract BACKGROUND: In the last decades, multiple myeloma (MM) prognosis has been changing dramatically. Induction with novel agents, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (aHSCT) is the standard of care for newly diagnosed (ND) and transplant-eligible MM patients (pts). In 2015, a new score was validated [Revised International Staging System (R-ISS)], including data related to high-risk cytogenetic abnormalities (CA) [del(17p) and/or t(4;14) and/or t(14;16)] and serum lactate dehydrogenase (LDH) levels. Few recent studies have supported R-ISS as a reliable prognostic tool for estimating survival in MM pts submitted to aHSCT. AIMS: To determine whether R-ISS is a valid risk model for predicting progression free survival (PFS) and overall survival (OS) among a cohort of real-life aHSCT pts. METHODS: We conducted a single center retrospective study of ND symptomatic MM pts treated with novel agents (bortezomib, thalidomide or lenalidomide) undergoing aHSCT between Jan/2007 and Dec/2017. We excluded all pts with no available information about ISS, LDH and CA [detected by fluorescence in situ hybridization (FISH)]. Response to treatment was evaluated according to the International Myeloma Working Group consensus criteria (2016). Statistical analysis was performed using STATA v.14.2 and significant levels were set at p<0.05. RESULTS: From the total number of 186 pts submitted to aHSCT, only 81 (45%) pts presented criteria to be included in our analysis; 62% were male, with a median age at aHSCT of 60y (28-70). IgG was the most frequent subtype (59%), followed by IgA (20%). At diagnosis, 38% of pts presented anemia, 14% renal impairment (RI), 20% hypercalcemia, 63% bone disease (BD) and 32% extramedullary disease (EMD). According to ISS, 30 (37%) pts presented stage I, 30 (37%) stage II, and 21 (26%) stage III at diagnosis. There were 38% pts with high-risk CA: 24% with del17p; 19% with t(4;14), and 20% with t(14;16). High LDH levels was seen in 48% of pts. Pts were re-staged at diagnosis according to R-ISS, resulting 17% in stage I, 61% in stage II, and 22% in stage III. Thus, 16 (20%) pts previously categorized as ISS I and 3 (4%) pts as ISS III were re-classified as R-ISS II. Median time from diagnosis to aHSCT was 9.7 months. All pts received induction therapy with novel agents (a bortezomib-based therapy in 89% of pts and an IMID-based in 12%), with 81% of pts responding to first line induction; 19% were refractory. At the time of aHSCT, all pts presented at least on partial response (PR) [62% at least very good partial response (VGPR)], with an increase in the proportion of pts in complete response (CR) from 15% to 20% before and after aHSCT, respectively. Maintenance therapy was performed in 31% of pts (79% thalidomide; 21% lenalidomide). At a median follow-up of 33.4 months, median OS had not been reached. Two-years OS was 62%. Median PFS from aHSCT was 67.4%.Neither high-risk CA nor high LDH levels individually predicted lower OS and PFS (p=NS). The 2-year OS for R-ISS I, II and III was 86 %, 61% and 44%, and the 2-year PFS was 79 %, 63% and 39%, respectively. In our cohort we observed statistical significance differences between R-ISS I and III at 2 years in what concerns PFS (p=0.025) and OS (p=0.017) . No differences were seen in between other R-ISS categories. When we stratified R-ISS stage II in two subgroups based on the presence or absence of high-risk CA no differences were found. Pts classified as R-ISS III presented anemia (p<0.001) and RI (p=0.001) more frequently, but no differences concerning hypercalcemia, BD or EMD. CONCLUSIONS: In our real-life cohort, R-ISS at diagnosis was a reliable tool only to predict both OS and PFS between R-ISS I and III and not between other R-ISS subgroups. The main reasons that explain the absence of significance between all R-ISS subgroups were probably the very low number of pts with available cytogenetics compared with the total number of pts submitted to aHSCT in our center and the short follow up of our study. Larger real-life studies with a longer follow up are necessary to determine if R-ISS is a good risk stratification model to applicate to NDMM pts submitted to aHSCT in the era of novel agents. Disclosures No relevant conflicts of interest to declare.

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Retrospective Analysis of the Efficacy of Triplet Therapy, Including Lenalidomide, in Newly Diagnosed Multiple Myeloma Patients Who Obtained Responses Less Than VGPR after Rd Therapy

Blood ◽

10.1182/blood-2019-131617 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5595-5595

Author(s):

Naoki Takezako ◽

Naoya Kaneko ◽

Airi Hamano ◽

Kenichi Ito ◽

Naohiro Sekiguchi ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Elderly Patients ◽

Poor Prognosis ◽

Staging System ◽

Initial Therapy ◽

Novel Agents ◽

Newly Diagnosed ◽

International Staging System ◽

Novel Agent

Background Although multiple myeloma remains an incurable disease, the triplet therapy with novel agents has significantly improved the prognosis. However, the utility of the novel agents is often not obtained in transplant-ineligible patients, particularly in unfit or frail patients because of the low tolerance. So, in real world, it is common to use a combination of lenalidomide and low dose dexamethasone (Rd), which are generally dose-adjusted. Certainly, in the elderly patients, triplet therapy including novel agents may be excessive treatment in terms of adverse events. However, patients with only partial response are known to have a poor prognosis, and it is important how to improve their prognosis. At our medical center, we select Rd therapy for elderly patients, except for fit patients, but we have switched to triplet therapy for patients who have not had a response above VGPR. Here, we retrospectively reviewed this treatment outcome. Method We retrospectively reviewed 71 transplant ineligible newly diagnosed multiple myeloma (NDMM) patients who received Rd therapy as initial therapy between November 2015 and March 2019. The median age was 73 years old (range 66~89). Patients received normal Rd therapy (lenalidomide 25 mg/day, day 1-21 (if they have normal renal function) and dexamethasone 20mg on days 1, 8, 15, 22) for every 4 weeks as initial therapy. If the response after 6 cycles was less than VGPR, another novel agent was added and treatment was continued as triplet therapy including lenalidomide. The International Staging System (ISS) were I in 15 (21.1%), II in 45 (63.3%) and III in 11 (15.5%). High-risk cytogenetics, defined as the presence of deletion 17, t(4;14) and t(14;16) by FISH analysis, were identified in 11 (15.4%) patients. The Revised International Staging System (R-ISS) were I in 14 (19.7%), II in 49 (69.0%) and III in 8 (11.2%). Results The overall response rate (ORR) after 6 cycles of Rd therapy was obtained in 69 (97.1%). including sCR in 5 (7.0%), CR in 3 (4.2%), VGPR in 23 (32.3%), and PR in 38 (53.5%). SD were observed in 2 patients (2.8%), respectively and they relapsed within six cycles. Twenty-nine out of 38 patients who had a response less than VGPR had changed to a triplet therapy with the addition of some novel agent (13 patients with elotuzumab, 5 patients with carfilzomib, 8 patients with ixazomib, and 3 patients with daratumumab). Forty-nine out of 71 cases (69.0%) achieved a response of at least VGPR, finally. The disease-free survival time was significantly longer in cases which obtained in excess of VGPR (figure). Grade 3 or greater toxicities occurring in 5% within 6 cycles, however, in triplet therapy, 6 patients (20.6%) were suffered from severe adverse events (most were infectious diseases such as pneumonia). Conclusion This retrospective analysis revealed that Rd therapy might be able to improve prognosis if patients obtain more than VGPR and even if treatment response is less than PR in the 6th cycle, triplet therapy might be effective to change the patients' prognosis. However, patients who do not reach VGPR even with triplet therapy have a poor prognosis and need further treatment. This results may be indicate that, in elderly NDMM patients, Rd therapy is sufficiently successful, and it is not always necessary to select triplet therapy as initial from the viewpoint of adverse events. Further study is warranted. Figure Disclosures Teshima: Novartis: Honoraria, Research Funding.

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Evaluation of the Revised International Staging System (R-ISS) in an Independent Cohort of Unselected Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.3045.3045 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3045-3045

Author(s):

Efstathios Kastritis ◽

Evangelos Terpos ◽

Maria Gavriatopoulou ◽

Magdalini Migkou ◽

Evangelos Eleutherakis-Papaiakovou ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

High Risk ◽

Board Of Directors ◽

Staging System ◽

New Drugs ◽

Primary Therapy ◽

Advisory Committees ◽

International Staging System ◽

Independent Cohort

Abstract The International Staging System (ISS), which is based on beta2-microblobulin (β2M) and serum albumin, has been widely used for the risk stratification of multiple myeloma (MM) patients, since 2003. Chromosomal abnormalities (CA) detected by iFISH have been also recognized as strong prognostic factors, while elevated serum lactate dehydrogenase (LDH) has been consistently associated with poor prognosis. In order to improve the prognostic power of ISS, IMWG has revised ISS (R-ISS) by adding high risk cytogenetics by iFISH and serum LDH: R-ISS-1 includes patients with ISS-1 (serum β2M level <3.5 mg/L and serum albumin level ≥3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)] and normal LDH levels (below the upper limit of normal (UNL)); R-ISS-3 includes patients with ISS-3 (serum β2M level >5.5 mg/L) and either high-risk CA or high LDH level; and R-ISS-2 includes all the other possible combinations. R-ISS was based on the data of 3,060 patients who had participated in clinical trials. However, it has not been validated in an independent cohort of unselected patients. Our aim was to evaluate R-ISS in consecutive, unselected patients, treated in a single center. Our study included 475 patients with available data for cytogenetics [t(4;14) and del17p by iFISH], LDH and ISS. Median age was 67 years (range 27-91); 53% were >65 years and 25% >75 years of age. Only 8.6% did not receive new drugs as primary therapy; 42% received IMiDs (19% thalidomide-based, 23% lenalidomide-based) and 49% bortezomib-based primary therapy, while 36% received ASCT. In the IMWG cohort, 65% had received ASCT, 6% no new drugs, 44% proteasome inhibitors and 66% IMiDs. Per ISS, 24% were ISS-1, 34% ISS-2 and 42% ISS-3. High risk cytogenetics (either t(4;14) or del17p) were present in 23.5% and elevated LDH in 15%. In the IMWG cohort used for the formulation of R-ISS, 38% were ISS-1, 38% ISS-2 and 24% ISS-3; thus, our patients had more often ISS-3 and less often ISS-1 disease. High risk CAs and elevated LDH were not different compared to our cohort of patients (24% and 13%, respectively). The difference in ISS disposition between the two cohorts probably reflects the unselected nature of our population, which also included patients with severe renal impairment who often are excluded from clinical trials. Per R-ISS, 85 (18%) patients had R-ISS-1, 83 (17.5%) had R-ISS-3 and 306 (64.5%) had R-ISS-2. The disposition in the original cohort was 28% for R-ISS-1, 62% for R-ISS-2 and 10% for R-ISS-3. This difference was due to the higher proportion of patients with ISS-3 disease in our cohort. The R-ISS disposition in those ≤65 years, was 21%, 60% and 19% for R-ISS-1, -2 and -3; among patients 66-75 years it was 19%, 63% and 18%, and among those >75 years it was 11%, 74% and 15%, respectively (p=0.128). The median follow up was 40 months; 57% of patients progressed or died and 63% have remained alive. Median PFS was 27 months and estimated median OS was 63 months. Median PFS for R-ISS-1, -2 and -3 was 34, 28 and 17 months, respectively (p<0.001). According to R-ISS, the probability of 3-year OS was 83%, 69% and 45% and of 5-year OS 77%, 53% and 19% for R-ISS-1, -2 and -3, respectively (p<0.001). In patients treated with ASCT, the probability for 5-year OS per R-ISS stage was 93%, 77% and 32%, respectively (p<0.001), while for patients not treated with HDM it was 64%, 41% and 13% (p<0.001). The probability for 5-year OS for patients treated with bortezomib was 95%, 69% and 18% for R-ISS-1, -2 and -3 (p<0.001) and for those treated with IMiDs, it was 68%, 41% and 23%, respectively (p=0.002). We evaluated the performance of R-ISS in patients ≤65, 66-75 and >75 years. In patients ≤65 years, the probability for 5-year OS was 84%, 71% and 29%, for R-ISS-1, -2 and -3 (p<0.001); for patients 66-75 years, it was 73%, 43% and 18% (p=0.001), while in patients >75 years, the median OS was >5 years, 35 and 29 month, respectively (p=0.122). Thus, R-ISS identified a group of patients >75 with favorable prognosis, although there was no significant difference in the OS for R-ISS-2 vs -3, probably due to the impact of other comorbidities and performance status of the very elderly. In conclusion, our data in consecutive, unselected patients, with differences in the characteristics and treatment approaches compared to the original IMWG cohort, verified that R-ISS provides significant prognostic information and it allows the identification of three different patient groups with clearly different outcome. Disclosures Terpos: Novartis: Honoraria; Celgene: Honoraria, Other: travel expenses; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Novartis: Honoraria; Celgene: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria.

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Limited value of the international staging system for predicting long-term outcome of transplant-ineligible, newly diagnosed, symptomatic multiple myeloma in the era of novel agents

International Journal of Hematology ◽

10.1007/s12185-014-1539-5 ◽

2014 ◽

Vol 99 (4) ◽

pp. 441-449 ◽

Cited By ~ 9

Author(s):

Junya Kuroda ◽

◽

Yuji Shimura ◽

Kensuke Ohta ◽

Hirokazu Tanaka ◽

...

Keyword(s):

Multiple Myeloma ◽

Staging System ◽

Novel Agents ◽

Newly Diagnosed ◽

Term Outcome ◽

Long Term Outcome ◽

International Staging System

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The Applicability of the International Staging System in Chinese Patients with Multiple Myeloma Receiving Bortezomib or Thalidomide-Based Regimens as Induction Therapy: A Multicenter Analysis

BioMed Research International ◽

10.1155/2015/856704 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Jing Lu ◽

Jin Lu ◽

Aijun Liu ◽

Weijun Fu ◽

Juan Du ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Significance ◽

Progression Free Survival ◽

Staging System ◽

Novel Agents ◽

Chinese Patients ◽

Prognostic System ◽

First Line Therapy ◽

Significant Difference ◽

International Staging System

The International Staging System (ISS) is the most important prognostic system for multiple myeloma (MM). It was identified in the era of conventional agents. The outcome of MM has significantly changed by novel agents. Thus the applicability of ISS system in the era of novel agents in Chinese patients needs to be demonstrated. We retrospectively analyzed the clinical outcomes and prognostic significance of ISS system in 1016 patients with newly diagnosed multiple myeloma in Chinese patients between 2008 and 2012, who received bortezomib- or thalidomide-based regimens as first-line therapy. The median overall survival (OS) of patients for ISS stages I/II/III was not reached/55.4 months/41.7 months (p<0.001), and the median progression-free survival (PFS) was 30/29.5/25 months (p=0.072), respectively. Statistically significant difference in survival was confirmed among three ISS stages in thalidomide-based group, but not between ISS stages I and II in bortezomib-based group. These findings suggest that ISS system can predict the survival in the era of novel agents in Chinese MM patients, and bortezomib may have the potential to partially overcome adverse effect of risk factors on survival, especially in higher stage of ISS system.

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