Del17p without TP53 mutation confers poor prognosis in intensively treated newly diagnosed multiple myeloma patients.

Blood ◽  
2020 ◽  
Author(s):  
Jill Corre ◽  
Aurore Perrot ◽  
Denis Caillot ◽  
Karim Belhadj Merzoug ◽  
Cyrille Hulin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Median Survival ◽  
Plasma Cells ◽  
Prognostic Indicator ◽  
Chromosome 17 ◽  
Poor Outcome ◽  
Number Of Patients ◽  
Double Hit ◽  
Very High

Despite tremendous improvements in the outcome of patients with multiple myeloma (MM) in the past decade, high-risk patients have not benefited from the approval of novel drugs. The most important prognostic factor is the loss of parts of the short arm of chromosome 17, known as deletion 17p (del(17p)). A recent publication (on a small number of patients) suggested that these patients are at very high-risk only if del(17p) is associated with TP53 mutations, the so-called "double-hit" population. To validate this finding, we designed a much larger study on 121 patients presenting del(17p) in >55% of their plasma cells, and homogeneously treated by an intensive approach. For these 121 patients, we performed deep next generation sequencing targeted on TP53. The outcome was then compared to a large control population (2505 patients lacking del(17p)). Our results confirmed that the "double hit" situation is the worst (median survival = 36 months), but that del(17p) alone also confers a poor outcome compared with the control cohort (median survival = 52.8 months vs 152.2 months, respectively). In conclusion, our study clearly confirms the extremely poor outcome of patients displaying "double hit", but also that del(17p) alone is still a very high-risk feature, confirming its value as a prognostic indicator for poor outcome.

Immunoglobulin Free Light Chains at Diagnosis: Predictors of Progression and Survival in Solitary Plasmacytoma of Bone.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5080-5080 ◽  
Author(s):  
David Dingli ◽  
Robert A. Kyle ◽  
Vincent S. Rajkumar ◽  
Grzegorz S. Nowakowski ◽  
Dirk R. Larson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Univariate Analysis ◽  
Prognostic Indicator ◽  
M Protein ◽  
Solitary Plasmacytoma ◽  
Time To Progression ◽  
Number Of Patients ◽  
M Proteins ◽  
Risk Of Progression

Abstract Background: Solitary plasmacytoma of bone (SBP) is a localized collection of monoclonal plasma cells that is potentially curable with local radiation therapy but associated with a high risk of progression to multiple myeloma. We hypothesized that an abnormal immunoglobulin free light (FLC) ratio at diagnosis may be a prognostic indicator of transformation risk. Methods: We identified a cohort of 133 patients with SBP for whom stored serum taken at the time of diagnosis was available. The diagnosis was ascertained and serum FLC determined in 126 patients. Results: From this cohort, 48 patients have progressed to myeloma and the median time to progression among those who progressed was 1.9 years. On univariate analysis, age (p<0.001), gender (p=0.035), abnormal FLC ratio at diagnosis (p=0.009) and persistence of serum or urine M-protein after therapy (p=0.0070 were all associated with a shorter overall survival (OS) and time to progression to multiple myeloma. Progression by Normal FLC(0.26–1.65) Progression by Normal FLC(0.26–1.65) On multivariate analysis, an abnormal FLC ratio retained its independence in a model that includes age at diagnosis but lost its significance when combined with persistence of the serum or urine M-protein. However, serum or urine M-proteins are not detectable in a significant number of patients with SBP and therefore not informative. Conclusion: The FLC ratio at the time of diagnosis of SBP is a powerful predictor of risk and a useful aid to management of patients with this condition.

New Aspects for Future Stratifications In Paediatric AML: Outcome According to Cytogenetics of 386 Patients Enrolled In Study AML-BFM 2004

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2741-2741
Author(s):  
Christine von Neuhoff ◽  
Annette Sander ◽  
Jutta Bradtke ◽  
Silja Roettgers ◽  
Andrea Teigler-Schlegel ◽  
...  
Keyword(s):  
High Risk ◽  
Chromosomal Aberrations ◽  
Fusion Gene ◽  
Risk Group ◽  
High Risk Group ◽  
Prognostic Impact ◽  
Liposomal Daunorubicin ◽  
Poor Outcome ◽  
Number Of Patients ◽  
Very High

Abstract Abstract 2741 Cytogenetic analyses are essential for stratification and prognosis in childhood AML. We analysed the frequency of chromosomal aberrations and the outcome according to the cytogenetic findings in 386 patients with data (92%) out of the total group of 422 German patients in study AML-BFM 2004. The aim was to evaluate the prognostic impact of specific chromosomal aberrations in a large cohort of patients treated according to this BFM protocol. Patients were <18 years of age and were diagnosed between 2004 and 2009. According to the AML-BFM risk criteria based on morphology, genetics and response on day 15 of therapy, patients were assigned to a high-risk (HR) and a standard risk (SR) group. Cytogenetic and FISH analyses-as well as RT-PCR if indicated-were performed according to standard protocols on bone marrow or peripheral blood prior to therapy. Results: the number of patients in different karyotypic groups and their outcome are given in the table below: SE = standard error, pOS = probability of overall survival, pEFS = probability of event-free survival, CIR = cumulative incidence of relapse at 5 years All patients with t(15;17) and/or PML/RARα fusion gene are surviving disease free, except for two patients who died during the first two weeks of treatment. It is noteworthy that all children with inv(16) and/or CBFβ/MYH11 fusion gene are surviving (pOS=100%). Compared to the results of study AML BFM 98, outcome of patients with MLL-rearrangements was significantly higher in study AML BFM 2004 (pEFS 35%, SE 5%, vs. pEFS 55%, SE4%) which may be due to more intensive treatment with liposomal daunorubicin (L-DNR) and 2-chlorodeoxyadenosine (2-CDA). Patients with the translocation t(9;11)(p22;q23) and/or the MLL/AF9 fusion gene [n=43] had a pEFS of 60% (SE 9%) and a pOS of 80% (SE 6%), whereas patients with translocation t(10;11)(p12;q23) and or the MLL/AF10 fusion gene [n=13] showed a poor outcome with a pEFS of 23% (SE 13%) and a pOS of 59% (SE 14%). Based on a literature review we defined a very-high-risk group (see definition in the table) which showed a very poor outcome both in study AML BFM 2004 (n=16, pEFS 30%, SE12%) and AML BFM 98 (n=22, pEFS 14%, SE 7%). In this very high risk group 25 patients of both studies achieved first complete remission (1st CR); 11 of them underwent allogeneic stem cell transplantation (SCT) (pEFS 52%, SE16%), 14 patients did not (pEFS of the 12 patients who had an EFS of at least 0.44 years: 13%, SE 11%), Mantel-Byar p=0.17). Conclusion: Our results confirm the favourable prognosis for patients showing the rearrangements t(8;21), t(15;17) and inv(16) and the unfavourable prognosis for those with complex karyotypes (3 or more chromosomal aberrations), deletions in 12p and t(10;11)(p12;q23). According to these results stratification of patients in further AML BFM studies will be even more differentiated, and patients of a genetically defined very high-risk group will have an indication for SCT in 1.CR. Disclosure: No relevant conflicts of interest to declare.

Deletion of the 17p Chromosomal Region Is Associated with a Very Poor Outcome in Multiple Myeloma Independently of the Type of Treatment.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1817-1817 ◽  
Author(s):  
Hervé Avet-Loiseau ◽  
Xavier Leleu ◽  
Murielle Roussel ◽  
Claire Mathiot ◽  
Denis Caillot ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Poor Prognosis ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Chromosome 17 ◽  
High Dose ◽  
Poor Outcome ◽  
Specific Association ◽  
High Dose Melphalan ◽  
Novel Drug

Abstract Abstract 1817 Poster Board I-843 Deletion of the short arm of chromosome 17 [del(17p)] is known to confer a poor prognosis in multiple myeloma (MM). However, no large study has been specifically dedicated to this purpose, especially in the novel drug era. We analyzed a series of 1324 patients with MM at diagnosis, treated within or according to IFM trials, and analyzed for del(17p). Most of the patients were under 65 years of age (1122 of the 1324 patients), and were treates either with a VAD-based induction or a Velcade®/Dexamethasone-based induction, followed by one or two courses of high-dose melphalan. Del(17p) was correlated to the major other prognostic parameters, both for event free survival and overall survival. Del(13) was observed in 71% of the patients with del(17p). A significant association was observed with anemia < 10g/dl (p=.05), with thrombocytopenia < 130 G/l (p<.0001), with hypercalcemia (p=.001), and b2-microglobulin>3.5 mg/l (p=.006). No specific association was observed with t(4;14) (17% of the del(17p)-positive patients displayed t(4;14)). Del(17p) was observed in 10% of the patients. Del(17p) was associated with a very poor outcome, both in young and elderly patients. Actually, the prognostic value was observed only in patients displaying del(17p) in at least 70% of their plasma cells. The median EFS and OS were 18 and 28 months respectively, versus 30 and 69 months for patients lacking the del(17p). A particularly poor outcome was observed in patients presenting both del17p and t(4;14), with a median EFS of 4.5 months and a median OS of 12 months. Of particular importance, none of the treatment modality (high-dose melphalan, thalidomide, bortezomib) overcame the poor prognosis associated with del(17p), although patients lacking del(17p) displayed a better outcome when treated with Vel/Dex or MP-Thalidomide. In conclusion, del(17p) is associated with an especially poor outcome, independently of the type of treatment, including novel drugs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Early Mortality and Aggressive Presentation Lead to Poor Outcomes in Patients with Newly Diagnosed Double Hit and Triple Hit Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3762-3762
Author(s):  
Charanpreet Singh ◽  
Sreejesh Sreedharanunni ◽  
Vandana Panakkal ◽  
Aditya Jandial ◽  
Arihant Jain ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Cause Of Death ◽  
Progressive Disease ◽  
Plasma Cells ◽  
Hazard Ratio ◽  
Newly Diagnosed ◽  
Common Cause ◽  
Double Hit

Abstract INTRODUCTION mSMART classifies high-risk Multiple Myeloma patients into Double Hit and Triple Hit Myeloma (DH/THM) on the basis of the number of high-risk cytogenetic abnormalities detected. The outcome of these patients with the use of proteasome inhibitors and IMiDs with upfront Auto HSCT is not known in the real-world setting. We retrospectively studied the outcome of these patients in a resource constrained setting. METHODS The case records of all newly diagnosed multiple myeloma patients who fulfilled the criteria for active myeloma between January 2018 and December 2020 were identified. The diagnosis of double hit and triple hit myeloma was based on mSMART classification (Presence of two or more of the following: IgH-FGFR3 translocation, IgH-MAF translocation, TP53 deletion, gain of chromosome 1q). Their case records were retrieved and information regarding baseline characteristics, therapy and outcomes was noted. RESULTS A total of 55 patients with newly diagnosed DH/THM were treated at our center during the study period. Median age of the cohort was 60 years with almost an equal number of male and female patients (M= 26; F= 29). Renal failure (serum creatinine &gt;2.0mg/dl) was present in 33 patients (60%) while bone lesions, anemia (Hemoglobin &lt;10 gm/dl) and hypercalcemia (serum calcium &gt;12mg/dl) were present in 44 (80%), 51 (92.7%) and 24 (43.6%) patients respectively. Six patients (10.9%) fulfilled the criteria for plasma cell leukemia. All but 2 patients had gain of 1q with at least 3 copies. The most common cytogenetic combination was IgH-FGFR3 translocation with gain of 1q, which was seen in 28 patients (50.9%). This was followed by co-occurrence of TP53 deletion with gain of chromosome 1q in 11 patients (20%). Nine patients (16.4%) had triple hit myeloma. Bortezomib was used in the initial therapy of 43 patients (78.2%) and IMiDs (lenalidomide, thalidomide and pomalidomide) were used in the initial therapy of 32 patients (58.2%). Most patients received triplet therapy (N=32; 58.2%) with the most common regimen being RVd. Nine patients (16.4%) died within the first month of diagnosis and another 7 died in next month [15 patients in 2 months (29.1%)]. The most common cause of death within 2 months was progressive disease (N=13; 81.3%). Twenty-two patients (40%) achieved VGPR or better with anti-myeloma therapy and 7 patients (12.7%) underwent autologous HCT. Of the 39 evaluable patients, 21 patients (53.8%) relapsed during follow up with a median EFS of 8 months. Of the 7 patients who underwent transplant, 5 patients have had a follow-up of more than 1 year, of whom 3 have relapsed. One patient with post-transplant relapse died with progressive disease and CMV colitis. Median follow up of the entire cohort was 11 months (Range- 0 to 35 months). After excluding patients who died within the first 2 months of diagnosis, the median follow up was 14 months (Range- 3 to 35 months). Thirty-three patients (60%) patients died during follow-up. The most common cause of death was active or progressive disease (25 patients, 78.1%). Median OS for the cohort was 13 months. On univariate analysis, survival was better for patients without renal injury at presentation (29 months vs 6 months; p=0.007) and patients with &lt;5% circulating plasma cells (14 months vs 2 months; p=0.045). Patients who achieved VGPR had a better OS than patients who did not (Not reached vs 3 months; p=0.000) as did patients who underwent auto transplant (Not reached vs 10 months; p=0.023). OS did not significantly differ with TP53 deletion status, or number of copies of 1q (3 or greater than 3). In the multi-variate analysis, presence of renal failure (Hazard ratio- 2.663; p-0.017) and &gt;5% circulating plasma cells (Hazard ratio- 3.082; p-0.020) were significantly associated with increased risk of mortality, while achievement of VGPR or better with therapy was associated with longer survival (Hazard ratio- 0.174; p-0.001). DISCUSSION The outcome of DH/THM remains poor in the real-world setting. The outcome was not affected by specific high-risk cytogenetic abnormalities or their combination in our study. Progressive disease within the first two months of diagnosis was the most common cause of death in more than 1/3 rd of the patients. Novel therapies and protocols are required to improve outcomes for this group of multiple myeloma patients. Disclosures No relevant conflicts of interest to declare.

Cytogenetic Findings and Pattern of Clonal Evolution Determine Survival in Patients with Primary or Secondary Myelofibrosis

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1543-1543
Author(s):  
Constantine S. Tam ◽  
Lynne V. Abruzzo ◽  
Katherine I. Lin ◽  
Jorge Cortes ◽  
Alice Lynn ◽  
...  
Keyword(s):  
High Risk ◽  
Median Survival ◽  
Clonal Evolution ◽  
Chromosome 17 ◽  
Trisomy 8 ◽  
Conventional Cytogenetic Analysis ◽  
Risk Patients ◽  
Secondary Myelofibrosis ◽  
Standard Risk ◽  
Very High

Abstract The significance of conventional cytogenetic analysis and the pattern of clonal evolution in patients with primary or secondary myelofibrosis (MF) are not well defined. In a cohort of 371 MF patients managed at the MD Anderson Cancer Center between 09/76 and 04/07, 337 (91%) had an adequate conventional cytogenetic study at the time of presentation. Seventy-eight percent had primary MF, 11% had post-PV MF, and 11% had post-ET MF. The patient characteristics (median and range) were: age 63 years (24–86); male 60%; previous therapy with radiation or alkylating agents 6%; hemoglobin 10.0 g/dL (6.2–16.0), transfusion-dependent 33%; white blood cell count 10.4 x 10^9/L (1.3–171.0), circulating blasts 1% (0–17); platelet count 203 x 10^9/L (1–1958); spleen size 6cm below LCM (0–30); performance status ≥2 in 6%. The median survival from presentation was 34 months, with a median follow-up of 39 months for the survivors. Conventional cytogenetic analysis performed at presentation (n = 337) demonstrated: 63% diploid; 9% deletion 20q; 7% abnormality (abn) of chromosome 5 or 7 or ≥3 abn (5/7/CPX); 5% deletion 13q; 5% translocations; 3% isolated trisomy 8; 3% abn of chromosome 17 (abn17); 2% trisomy 9; 3% other abn. The survival of patients with standard-risk cytogenetic abnormalities was similar to patients with normal diploid karyotypes (median survival [mOS] 34 months), and included deletion 20q (mOS 53 months), deletion 13q (mOS 52 months), translocations (mOS 61 months), isolated trisomy 8 (mOS 30 months), and trisomy 9 (no deaths at median 50 months). Among the standard-risk cytogenetic categories, the co-existence of an additional abnormality not affecting chromosomes 5, 7 or 17 had no significant impact on survival (p&gt;0.50). The median survival by cytogenetic risk were: standard-risk (diploid or favorable cytogenetic findings), 40 months; high-risk (5/7/CPX), 15 months; very high-risk (abn17), 5 months [p&lt;0.0001]. The Lille score (Blood 88:1013) had prognostic significance in standard cytogenetic risk patients, but had no effect on survival among high and very high cytogenetic risk patients. Clonal evolution (CE) was ranked according to the baseline cytogenetic risk categories, and occurred in 44 (28%) of 158 evaluable patients at a median of 17 months. Of these, one occurred at the development of blast phase, and two were already in the very high risk cytogenetic category. The impact of CE on survival was assessed in the remaining 41 patients (44 events). The median post-CE survivals were: new standard risk clone (11%), 31 months; standard risk abn in existing clone (50%), 21 months; 5/7/CPX abn (20%), 18 months; abn17 (18%), 12 months. We conclude that the conventional cytogenetic findings at presentation and the pattern of clonal evolution predict survival independent of established prognostic models. The occurrence of chromosome 17 abn at presentation and during the disease course identifies very high risk patients with a median survival of 12 months or less.

scholarly journals Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Laurie Herviou ◽  
Sara Ovejero ◽  
Fanny Izard ◽  
Ouissem Karmous-Gadacha ◽  
Claire Gourzones ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Histone H4 ◽  
Myeloma Cells ◽  
Functional Studies ◽  
Replicative Stress ◽  
Poor Outcome ◽  
Subsequent Decrease ◽  
Lysine Methyltransferase

Abstract Background Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. In addition to a wide panel of genetic mutations, epigenetic alterations also appear as important players in the development of this cancer, thereby offering the possibility to reveal novel approaches and targets for effective therapeutic intervention. Results Here, we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for the mono-methylation of histone H4 at lysine 20, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Primary malignant plasma cells are particularly addicted to the activity of this epigenetic enzyme. Indeed, the inhibition of SETD8 by the chemical compound UNC-0379 and the subsequent decrease in histone H4 methylation at lysine 20 are highly toxic in MM cells compared to normal cells from the bone marrow microenvironment. At the molecular level, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and, as observed in other cancers, triggers an activation of the tumor suppressor p53, which together cause an impairment of myeloma cell proliferation and survival. However, a deadly level of replicative stress was also observed in p53-deficient myeloma cells treated with UNC-0379, indicating that the cytotoxicity associated with SETD8 inhibition is not necessarily dependent on p53 activation. Consistent with this, UNC-0379 triggers a p53-independent nucleolar stress characterized by nucleolin delocalization and reduction of nucleolar RNA synthesis. Finally, we showed that SETD8 inhibition is strongly synergistic with melphalan and may overcome resistance to this alkylating agent widely used in MM treatment. Conclusions Altogether, our data indicate that the up-regulation of the epigenetic enzyme SETD8 is associated with a poor outcome and the deregulation of major signaling pathways in MM. Moreover, we provide evidences that myeloma cells are dependent on SETD8 activity and its pharmacological inhibition synergizes with melphalan, which could be beneficial to improve MM treatment in high-risk patients whatever their status for p53.

scholarly journals Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2

Blood ◽  
2011 ◽  
Vol 117 (18) ◽  
pp. 4696-4700 ◽  
Author(s):  
Nikhil C. Munshi ◽  
Kenneth C. Anderson ◽  
P. Leif Bergsagel ◽  
John Shaughnessy ◽  
Antonio Palumbo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
In Situ Hybridization ◽  
High Risk ◽  
Risk Stratification ◽  
Fluorescence In Situ Hybridization ◽  
High Serum ◽  
Β2 Microglobulin ◽  
Poor Outcome ◽  
13Q Deletion

Abstract A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4;14) and del17p, and detection by fluorescence in situ hybridization of t(4;14), t(14;16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serum β2-microglobulin level and International Staging System stages II and III, incorporating high β2-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations.

Risk Stratification and Targets in Multiple Myeloma: From Genomics to the Bedside

2018 ◽  
pp. 675-680 ◽  
Author(s):  
Aurore Perrot ◽  
Jill Corre ◽  
Hervé Avet-Loiseau
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Plasma Cells ◽  
Mechanisms Of Action ◽  
The Past ◽  
Novel Drugs ◽  
Genetic Abnormalities ◽  
Frequent Mutations ◽  
Risk Patients ◽  
First Relapse

In the past 15 years, significant improvements in overall survival have been observed in multiple myeloma (MM), mainly due to the availability of novel drugs with variable mechanisms of action. However, these improvements do not benefit all patients, and some of them, defined as high risk, still display short survival. The most important risk factors are the genetic abnormalities present in the malignant plasma cells. The most important high-risk features are the del(17p), the del(1p32), the t(4;14), and 1q gains. Assessing these markers is mandatory at diagnosis and at least at first relapse, since it has been clearly shown that the lenalidomide-dexamethasone combination is not efficient in these high-risk patients. In contrast, a triplet combination adding a proteasome inhibitor or a monoclonal antibody to the lenalidomide-dexamethasone backbone clearly improves the survival. Another way to improve the outcome would be to specifically target genetic abnormalities with specific inhibitors. The sequencing of more than 1,000 MM exomes revealed again a huge heterogeneity. The most frequent mutations involve the KRAS and NRAS genes (20%–25% each). However, to date, no good RAS-inhibitors are clinically available, preventing targeted therapy. The only drugable target is the V600E BRAF mutation. Unfortunately, this specific mutation is present in only 3% of the patients. Finally, it has been recently reported a specific efficiency of the BCL2-inhibitor venetoclax in patients with the t(11;14) translocation, which is found in 20% of the patients.

scholarly journals Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS)

Leukemia ◽  
2020 ◽  
Vol 34 (7) ◽  
pp. 1840-1852 ◽  
Author(s):  
C. Ola Landgren ◽  
Ajai Chari ◽  
Yael C. Cohen ◽  
Andrew Spencer ◽  
Peter Voorhees ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Primary Endpoint ◽  
Total Duration ◽  
Intermediate Risk ◽  
Active Monitoring ◽  
Death Rates ◽  
Smoldering Multiple Myeloma ◽  
Number Of Patients

Abstract Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules. At the prespecified primary analysis (15.8-month median follow-up), the complete response (CR) rates (co-primary endpoint) were 2.4%, 4.9%, and 0% for intense, intermediate, and short dosing, respectively; the co-primary endpoint of CR rate >15% was not met. Progressive disease (PD)/death rates (number of patients who progressed or died divided by total duration of progression-free survival [PFS] in patient-years; co-primary endpoint) for intense, intermediate, and short dosing were 0.055 (80% confidence interval [CI], 0.014–0.096), 0.102 (80% CI, 0.044–0.160), and 0.206 (80% CI, 0.118–0.295), respectively, translating to a median PFS ≥24 months in all arms (P < 0.0001, <0.0001, and =0.0213, respectively). With longer follow-up (median follow-up, 25.9 months), CR rates were 4.9%, 9.8%, and 0% for intense, intermediate, and short dosing, respectively. PD/death rates for intense, intermediate, and short dosing were 0.059 (80% CI, 0.025–0.092), 0.107 (80% CI, 0.058–0.155), and 0.150 (80% CI, 0.089–0.211), respectively, again translating to a median PFS ≥ 24 months in all arms (P < 0.0001 for all arms). Twenty-four–month PFS rates were 89.9% (90% CI, 78.5–95.4%), 82.0% (90% CI, 69.0–89.9%), and 75.3% (90% CI, 61.1–85.0%) for intense, intermediate, and short dosing, respectively. Pharmacokinetic analyses indicated that intense dosing maintained target-saturating trough concentrations in most patients throughout weekly, every-2-week, and every-4-week dosing periods. No new safety signals were observed. These data provide the basis for an ongoing phase 3 study of daratumumab in SMM.

scholarly journals Peripheral blood monoclonal plasma cells as a predictor of survival in patients with multiple myeloma [see comments]

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1780-1787 ◽  
Author(s):  
TE Witzig ◽  
MA Gertz ◽  
JA Lust ◽  
RA Kyle ◽  
WM O'Fallon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
High Risk ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Cell Labelling ◽  
Newly Diagnosed ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Beta 2 Microglobulin

Abstract The purpose of this study was to quantitate the number and labeling index of monoclonal plasma cells in the blood of patients with newly diagnosed multiple myeloma (MM) to learn if these values were independent prognostic factors for survival. Patients were candidates for this study if they had untreated myeloma requiring therapy, were evaluated at our institution between 1984 and 1993, and had a sample of blood analyzed with a sensitive immunofluorescence technique for monoclonal plasma cells and the blood B-cell labelling index (BLI). The % blood monoclonal plasma cells (%BPC) and the BLI were analyzed along with stage, marrow plasma cell LI, % marrow plasma cells, calcium, creatinine, albumin, beta-2-microglobulin, and C-reactive protein as univariate and multivariate factors for survival. Eighty percent of the 254 patients accrued to this study had monoclonal BPC detected. The median % BPC was 6% and 57% (144 of 254) of patients had a high number (> or = 4%). Patients with > or = 4% BPC had a median survival of 2.4 years vs 4.4 years for those with < 4% BPC (P < .001). The BLI was also prognostic (P = .008). In a multivariate analysis, the % BPC, age, albumin, stage, marrow plasma cell LI, and the BLI were independent factors for survival. The %BPC and the marrow plasma cell LI best separated the group into low, intermediate, and high risk myeloma with median survivals of 52, 35, and 26 months, respectively. Patients with high %BPC were less likely to have lytic bone disease from their MM (P = .002). The %BPC and the BLI are independent prognostic factors for survival and are useful in identifying patients as low, intermediate, and high risk. Clonal cells in the blood should be quantified in future clinical trials for myeloma.

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