scholarly journals Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression

2020 ◽  
Vol 38 (21) ◽  
pp. 2380-2389 ◽  
Author(s):  
Mark Bustoros ◽  
Romanos Sklavenitis-Pistofidis ◽  
Jihye Park ◽  
Robert Redd ◽  
Benny Zhitomirsky ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Disease Progression ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Mitogen Activated Protein Kinase ◽  
Prognostic Models ◽  
Single Nucleotide Variants ◽  
Smoldering Multiple Myeloma ◽  
Risk Of Progression

PURPOSE Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.

Multicenter, Randomized, Open-Label, Phase III Trial of Lenalidomide-Dexamethasone (Len/dex) Vs Therapeutic Abstention in Smoldering Multiple Myeloma at High Risk of Progression to Symptomatic MM: Results of the First Interim Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 614-614 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Lucía López-Corral ◽  
Miguel T Hernández ◽  
Javier de la Rubia ◽  
Juan José Lahuerta ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Disease Progression ◽  
Early Treatment ◽  
Interim Analysis ◽  
Phase Iii ◽  
Gi Bleeding ◽  
Phase Iii Trial ◽  
Smoldering Multiple Myeloma ◽  
Risk Of Progression

Abstract Abstract 614 Smoldering MM (sMM) is a plasma cell (PC) disorder defined by the presence of ≥10% of PC and/or a serum M-component (MC) ≥3g/dl without end-organ damage. Recent studies have identified a subgroup of sMM at high risk of progression to active MM (>50% at 2 y): patients with both PC ≥10% & MC ≥3g/dl (Kyle R. NEJM 2007) or ≥95% aberrant PC (aPC) by immunophenotyping (Pérez E. Blood 2007) or abnormal FLCs (Dispenzieri A. Blood 2008). Standard of care for sMM is monitoring without treatment until disease progression. Several small studies have explored the value of early treatment with either conventional agents (melphalan/prednisone) or novel drugs (thalidomide, interleukin-1b), with no clear benefit. It should be noted that these trials didn't focus on high-risk sMM. In this phase III trial we investigated whether early treatment prolongs the time to progression (TTP) in sMM patients at high risk of progression to active MM. Patients were randomized to receive Len-dex versus no treatment. The high risk population was defined by the presence of both PC ≥10% and MC ≥3g/dl or if only one criterion was present, patients must have a proportion of aPC within the total PCBM compartment by immunophenotyping of ≥95% plus immunoparesis. 120 patients are planned to be recruited. The 60 patients randomized to the Len-dex arm receive nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1-21 plus dexamethasone at dose of 20 mg daily on days 1-4 and 12-15 (total dose: 160mg) (induction phase); subsequently maintenance with Lenalidomide at dose of 10 mg on days 1-21 every two months administered until disease progression. Between October 2006 and June 2008, 80 patients were randomized. In this interim analysis, we present the first 40 patients recruited. According to baseline characteristics, both groups were well balanced. In an ITT analysis (n=40), based on IMWG criteria, the overall response rate was 90%, including 53% PR, 21% VGPR, 11% CR and 5% sCR. If we select the group of 16 patients who completed the nine cycles, the ORR was 100%, including 27% VGPR, 13% CR and 7% sCR. After a median follow-up of 16 months (range:12-20), no disease progression was observed in the Len-dex arm, while 8 patients progressed to active MM in the therapeutic abstention arm with a median TTP from inclusion in the trial of 17.5 months (p<0.002). It should be noted that 6 of these 8 patients developed bone lesions as a symptom of active MM. As far as toxicity is concerned, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 2 patients G3 asthenia, 1 pt G3 diarrhea and 3 patients G3 DVT. Serious AEs occurred in 5 patients, 3 of these were dexamethasone-related (GI bleeding, delirium and glaucoma) and 2 were lenalidomide-related (two infections). Two SAEs lead to early discontinuation of the treatment (infection and delirium), and another 2 additional patients discontinued at pt's request. Four patients needed to reduce lenalidomide from 25 to 15 mg due to non-hematological AEs (asthenia (2), diarrhea (1) and GI bleeding (1). In conclusion, these preliminary results show that in sMM patients at high-risk for progression to active MM, delayed treatment is associated with early progression (median time 17.5 months) with bone disease, while so far Len-dex has been able not only to prolong the TTP (without any progression so far) but also to induce CRs with a manageable and acceptable toxicity profile. Disclosures: Mateos: Celgene: Honoraria. Off Label Use: Lenalidomide is not approved for the treatment of smoldering multiple myeloma patients. de la Rubia:Janssen-Cilag: Honoraria; Celgene: Honoraria. Rosiñol:Janssen-Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen-Cilag: Honoraria; Celgene: Honoraria. de Arriba:Janssen-Cilag: Honoraria; Celgene: Honoraria. Quintana:Celgene Corporation: Employment. Garcia:Celgene Corporation: Employment. San-Miguel:Celgene Corporation: Honoraria, Speakers Bureau.

Smoldering Multiple Myeloma: When to Observe and When to Treat?

2015 ◽  
pp. e484-e492 ◽  
Author(s):  
María-Victoria Mateos ◽  
Jesús-F San Miguel
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Correct Diagnosis ◽  
Standard Of Care ◽  
Current Standard ◽  
Smoldering Multiple Myeloma ◽  
Risk Of Progression ◽  
Bone Marrow Plasma ◽  
Risk Of Disease ◽  
Definition Of

Smoldering multiple myeloma (SMM) is an asymptomatic disorder characterized by the presence of at least 3 g/dL of serum M-protein and/or 10% to 60% bone marrow plasma cell infiltration with no myeloma-defining event. The risk of progression to active multiple myeloma (MM) is not uniform and several markers are useful for identifying patients at high risk of progression. The definition of the disease has recently been revisited and patients with asymptomatic MM at 80% to 90% of progression risk at 2 years are now considered to have MM. Although the current standard of care is not to treat, a randomized trial in patients with high-risk SMM that compared early treatment versus observation demonstrated that early intervention resulted in substantial benefits in terms of time to progression and overall survival (OS). These findings highlight the need to follow a correct diagnosis by an accurate risk stratification to plan an optimized follow-up according to the risk of disease progression.

scholarly journals Molecular Resistance Mechanisms in Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 471-471
Author(s):  
Santiago Barrio Garcia ◽  
Umair Munawar ◽  
Thorsten Stuehmer ◽  
Hermann Einsele ◽  
K. Martin Kortüm
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Disease Progression ◽  
Tp53 Mutation ◽  
Conflicts Of Interest ◽  
Clonal Selection ◽  
Tumor Therapy ◽  
Genetic Alterations ◽  
Detection Range

Abstract Mechanisms of drug resistance in Multiple Myeloma (MM) are poorly understood. Mutations and/or changes in the protein expression of the CRBN pathway and proteasome subunits have been identified to induce resistance to IMiDs and PIs. However, only few patients are affected by these alterations. To determine the specific genomic fingerprint of MM relapse we selected 57 MM patients from the CoMMpass trial (version IA11) that have genomic data of paired samples available (diagnosis/relapse). 35 of them have also sequential FISH-seq data. We focused on acquired mutations in first relapse and filtered all mutations and genetic alterations already present at diagnosis. Doing so, we found 1.274 mutations, representing an average of 23 new mutations/patient (range; 2-76). Of interest, 66% of the acquired mutations were present in a sub-clonal level (Variant read frequency (VRF) < 25%). Most common mutations include known hotspots of the RAS pathway (NRAS 12%, KRAS 7% and BRAF 4%). Notably, all 7 NRAS mutations in relapse were located at Q61K, suggesting a functional role of disease progression for this specific and known hotspot location. In total 5 of 35 cases (14%) with FISH-seq data developed a 17p13 deletion in relapse. Of these, three patients acquired a bi-allelic alteration in addition to a preexisting TP53 mutation and one developed a biallelic inactivation of TP53 (VRF = 100%), through parallel acquisition of del17p and TP53 mutation. Gain of 1q21 was observed in relapse in 5 of 35 (14%) cases, and one 1q gain was lost from diagnosis to relapse. Two cases (4%) presented mutations in IMiD treatment related genes, with two mutations in the CRBN pathway. One harbored a missense mutation in the Lenalidomide (LEN) degron sequence of IKZF3 (G159A) (VRF = 36%), known to be essential for the IMiD action in vitro, 45 months after continuous exposition to LEN . The other case presented two subclonal frameshift mutations in CUL4B (VRF = 5% and 32%), detected after more than three years of LEN containing therapy. We functionally validated in vitro LEN resistance through CRISPR/Cas9 knockout of CUL4B, suggesting a resistance inducing effect of the acquired CUL4B mutations. Six cases (11%) harbored acquired mutations in proteasome subunit genes (PSMC2, PSMC6, PSMD8, PSME4, PSMB9 (two mutations)), all of them had undergone prior proteasome inhibitor (PI) containing therapy. We validated earlier the 19S protein subunits PSMC6 and PSMC2 (KO and/or point mutations) as inducers of PI resistance in vitro, thus we hypothesize contribution to resistance induction / disease progression through these 19s mutations. Remarkably ubiquitin (E3, E2 and SUBs) and histone related genes (histones and histone methylases and deacetylases) were found mutated in 51% and 19% of the relapsed patients. Genes for drug transporters (ATP-binding cassette (ABC) and Solute Carrier (SLC) transporters) were hit in 32% of cases and genes for mucins (previously related with genotoxic agents and immunotherapy resistance) in 19%. Notably, RRBP1 presented 10 mutations in 6 patients (11%) with the mutations clustering within 30 amino-acids (aa) of exons 9 and 10 and 3 hotspots (2 patients each) in aa Q426P, K430R and Q436P. RRBP1 is involved in the binding of the ribosome to the endoplasmic reticulum (ER) and is related with the unfolded protein response and ER stress via GRP78. All the patients with RRBP1 mutations were pretreated with PI inhibitors and exhibited worst survival outcome affecting PFS (Pval<0.001) and OS (Pval=0.0016) in this limited dataset. The mutations were detected on average 433 days (range: 258-568) after diagnosis. Five of the 6 patients died on average 180 days after RRBP1 mutation detection (range: 18-446) further suggesting high risk features of such acquired mutations. In summary, we observe clonal selection of known high-risk related alterations like TP53 mutations, 17p deletions or 1q13 in early relapse data of the CoMMpass trial. Furthermore we identify RRBP1 mutations as a new acquired high-risk biomarker of MM. Alterations are specifically related to subclonal selection by therapy, thus we suggest that the definition of high-risk disease in MM needs to be revisited and should also include clonal selection processes under anti-tumor therapy. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Dynamic follow‐up of smoldering multiple myeloma identifies a subset of patients at high risk of progression

2020 ◽  
Author(s):  
Charlotte Gran ◽  
Vincent Luong ◽  
Johanna B. Bruchfeld ◽  
Johan Liwing ◽  
Gabriel Afram ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Smoldering Multiple Myeloma ◽  
Risk Of Progression

scholarly journals Genomic profiling of smoldering multiple myeloma identifies patients at a high risk of disease progression.

2019 ◽  
Vol 19 (10) ◽  
pp. e5-e6 ◽  
Author(s):  
Mark Bustoros ◽  
Romanos Sklavenitis-Pistofidis ◽  
Jihye Park ◽  
Robert Redd ◽  
Binyamin Zhitomirsky ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Disease Progression ◽  
Genomic Profiling ◽  
Smoldering Multiple Myeloma ◽  
Risk Of Disease

scholarly journals Three-Dimensional Telomere Analysis Using Teloview® Technology Identifies Smouldering Myeloma Patients with High Risk of Progression to Full Stage Multiple Myeloma in a Proof of Concept Cohort

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Sherif Louis ◽  
Aline Rangel-Pozzo ◽  
Hans Knecht ◽  
Sabine Mai
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Disease Progression ◽  
Survival Rates ◽  
Three Dimensional ◽  
Proof Of Concept ◽  
Publicly Traded ◽  
Therapeutic Modalities ◽  
Risk Of Progression ◽  
First Time

Multiple Myeloma (MM) remains incurable in spite of the recent development of several advanced therapeutic modalities. Similar to other incurable diseases, the early diagnosis and treatment of MM patients may lead to better prognosis and increased survival rates. Multiple myeloma follows two asymptomatic precursor lesions, monoclonal gammopathy of undetermined significance (MGUS) and smouldering myeloma (SMM) [1]. In current clinical practice patients diagnosed with MGUS or SMM are monitored but not treated. MGUS and SMM may progress to the full stage of multiple myeloma at any time without clinically detectable signals. While 1% of MGUS patients progress to full stage MM every year, 10% of SMM patients progress to full stage MM every year [1]. In this study, we report for the first time that the 3-dimensional telomeres analysis using the TeloView® software platform is able to identify SMM patients with high risk of progression to full stage MM. The prospective study we conducted included a proof of concept cohort of total 21 SMM patients, 16 patients that remained stable for over 5 years, and 5 patients progressed to full stage multiple myeloma within 1 to 3 years from point of diagnosis. The disease progression of high risk SMM patients was confirmed clinically by MM caused morbidity. TeloView® analysis of the 2 SMM patient-groups revealed with high significance (p &lt;0.001) distinct telomeres profiles of the stable patients versus the patients who progressed to full stage MM across 5 independent telomeric parameters measured by TeloView®. The study was conducted blindly on the diagnostic specimens suggesting the ability of TeloView® analysis to stratify SMM patients at point of diagnosis. The results we report have the potential, for the first time, to guide evidence-based decisions to treat SMM patients with high risk of progression, addressing a critical unmet clinical need in the management of MM. Follow up studies including expanded cohorts are needed to validate the results of this study, and to confirm the utility of TeloView® technology to predict the progression of SMM patients on the level of the individual patient. References: Boutros M. et al Genomic Profiling of Smouldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression. J Clin Oncol. 2020 Jul 20;38(21):2380-2389 Disclosures Louis: Telo Genomics Corp.: Consultancy, Current equity holder in publicly-traded company. Knecht:Telo Genomics Corp.: Consultancy, Current equity holder in publicly-traded company. Mai:Telo Genomics Corp.: Consultancy, Current equity holder in publicly-traded company.

Smoldering Multiple Myeloma (SMM) at High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) as Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1935-1935 ◽  
Author(s):  
María-Victoria Mateos ◽  
Lucía López-Corral ◽  
Miguel Hernández ◽  
Pilar Giraldo ◽  
Javier De La Rubia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Plasma Cells ◽  
Phase Iii ◽  
Symptomatic Disease ◽  
Smoldering Multiple Myeloma ◽  
Risk Of Progression

Abstract Abstract 1935 Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM), but no evidence of end-organ damage. There are several risk factors predicting high-risk of progression to symptomatic disease (>50% at 2 years): >10% of PCs in BM, serum MC >30g/L, >95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is close follow-up without treatment until progression disease. Several trials have evaluated the role of early treatment with convencional agents (melphalan), bisphosphonates and novel agents (thalidomide, anti-IL1a), with no clear benefit, but they didn't focus on high-risk patients. In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progresión (TTP) to symptomatic disease. The high risk population was defined by the presence of both >PC 10% and MC >30g/L or if only one criterion was present, patients must have a proportion of aberrants PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis. Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (ammended in May 2010 into monthly). The 124 planned patients were recruited between October 2006 and June 2010, and 118 were evaluables (three in Len-dex and three in therapeutic abstention arm didn't meet inclusion criteria). This second interim analysis was planned when all patients were recruited. According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 75%, including 51% PR, 12% VGPR, 5% CR and 7% sCR. If we select the group of 33 patients who completed the nine induction cycles, the ORR was 91%, including 15% VGPR, 9% CR and 9% sCR. After a median of 8 cycles of maintenance therapy (1-15), the sCR increased to 16%. After a median follow-up of 16 months (range:1-33), four patients progressed to symptomatic disease in the Len-dex arm: two of them during maintenance therapy after 24 and 28 months from inclusion and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, nine patients have developed biological progression during maintenance, but in all but one of these, Len has been able to control the disease without CRAB symptoms (median of 9·5 months (1-18)). In the therapeutic abstention arm, 21 out of 61 patients progressed to active MM. The estimated hazard ratio was 6·7 (95%CI= 2·3-19·9), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p<0.0001). It should be noted that 10 out of these 21 patients developed bone lesions as a symptom of active MM. Deaths in the Len-dex and no treatment arms were 1 and 2, respectively (p=0·6). As far as toxicity is concerned, during induction therapy, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 4 patients G3 asthenia 2 patients G3 diarrhea and 1 patient G3 skin rash; 3 patients developped G2 DVT. During maintenance, no G4 AEs were reported and only 1 patient developed G3 infection. In conclusion, this second interim analysis shows that in high-risk SMM patients, delayed treatment resulted in early progression to symptomatic disease (median 25 months), while Len-dex as induction followed by Len as maintenance significantly prolonged the TTP (HR: 6·7), with excelent tolerability; moreover, biological progressions occurring under maintenance have remained controlled over a prolonged period of time. Disclosures: Mateos: Celgene: Honoraria. Off Label Use: Lenalidomide is not approved for the treatment of smoldering multiple myeloma. De La Rubia:Celgene: Honoraria. Rosiñol:Celgene: Honoraria. Lahuerta:Celgene: Honoraria. Palomera:Celgene: Honoraria. Oriol:Celgene: Honoraria. Garcia-Laraña:Celgene: Honoraria. Hernández:Celgene: Honoraria. Leal-da-Costa:Celgene: Honoraria. Alegre:Celgene: Honoraria. Quintana:Celgene: Employment. Baquero:Celgene: Employment. García:Celgene: Honoraria. San Miguel:Celgene: Honoraria.

scholarly journals International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)

2020 ◽  
Vol 10 (10) ◽  
Author(s):  
María-Victoria Mateos ◽  
Shaji Kumar ◽  
Meletios A. Dimopoulos ◽  
Verónica González-Calle ◽  
Efstathios Kastritis ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
High Risk ◽  
Risk Stratification ◽  
Low Risk ◽  
Intermediate Risk ◽  
Smoldering Multiple Myeloma ◽  
Risk Stratification Model ◽  
Risk Of Progression ◽  
Progression Risk

Abstract Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2–3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable.

Sign in / Sign up

Export Citation Format

Share Document