Treatment of Smoldering Multiple Myeloma: Ready for Prime Time?

The current standard of care for smoldering multiple myeloma (SMM) is observation until there is end-organ involvement. With newer and more effective treatments available, a question that is increasingly asked is whether early intervention in patients with SMM will alter the natural history of their disease. Herein, we review the evolving definition of SMM and risk stratification models. We discuss evidence supporting early intervention for SMM—both as a preventative strategy to delay progression and as an intensive treatment strategy with a goal of potential cure. We highlight ongoing trials and focus on better defining who may require early intervention.

Download Full-text

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

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2015.35.e484 ◽

2015 ◽

pp. e484-e492 ◽

Cited By ~ 5

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.

Download Full-text

E3A06: Randomized phase III trial of lenalidomide versus observation alone in patients with asymptomatic high-risk smoldering multiple myeloma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8001 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8001-8001 ◽

Cited By ~ 5

Author(s):

Sagar Lonial ◽

Susanna J. Jacobus ◽

Matthias Weiss ◽

Shaji Kumar ◽

Robert Z. Orlowski ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Phase Ii ◽

Imaging Techniques ◽

Single Agent ◽

Standard Of Care ◽

Phase Iii ◽

Rank Test ◽

Current Standard ◽

Smoldering Multiple Myeloma

8001 Background: Smoldering multiple myeloma (SMM) is a precursor to myeloma, wherein current standard of care is observation (obs). Data from a randomized Spanish trial (Mateos et al, NEJM 2015) suggest that lenalidomide(len)/dexamethasone improves time to developing myeloma (TTP) and overall survival (OS) for patients (pts) with high risk (HR) SMM over obs. However, pts were not screened with advanced imaging techniques, used a HR definition that is not routinely available, and combination therapy limited the ability to isolate the effect of len, and thus has not become standard of care. Methods: E3A06 is a randomized phase III intergroup trial, testing the effect of single agent len compared with obs for pts with intermediate or high risk SMM. In an initial phase II run in all pts received len to demonstrate safety. Eligibility required ≥10% PCs and abnormal serum FLC ratio (<0.26 or >1.65). The primary endpoint was progression PFS was estimated by the Kaplan-Meier method and compared using the one-sided stratified log-rank test. Results: PII enrolled 44 pts and PIII randomized 182 pts to either len (n=90) or obs (n=92) [stratified on time since SMM diagnosis ≤1y vs >1y]. Baseline characteristics were similar between the arms. 80% (PII) and 51% (PIII) are off len, primarily due to adverse events (AE) or pt withdrawal. Among the len treated pts, G3/4 non-hematologic AE occurred in 28% of PIII pts with fatigue being most common (n=5). G4 hematologic AE rate was 5.7%, primarily neutropenia (n=4). 3-year cumulative incidence of invasive SPMs was 5.2% (len) and 3.5% (obs). Overall response rate was 47.7% for the phase II study, and in phase III, 48.9% for the len arm, and 0% for the obs arm. Median follow up was 71 months (PII), and 28 months (PIII). 3-year PFS was 87% for the PII cohort. One, 2 and 3-year PFS was 98%, 93%, and 91% for len, and 89%, 76%, and 66% for the obs arm (HR 0.28, p=0.0005) favoring the len arm. No difference in QOL score was noted between arms. Conclusions: Overall, this trial represents the largest randomized trial in SMM to date. In conjunction with the Spanish data, this trial may support a change in clinical practice. Clinical trial information: NCT01169337. [Table: see text]

Download Full-text

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies

Blood ◽

10.1182/blood-2011-01-270140 ◽

2011 ◽

Vol 117 (21) ◽

pp. 5573-5581 ◽

Cited By ~ 110

Author(s):

Neha Korde ◽

Sigurdur Y. Kristinsson ◽

Ola Landgren

Keyword(s):

Multiple Myeloma ◽

Early Treatment ◽

Monoclonal Gammopathy ◽

Treatment Strategies ◽

Standard Of Care ◽

Current Standard ◽

Smoldering Multiple Myeloma ◽

Molecular Events ◽

Unknown Significance ◽

Risk Of Progression

Abstract Monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic plasma cell dyscrasias, with a propensity to progress to symptomatic MM. In recent years there have been improvements in risk stratification models (involving molecular markers) of both disorders, which have led to better understanding of the biology and probability of progression of MGUS and SMM. In the context of numerous molecular events and heterogeneous risk of progression, developing individualized risk profiles for patients with MGUS and SMM represents an ongoing challenge that has to be addressed by prospective clinical monitoring and extensive correlative science. In this review we discuss the current standard of care of patients with MGUS and SMM, the use of risk models, including flow cytometry and free-light chain analyses, for predicting risk of progression. Emerging evidence from molecular studies on MGUS and SMM, involving cytogenetics, gene-expression profiling, and microRNA as well as molecular imaging is described. Finally, future directions for improving individualized management of MGUS and SMM patients, as well as the potential for developing early treatment strategies designed to delay and prevent development of MM are discussed.

Download Full-text

Similar Incidence of Typhlitis in Patients Receiving Various Doses of Daunorubicin or Idarubicin As Induction for Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.3725.3725 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3725-3725

Author(s):

Amanda N Seddon ◽

Angela G Michael ◽

Nelly G. Adel ◽

Martin S. Tallman ◽

Oguz Akin ◽

...

Keyword(s):

Clinical Symptoms ◽

Conflicts Of Interest ◽

Standard Of Care ◽

Adult Patients ◽

Cell Transplant ◽

Current Standard ◽

Ileocecal Region ◽

Concomitant Infection ◽

Potential Factors ◽

Definition Of

Abstract Background: The current standard of care for the treatment of patients with newly diagnosed AML is an anthracycline plus cytarabine. Both anthracyclines and cytarabine have been associated with the development of typhlitis, a serious adverse event characterized by inflammation of the bowel wall in patients with profound neutropenia, diagnosed via abdominal CT imaging and clinical symptoms. Given the paucity of available data, the aim of our study was to determine the incidence of typhlitis among AML patients receiving induction with either idarubicin 12 mg/m2 (IDA), daunorubicin 60 mg/m2 (DNA60), or daunorubicin 90 mg/m2 (DNA90). Methods: Adult patients with AML or MDS receiving either daunorubicin or idarubicin along with cytarabine as part of their induction regimen between 1/1/2009 and 6/30/2013 were included. A definition of typhlitis required CT confirmation of inflammation of the cecum, according to CTCAE version 4.03 along with clinical symptoms. Two radiologists (OA, JC) blinded to the treatment and outcomes independently reviewed CT scans. Two additional definitions including inflammation of the ileocecal region only and enterocolitis were also evaluated. All statistical analyses were performed on SAS software version 9.3. P values were calculated using Fisher Exact and Wilcoxon tests. Inter-rater reliability was assessed with Cohen’s Kappa. Results: Baseline characteristics were similar among the 3 treatment groups with the exception of age. The median age was lower in the DNA90 arm (79 years, 74 years, and 49 years in the IDA group, DNA60 group, and DNA90 group, respectively). A pre-existing GI disorder was reported in 24.1% IDA, 25.7% DNA60, and 22.4% DNA90 patients. Of the 202 total patients, the two radiologists determined that 40 (20%) and 38 (19%) developed typhlitis, based on the predefined standard. Tables 1 and 2 illustrate the relationship between treatment arm and associated incidence of typhlitis. The incidence in each treatment group did not statistically differ (p=0.23 and p=0.29). When the definition was broadened to include ileocecal region and enterocolitis, the incidence increased (Tables 1 and 2). The inter-reliability ratings of the 2 radiologists’ evaluations for each definition indicated substantial agreement (0.803 cecum, 0.834 ileocecal region only, and 0.752 enterocolitis). Neither the anthracycline chosen, nor the dose had a statistically significant impact on the incidence of typhlitis. Of all patient and treatment specific risk factors assessed for association with development of typhlitis (pre-existing GI disorder, rheumatologic disorder or cancer, prior RT, stem cell transplant or anthracycline exposure, cytarabine regimen or AML risk group), none were found to be statistically significant. In patients that developed typhlitis, approximately 56% and 51% had a concurrent documented infection around the typhlitis episode (Tables 1-2). Conclusion: To our knowledge, this is the first study to compare the incidence of typhlitis in adult patients receiving idarubicin or daunorubicin for the treatment of AML. While the cumulative incidence of typhlitis was higher than in published literature, the incidence was similar irrespective of the anthracycline chosen or dose. Of the potential factors that may have contributed to the development of typhlitis, none were significantly associated with typhlitis. All patients were managed conservatively with broad-spectrum antibiotics. A more definitive definition of typhlitis may help clinicians identify affected patients sooner and choose appropriate targeted therapy. Abstract 3725. Table 1. Association of treatment to Radiologist 1-rated typhlitis Enterocolitis Ileocecal region only Cecum No Yes P No Yes P No Yes P Treatment 0.52 0.68 0.23 DNA60 58 (78%) 16 (22%) 58 (78%) 16 (22%) 61 (82%) 13 (18%) DNA90 34 (69%) 15 (31%) 35 (71%) 14 (29%) 35 (71%) 14 (29%) IDA 58 (73%) 21 (27%) 60 (76%) 19 (24%) 66 (84%) 13 (16%) Concomitant infection Yes 11 (26%) 32 (74%) 13 (30%) 30 (70%) 19 (44%) 24 (56%) Abstract 3725. Table 2. Association of treatment to Radiologist 2-rated typhlitis Enterocolitis Ileocecal region only Cecum No Yes P No Yes P No Yes P Treatment 0.86 0.98 0.29 DNA60 57 (77%) 17 (23%) 57 (77%) 17 (23%) 62 (84%) 12(16%) DNA90 36 (73%) 13 (27%) 37 (76%) 12 (24%) 36 (73%) 13 (27%) IDA 58 (73%) 21 (27%) 61 (77%) 18 (23%) 66 (84%) 13 (16%) Concomitant infection Yes 11 (26%) 32 (74%) 13 (30%) 30 (70%) 21 (49%) 22 (51%) Disclosures No relevant conflicts of interest to declare.

Download Full-text

Monoclonal gammopathies of undetermined significance and smoldering myeloma

Acta Haematologica Polonica ◽

10.2478/ahp-2020-0035 ◽

2020 ◽

Vol 51 (4) ◽

pp. 193-202

Author(s):

Artur Jurczyszyn ◽

Ruth Hutch ◽

Anna Waszczuk-Gajda ◽

Anna Suska ◽

Katarzyna Krzanowska ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Standard Of Care ◽

Current Standard ◽

Malignant Plasma Cell ◽

Plasma Cell Disorder ◽

Smoldering Myeloma ◽

Cell Disorder ◽

Undetermined Significance

AbstractMonoclonal gammopathy of undetermined significance (MGUS) is a clonal plasma cell disorder implicated as a precursor of multiple myeloma (MM), while smoldering multiple myeloma (SMM) is a malignant plasma cell disorder without evidence of a myeloma-defining event(s) (MDE). This is a review article of both disorders outlining their current definition and management according to the current standard of care. We focus on the pathogenesis of MM and the role of MGUS and SMM in the development of active MM. MGUS is a benign disorder and, subsequently, is followed by observation. In contrast, for SMM, although the current standard of care is “watch and wait”, this paper will explore the circumstances in which treatment should be considered to prevent MDE.

Download Full-text

Moving Beyond Gleason Scoring

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2018-0242-ra ◽

2019 ◽

Vol 143 (5) ◽

pp. 565-570 ◽

Cited By ~ 3

Author(s):

Brian Miles ◽

Michael Ittmann ◽

Thomas Wheeler ◽

Mohammad Sayeeduddin ◽

Antonio Cubilla ◽

...

Keyword(s):

Biochemical Recurrence ◽

Host Response ◽

Cancer Survival ◽

Predictive Ability ◽

Standard Of Care ◽

Molecular Data ◽

Current Standard ◽

Reactive Stroma ◽

Response Measures ◽

Definition Of

Context.— The combination of grading and staging is the basis of current standard of care for prediction for most cancers. D. F. Gleason created the current prostate cancer (PCa) grading system. This system has been modified several times. Molecular data have been added. Currently, all grading systems are cancer-cell based. Objective.— To review the literature available on host response measures as reactive stroma grading and stromogenic carcinoma, and their predictive ability for PCa biochemical recurrence and PCa-specific death. Data Sources.— Our own experience has shown that reactive stroma grading and the subsequently binarized system (stromogenic carcinoma) can independently predict biochemical recurrence and/or PCa-specific death, particularly in patients with a Gleason score of 6 or 7. Stromogenic carcinoma has been validated by 4 other independent groups in at least 3 continents. Conclusions.— Broders grading and Dukes staging have been combined to form the most powerful prognostic tools in standard of care. The time has come for us to incorporate measures of host response (stromogenic carcinoma) into the arsenal of elements we use to predict cancer survival, without abandoning what we know works. These data also suggest that our current definition of PCa might need some revision.

Download Full-text

Peripheral Blood Stem Cell (PBSC) Harvest Is More Expensive Following Bortezomib-Based Therapy in Multiple Myeloma (MM), Related to Increase Number of Days of Collect.

Blood ◽

10.1182/blood.v114.22.1373.1373 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1373-1373

Author(s):

Matthieu Barthelemy ◽

Florence Boulanger ◽

Houria Debarri ◽

Laurent Pascal ◽

Pierre Samarcq ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Induction Therapy ◽

Young Patients ◽

Standard Of Care ◽

Induction Treatment ◽

High Dose ◽

Front Line ◽

History Of ◽

The Cost

Abstract Abstract 1373 Poster Board I-395 Background: High-dose therapy is the front line treatment of reference in young patients with Multiple Myeloma (MM). Although induction therapy remains a matter of controversy, bortezomib-based therapy is considered more and more as a standard of care. Prior to autologous stem cell transplantation (ASCT), patients undergo PBSC collect, usually starting after cycle 2 to 4 of the induction treatment. Currently, patients receive one transplant at front line, but most of the patients will benefit throughout the MM disease history of a second or a third ASCT procedure. We have noticed that the number of days of collection vary from patient-to-patient following bortezomib-based induction therapy. This increase in collection procedures might increase the cost of PBSC harvest with more patients discomfort and staff unavailability. We have therefore further studied the quality, yields and days of collection in myeloma patients following bortezomib-based therapy as compared to other regimens-based treatment courses. Material and Method: We retrospectively studied 70 patients with myeloma that underwent PBSC harvestsafter mobilization with GCSF following debulking with bortezomib-based therapy (58 days of procedures – 26 patients) versus other agents-based therapy [65 days of procedure – 44 patients; VAD vincristine, adriamycin, dexamethasone). Results: -Yields. CD34 Mobilization is lower following bortezomib-based therapy as compared to other regimen-based therapy. Similarly, more days of collection are also needed to collect the requested yield of PBSC. -Engrafment. No significant differences regarding engraftment was noticed among the 2 groups studied. The days to neutrophil and platelet counts recovery, the number of days with fever and the number of red cell and platelet transfusions were not significantly different between the 2 groups, mobilization following bortezomib-based therapy versus other regimen-based therapy, respectively. Conclusion: In our series, bortezomib-based induction regimen does not increase the number of PBSC harvest failure and the quality of engraftment was identical to other regimen-based induction treatment. However, CD34 mobilization was lower following bortezomib-based therapy, which explains lower daily harvest counts and therefore an increase number of days of collection in bortezomib-based treated patients. Therefore, PBSC harvest procedure following bortezomib-based therapy significantly increases the cost of PBSC collection. These results need to be confirmed in larger studies. New agents in use for mobilization might be considered for future PBSC collection in bortezomib-based treated patients. Disclosures: Leleu: Janssen Cilag: Research Funding.

Download Full-text

The PI3K Inhibitor GDC-0941 Synergizes with Standard of Care Therapies to Induce Growth Inhibition and Apoptosis of Multiple Myeloma Cells.

Blood ◽

10.1182/blood.v114.22.3788.3788 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3788-3788

Author(s):

Veerendra Munugalavadla ◽

Leanne Berry ◽

Changchun Du ◽

Sanjeev Mariathasan ◽

Dion Slaga ◽

...

Keyword(s):

Multiple Myeloma ◽

Research Funding ◽

Single Agent ◽

Standard Of Care ◽

Rational Approach ◽

Current Standard ◽

Employment Equity ◽

Specific Flow ◽

Equity Ownership

Abstract Abstract 3788 Poster Board III-724 Multiple myeloma (MM) is a malignancy characterized by clonal expansion and accumulation of long-lived plasma cells within the bone marrow. Phosphatidylinositol 3' kinase (PI3K) -mediated signaling is frequently dysregulated in cancer and controls fundamental cellular functions such as cell migration, growth, survival and development of drug resistance in many cancers, including MM, and therefore represents an attractive therapeutic target. Here, we demonstrate in vitro, that a potent and selective pan-isoform PI3Kinhibitor, GDC-0941, modulates the expected pharmacodynamic markers, inhibits cell-cycle progression and induces apoptosis; overcomes resistance to apoptosis in MM cells conferred by IGF-1 and IL-6; and is additive or synergistic with current standard of care drugs including dexamethasone, melphalan, lenolidamide and bortezomib. In cell lines we find sensitivity to GDC-0941 is positively correlated with pathway activation as determined by phospho-AKT-specific flow-cytometry and Western-blot analysis. Preliminary results indicate apoptosis of MM cells is correlated with increased expression of the proapoptotic BH3-only protein BIM; mechanisms of increased apoptosis in MM will be further explored and an update presented. We further extend these in vitro findings to show that GDC-0941 has activity as a single agent in vivo and combines well with standard of care agents in several murine xenograft models to delay tumor progression and prolong survival. Our results suggest that GDC-0941 may combine well with existing therapies, providing a framework for the clinical use of this agent, and a rational approach to improving the efficacy of myeloma treatment. Disclosures: Munugalavadla: Genentech: Employment, Patents & Royalties. Berry:Genentech: Employment, Patents & Royalties. Du:Genentech, Inc.: Employment, Equity Ownership. Mariathasan:Genentech: Employment, Patents & Royalties. Slaga:Genentech: Employment, Patents & Royalties. Sun:Genentech Inc.: Employment. Chesi:Genentech, Inc.: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Bergsagel:Genentech: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Ebens:Genentech, Inc.: Employment, Equity Ownership, Patents & Royalties.

Download Full-text

Comparison of three different serum-free light-chain assays—implications on diagnostic and therapeutic monitoring of multiple myeloma

Blood Cancer Journal ◽

10.1038/s41408-019-0267-8 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Aneta Schieferdecker ◽

Sebastian Hörber ◽

Monika Ums ◽

Britta Besemer ◽

Carsten Bokemeyer ◽

...

Keyword(s):

Multiple Myeloma ◽

Standard Of Care ◽

Therapeutic Monitoring ◽

Assay Method ◽

Serum Free ◽

Serum Free Light Chain ◽

Single Center Study ◽

Serum Free Light Chains ◽

Definition Of

AbstractThe measurement of serum-free light chains (FLC) is standard of care in the diagnosis and management of multiple myeloma (MM). The revised international myeloma working group (IMWG) implemented the involved FLC/noninvolved FLC (iFLC/niFLC) ratio as a biomarker for MM requiring treatment. Recently, a new definition of high-risk smoldering MM (SMM) including iFLC/niFLC ratio was published. These recommendations were solely based on a single assay method (Freelite assay). Today, two additional assays, N Latex FLC and ELISA-based Sebia FLC, are available. Here, we report on a single-center-study comparing results of all three different assays for FLC correlation and its potential implications for diagnostic and clinical use. In total, 187 samples from 47 MM patients were examined, and determination of FLC was performed. Comparison analyses showed similar FLC results for Sebia FLC and N Latex FLC assay with markedly lower absolute values for κ/λ ratio compared with Freelite. Values of λ FLC exhibited high variability. The ratio of iFLC/niFLC showed significant discrepancies among these assays. Our data demonstrate that the three available assays may result in markedly discrepant results, and should not be used interchangeably to monitor patients. Furthermore, modifications of the assay-specific diagnostic (iFLC/niFLC) thresholds for SMM and MM are recommended.

Download Full-text