Fonseca, Rafaël

Abstract Background Waldenström macroglobulinaemia (WM) is an uncommon indolent B-cell lymphoproliferative characterized by bone marrow infiltration by lymphoplasmacytic cells and an IgM paraproteinemia. This study analyzed the impact of cytogenetics in WM and the pattern of evolution in 73 cases from the Mitelman database and 14 cases evaluated at the Mayo Clinic Arizona (MCA). Patients and Methods The Mitelman database of Chromosome aberrations in cancer (Mitelman et al., 2007) was searched, and 73 WM karyotypes were selected. We also evaluated 14 cases seen at MCA with karyotype analysis at diagnosis. An Excel spreadsheet in which the rows of the first column were labeled to represent each band of a 360-band human chromosome ideogram was created as previously described (Hoglund et al., 2001; Horsman et al., 2003) All karyotypes were scored individually in successive columns for net gain and loss of each chromosome band (loss=0 and gain=1). Recurrent abnormalities were defined as those that were involved in >5% of cases. Histograms of the number of abnormalities per tumor (NAPT) were then plotted, and the modal value extracted as variable called time to occurrence. Statistics correlation between the presence and absence of different abnormalities was analyzed using Spearman correlation matrices. P value of <0.05 was considered as statistical significan Results In total 73 cases of newly diagnosed WM from the Mitelman database were included in the analysis. The median chromosome number was 46 (Range 40 to 49).The most common abnormalities were loss of 6q21 (10%) (Fig 1), +3 (7.1%), loss of X (6%) and −10, −20, −21, +12, +18 and +5 (5.71% respectively). The most common translocation was t(8;14) (4%).The most recurrent breakpoints in our series include: 14q32 (6%), 6q21 (5%), 8q24 (5%), 18q21 (4%) and 19q13 (4%). In the MCA cohort, 14 karyotypes were reviewed and only 3 cases exhibited an abnormal result. Deletion of 6q21, 20q11 and a Robertsonian translocation t(13;14) were reported (3/11, 21%). In the 6q21 case, FISH analysis confirmed the deletion of BLIMP1 on 6q. One case exhibited a 20q deletion in a WM with kidney amyloidosis patient. Discussion In this comprehensive analysis we show a very small complexity of recurrent abnormalities expressed by conventional karyotype analysis in WM. The incidence of 6q21 deletion was 10% by conventional cytogenetics and it is been reported as high as 34% when analysed by FISH (54% when cytoplasmic immunoglobulin M-FISH was used). Interestingly we report the case of a patient with 20q deletion at diagnosis in the MCA cohort. To date, only a limited number of cases with del(20q) as a sole cytogenetic anomaly have been reported in plasma cell dyscrasias, either at diagnosis or later in the disease course. The recurrent immunoglobulin gene translocation is known to be involved in the initial oncogenetic events in plasma cell dyscrasias and, so it is important to identify whether there are any masked translocations involving immunoglobulin genes and 20q in these cases. Figure 1. 6q21 deletion and Waldenstrom Macroglobulinaemia Figure 1. 6q21 deletion and Waldenstrom Macroglobulinaemia

Abstract Genetic abnormalities are important in the pathobiology of myeloma and established prognostic factors. High-density aCGH allow global unbiased detection of genomic gains and losses. In this study, we attempt to identify survival critical genomic aberrations by correlating aCGH-defined abnormalities with survival in 2 different cohorts of patients. aCGH was performed in 64 MM patients treated with high dose therapy from the Mayo Clinic using Agilent’s 44k DNA microarray genechip. In addition, a publicly available aCGH dataset performed in 67 MM patients treated with total therapy from the University of Arkansas Medical School using the lower density Agilent 22k chip (Human 1A v2) was also analyzed. Base 2 logarithms of the ratios between red and green intensities (log-ratios) were treated as a primary measure of copy number ratio between tumor and normal samples. To detect the regions of genomic aberration, values of a sliding window of 15 consecutive log-ratios were compared with those of an artificial ‘reference’ chromosome using the Wilcoxon rank sum test. The reference chromosome, constructed for each sample, was assembled by collecting log-ratio values close to zero. For this, 15 randomly sampled log-ratios from autosomal regions whose p-value of Wilcoxon signed rank test against 0 was larger than 0.05 were recursively accepted until the number of log-ratios in the assembled reference chromosome reached 1000. The p-values and their corresponding false discovery rates (q-values) for the copy number gain or loss were calculated independently for each sliding window and assigned to the center position of corresponding sliding window. The survival difference was examined between samples that had gained or lost a chromosomal region (sliding window) and samples that had not using the method of Kaplan-Meier and the statistical significance was assessed by the log-rank test. The sliding window was identified as gained or lost if P-value < 10 −4 and Q-value < 10[suo]-3. Sliding windows whose gains or losses led to poor survival with log-rank test p-value < 0.5, corresponding q-value < 0.5, and happened to ≥ 10% of all samples were retained. Several regions of genomic gains and losses were significantly associated with poorer survival with 5 deletion hotspots common between the 2 datasets (Table). We validated the prognostic significance of these survival critical loci using FISH in an independent dataset of 169 patients treated with high dose therapy. Clustering of these survival critical loci revealed clusters of MM characterized by low, intermediate or high number of these abnormalities, which are independent of ploidy and translocations subtypes. These subgroups have significantly different survival. In addition, the clustering analysis suggests the chromosome 13 loss is an early event whereas chromosome 1 abnormalities are late events. Our strategy therefore identified novel regions of genomic aberration that are important prognostically. However, it is likely that these regions are manifestation of genomically unstable tumors with complex abnormalities that have poorer prognosis. Chr Start End Length Cytoband 1 74,137,824 75,972,544 1,834,720 p31.1 1 62,433,123 84,792,809 22,359,686 p31.3 – p22.3 20 4,100,452 6,189,410 2,088,958 p13 – p12.3 20 6,717,170 13,142,205 6,425,035 p12.3 – p12.1 20 4,708,668 10,566,333 5,857,665 p13 – p12.2

Abstract INTRODUCTION The bone marrow plasma cell labeling index (PCLI) and the beta 2 microglobulin (β2M) when combined provide a powerful staging system highly predictive of outcomes in myeloma patients (Greipp et. al., Blood, 81:3382–87, 1993). This staging system lacks information on cytogenetics and it has been demonstrated that deletion 13 (Δ13) by conventional cytogenetics is associated with poor outcomes. In conventionally treated patients Δ13 by FISH is an independent prognostic variable. We analyzed the importance of Δ13 by FISH in a cohort of patients receiving high dose therapy and assessed its value relative to known prognostic parameters, PCLI and β2M. PATIENTS AND METHODS 238 patients undergoing high dose therapy between January 1990 and September 2001 were studied. The minimum follow-up of patients was 34 months. The median age of the cohort 56 years. Interphase fluorescence in situ hybridization with Probes LSI13/D13S319 was performed with simultaneous immunofluorescent detection of bone marrow plasma cells by the presence of cytoplasmic immunoglobulin. PCLI was done by a slide-based immunofluorescence method with antibodies to bromodeoxyuridine. RESULTS Of the 238 patients studied 215 had a successful FISH analysis and 212 of these had a bone marrow labeling index. Deletion 13 was absent in 104 patients (48%) and present in 111 patients. The overall survival and time to progression for patients lacking and having deletion 13 was 47.8 vs 26.4 (OS) and 19.0 vs 11.7 (TTP)months respectively. A Cox model was constructed with the PCLI, the presence or absence of deletion 13 and serum β2M. Although all three variables were independently predictive of survival and time to progression, the β2M was the weakest of these three variables. The hazard function for survival for PCLI, deletion 13 and β2M was 1.4, 1.6 and 1.1 respectively. A staging system was constructed assigning 1 point for the presence of deletion 13 or a PCLI ≥ 1%. Patients fell into 3 categories of 0 points (N=69), 1 point (N=104) and 2 points (N=39). The overall survival for the three groups respectively were 56.5, 36.6 and 13.7 months (figure). The time to progression for the three groups were 22.3, 15.4 and 8 months (P<0.001). When analysis was limited to those patients transplanted within 12 months of diagnosis the results remained significant (P<0.003) with median survivals of stage 0, 1 and 2 of 72.5, 59.1 and 15.4 months respectively. TTP for stage 0, 1 & 2 in this same cohort of patients transplanted < 12 mos after diagnosis is 30.6, 21.5 & 8.2 months respectively. CONCLUSION Deletion 13 by FISH is an independent predictor of survival and time to progression providing information independent of the β2M and the PCLI. Combining the PCLI with FISH del 13 identifies patients who following transplant have a median time to progression of 8 months and a median OS of 13.7 months. This group may not benefit from autologous transplant and are candidates for novel therapeutic approaches. Figure Figure

Abstract Events mediating transformation from the pre-malignant MGUS to MM is largely unknown. Previous studies have highlighted RAS mutation as a progression event. However, this abnormality is present in only a small subset of patients. Global gene expression differences between MGUS and MM have been reported but provided little coherent biological insights. To define progression events, we examined the differences in gene expression profiles (GEP, Affymetrix U133A genechip) between 101 MM and 22 MGUS using a powerful functional genomic tool, Gene Set Enrichment Analysis (Subramanium et al PNAS 2005), that allow extraction of biological information based on enrichment of genes associated with a phenotype within gene-sets derived experimentally or extracted from database. We found that a predominant theme relating to MM progression is the over-expression of proliferation related genes in MM highlighted by the enrichment of cell cycle related gene-sets. Another common theme is the enrichment of gene-sets relating to MYC activation. Seven of eight gene-sets related to MYC activation in the database are significantly enriched (p-value <0.05 and false detection rate <0.05). Leading edge (enriched genes) analysis of enriched MYC-related and proliferation-related gene-sets revealed a core, overlapping signature of 8 genes specific to MYC and not proliferation. These genes are further verified as MYC transcriptional targets using Metacore, a network analysis tool. In addition, 7 of the 8 genes had been validated as MYC target genes by chromatin immunoprecipitation previously (www.myccancergene.org). We validated this signature in independent publicly available cell lines and mouse gene expression experiments where this signature is present in mammary epithelial cell lines engineered to over-express MYC but not E2F3, SRC and BCAT, and mouse embryonic fibroblast over-expressing MYC but not HER2 or with RB knocked-out. In addition, analysis of proliferation index in these datasets showed that there is dissociation of proliferation from this signature. This showed conclusively that our signature is MYC specific and not related to proliferation. Of interest, the signature is also present in cell lines with activating RAS mutation, which also have high expression of MYC, suggesting that MYC activation is a downstream effect of activated RAS signaling. Indeed, in our patient cohort, most patients with RAS mutation express this signature. When applied to 2 large GEP MM patient cohorts, this signature was not present in normal plasma cells, rarely present in MGUS, and present in a significant proportion of MM and almost all the human myeloma cell lines. When analyzed in the context of other B-cell malignancies, the signature is very strong in Burkitt’s lymphoma, present in most myeloma but absent in chronic lymphocytic leukemia, Waldenstrom Macroglobulinemia, and normal B-cells. Our analysis therefore suggests that MYC activation may be a unifying pathological event in MGUS to MM progression. As MYC translocations occur in only about 13% of newly diagnosed MM patients, activating RAS mutations and other trans-mechanisms may mediate MYC activation. Our recent demonstration that sporadic MYC activation in a mouse strain prone to monoclonal gammopathy led to MM development provides important functional proof.

Abstract The use of high-resolution aCGH allows for whole genome screening for copy number changes even in tumors that rarely produce metaphase spreads. The aim of this study was to characterize the aCGH findings in B-CLL, lung MALT lymphoma, Waldenström’s Macroglobulinemia (WM), Multiple Myeloma (MM) and human myeloma cell lines (HMCLs). This study includes 301 B-cell malignancy samples (19 B-CLL, 19 MALT, 20 WM, 48 HMCLs and 195 MM) and an additional 76 melanoma samples. We found MM to have the highest number of abnormalities per karyotype, with 15.8±7.5 (mean ± SD) and 20.6±17.0 in hyperdiploid (H) and non-hyperdiploid MM (NH), respectively. The remaining diseases have a significantly lower number of abnormalities: 5.5±4.5 in B-CLL, 3.5±1.96 in MALT and 4±3.5 in WM. Aneuploidy and biallelic deletions were rare events in these three diseases. B-CLL has two highly recurrent abnormalities involving 11q22-q23 (29%) and 13q14.3 (33%). A minimal deleted region (MDR) of ∼108Kb was identified at 11q comprising ACAT1, NPAT and ATM. In 13q, a 280Kb MDR was recognized, including TRIM13, KCNRG, mir-15a and mir-16. The subgroup of MALT patients with t(11;18) had very few abnormalities and the majority are a consequence of unbalanced translocations (MALT, BIRC2 and BIRC3 deletions). In the remaining MALT samples, trisomy 3 and 18q gain were the most common abnormalities (31% each). The 6q16.3-q26 deletion was the most common abnormality in WM (45%). In 4 of 9 patients with 6q deletion there was an associated 6p gain. The same observation was found in 2 of 3 patients with 8p loss and concomitant 8q gain. Interestingly, 6p and 8q gain were not identified in patients without 6q and 8p deletions. Deletion of 17p was the most common recurrent abnormality observed in our panel of B-cell cancers, being identified in MM, WM and B-CLL. In B-CLL and WM, small mono and biallelic deletions of the NF-kB negative regulators, TRAF3 and NFKBIA, were identified, suggesting a potential involvement of this pathway in the pathogenesis of these diseases. Hierarchical clustering of the aCGH data in MM identified 3 distinct groups, NH-MM, H-MM and MM with deletions of chromosome 13 and 14. Interestingly, MGUS and SMM were more commonly clustered with H-MM. Several sub-clusters were observed in the H-MM group, the most prominent being made up exclusively of patients from TC class D1. This cluster was characterized by the presence of trisomy 11 and 21. The 11q13 TC group clustered and was highly associated with 11q amplifications due to unbalanced t(11;14). The 6q deletion defined a cluster with WM, MM and Melanoma patient with that abnormality. In the case of B-CLL and MALT, the only identifiable clusters were observed in cases with 13q loss and trisomy 3, respectively. These results highlight both, the common and unique aCGH findings in several B-cell cancers. By hierarchical clustering, MM was significantly divergent from the rest of the B-cell diseases. Due to the limited number of abnormalities in B-CLL/MALT/WM, the clustering of these groups was exclusively based on the common abnormalities. The use of aCGH has refined the MDRs of 11q and 13q in B-CLL. Additionally, the identification of deletions affecting the NF-kB pathway in B-CLL and WM has prompted us to hypothesize on the importance of constitutive NF-κB activation in these diseases.

Abstract MM is characterized by widespread genomic instability. Two broad genetic subtypes of MM defined by ploidy exist. Hyperdiploid MM (H-MM) is characterized by trisomies of chromosome 3, 5, 7, 9, 11, 15, and 19, and generally lacked primary translocations involving the immunoglobulin heavy chain locus (IgH) whereas the non-hyperdiploid MM (NH-MM) is characterized by primary IgH translocations such as t(11;14), t(4;14) and t(14;16). Using high-density array comparative genomic hybridization (aCGH, Agilent 44K array), we catalogued the different aberrations on each chromosome arm and also the total number of aberrations per tumor (NAPT), as an indication of the degree of genomic instability, in a large cohort of 194 MM patients. Both H-MM and NH-MM have high number of genomic aberrations, 15.8±7.5 (mean ± standard deviation) versus 20.6±17.0 respective. NH-MM has significantly more genomic losses (11.8±11.0 versus 4.1±3.8), whereas H-MM has slightly more genomic gains (11.7±5.0 versus 8.8±9.0). Most of the abnormalities in NH-MM are structural abnormalities whereas they are mainly whole chromosome abnormalities in H-MM. Based on these abnormalities, we cluster the patients using hierarchical clustering. The 2 main branch of the resulting dendogram delineate hyperdiploid and non-hyperdiploid patients. Sub-clusters of each ploidy subtype are apparent. For H-MM, a cluster with mainly trisomies, including that of chromosome 21, and another cluster with additional deletions (13, 16q, and less trisomy 21 and trisomy 11) were apparent. For NH-MM, a group with 1q amplification and 13 deletion, which also tend to have loss of chromosome 4, 6q, 16q and 14, and another group with little abnormalities or just 6q loss, and chromosome 13 and 14 loss were identified. We identified some genetic difference between NH-MM and H-MM in additional to known difference such as the trisomies and chromosome 13 deletion. Loss of chromosome 4 (18% versus 0.9%, p<0.0001), loss of chromosome 14 (33% versus 16%, p=0.02) and loss of chromosome 22 (21% versus 4%, p=0.0008) are more common in NH-MM. Based on the distribution of NAPT, a cut-off of 20 abnormalities per tumor segregate the patients into 2 groups with significantly different survival. Those with greater NAPT have significantly shorter survival (median overall survival of 20 months versus 88 months, Log-rank p=0.006). There is no correlation between NAPT and ploidy or presence of chromosome 1 abnormalities suggesting that genomic complexity itself is associated with survival. Our study showed that both H-MM and NH-MM are genomically unstable although the pattern of abnormalities is distinct. In addition, based on clustering analysis, new pattern of genetic abnormalities are observed that allow further refinement of the ploidy subtypes. In addition, genomic complexity is also an important prognostic factor.

Abstract Chromosome 13 abnormalities (Δ13), monosomy or deletion, are seen in greater than 50% in patients with Multiple Myeloma (MM) and are associated with poor survival and reduced response to therapy. Δ13 is suggestive of a tumor suppressor model. In this study, we use a comprehensive, high-throughput approach involving array-based technologies to identify genes on chromosome 13 that are important in the pathogenesis and/or progression of MM. Array-based Comparative Genomic Hybridization (aCGH) is being conducted to identify a minimum region of 13q loss in a series of MM cell lines and patient samples. DNA is isolated, labeled and hybridized with a differentially labeled normal DNA reference to determine gene/genomic copy number changes. Arrays are analyzed to search for the minimum region of loss based upon single copy loss for a series of nearby mapping transcripts in each cell line. Data will be cross-referenced to determine the true minimum region of 13q loss in MM. Also, to discover genes harboring potential inactivating mutations, we are using inhibition of nonsense-mediated RNA decay (NMD) coupled with cDNA microarray. This modification of the Gene Identification by NMD Inhibition (GINI) method, first introduced by Noensie and Dietz (2001), is used to identify genes on chromosome 13 that may be inactivated due to premature truncating codons (PTCs). This method is based upon a cell’s natural ability to survey for and degrade RNA species that contain PTCs by activation of the nonsense mediated RNA decay (NMD) pathway. Treating cells with the drug Emetine can inhibit NMD and increase the expression of genes likely harboring truncating mutations. Preliminary data have revealed several candidate genes, with increased ratios after Emetine treatment, which map to chromosome 13. Upon defining a minimum region of loss based upon aCGH data, we will prioritize genes from our NMD study for mutational analysis. It our hope to also perform an array-based CpG island screen to simultaneously analyze all CpG islands on chromosome 13 to detect genes possibly inactivated by hypermethylation. This comprehensive, organized approach incorporating high-throughput techniques for the detection of genomic loss, mutation, and methylation is the first of its kind to our knowledge and may maximize the potential for the identification of a 13q tumor suppressor in MM.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell dyscrasia with limited therapeutic options. Based on the observed 25 to 50% partial response rates in myeloma patients, thalidomide has been tried in patients with AL. Two reports (Dispenzieri et al, Amyloid10:247; 2003; Seldin et al, Clinical Lymphoma3:241; 2003) have demonstrated that standard dose, single agent thalidomide (≥ 200 mg per day) has a higher than expected rate of adverse events in AL patients without hematologic or organ response, potentially due to rapid patient attrition. We therefore performed a prospective clinical trial using low dose, single agent thalidomide in patients with AL. Methods: In August 2001, we began accrual to a phase II trial of low dose thalidomide for patients with AL. Eligibility included: age ≥ 18 years, creatinine <3mg/dL, total bilirubin < 3 mg/dL, ANC ≥ 1 x 10(9)/L, left ventricular ejection fraction of >45%, histochemical proof of amyloid and a monoclonal plasma cell dyscrasia, symptomatic organ involvement, and ability to supply informed consent. Patients were started with thalidomide 50 mg per day, with a dose escalation to a maximum dose of 400 mg per day over a 19 week period as tolerated. Patients were evaluated monthly by their physician. These office visits were staggered with telephone toxicity checks monthly by the primary investigator. The endpoint of the study was hematologic and organ response by 12 months. Results: Eighteen patients were treated. The median age was 66 years (range 43–83). Eight were male. Twenty-eight percent had an ECOG performance status of 2 or 3. Five patients (28%) had received no prior therapy. Five had received one prior regimen; 6, two prior; and 2, ≥ three. Three had received prior PBSCT. Sixteen patients had a monoclonal lambda plasma cell disorder; two, monoclonal kappa. Immunoglobulin heavy chains were IgG (n=9), IgM (n=5), IgA (n=1), and none (n=3). Twelve patients (67%) had cardiac involvement; twelve (67%) renal; two liver; two symptomatic gastrointestinal; one pulmonary; and two nerve involvement. Study participants had significant symptomatology at baseline with dyspnea (n=12), light-headedness (n=6), and edema (n=13). Median number of organs involved was 1, range (1 to 4). Median time on study drug was 5.6 months, range 0.7–24 months. Reasons for discontinuation included: progression, 7 (39%); 3 each (17%) for adverse events, death, and patient refusal; and other causes in 2. The median tolerated dose was 100 mg. There were no hematologic responses observed. The overall organ response rate was 11%. There was one renal response at 1 year and a gastrointestinal response at 3 months with 24 hour fecal fat changing from 21 to 8.7 grams. The most common adverse effects attributable to thalidomide were: constipation (78%), edema (44%), sinus bradycardia (17%), dyspnea (11%), and paresthesias (11%). Light-headedness, rising creatinine, thrombosis, infection, syncope, and rash was attributed to the thalidomide in 5.6% of patients. Conclusions: Low dose thalidomide is tolerable in this fragile group of patients, but as a single agent efficacy is limited. Further study of combination therapy of thalidomide and low dose dexamethasone may be warranted. A study using the next generation immune modulatory drug Revlimid is scheduled to open to accrual. Funded by NIH grant CA 91561 and Celgene.

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1, a member of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the mammalian target of rapamycin (mTOR) could produce tumor responses in patients (pts) with MCL. Patients and Methods: Eligible pts had biopsy-proven, cyclin D1 positive MCL and had relapsed or were refractory to therapy. Pts received CCI-779 250 mg IV every week as a single agent. Pts were re-staged after 1 cycle (4 doses) and every 3 cycles thereafter. Pts with a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission (CR) and then were observed. Results: Thirty-five pts were enrolled and evaluable for toxicity; 1 patient had MCL by histology but was cyclin D1 negative and ineligible for efficacy evaluation. The median age was 70 years (range, 38–89), 91% were stage 4, and 69% had ≥ 2 extranodal sites. Pts had received a median of 3 prior therapies (range, 1–11) and 54% were refractory to their last treatment. The overall response rate was 38% (13/34) with 1 CR (3%) and 12 PRs (35%), surpassing the pre-defined criteria for a promising agent. Responses tended to occur rapidly with median time to response of 1 month (range, 1–8). To date, 26 patients have progressed, with a median time-to-progression of 6.8 months (95% CI: 3.8 – 9.7). Median duration of response for the 13 responders was 5.7 months (95% CI: 5.2 – 13.2). Overall, 32 out of 35 patients who received treatment had grade 3 or 4 toxicity. The most common toxicities were hematologic with grade 3 (n=24) or grade 4 (n=4). Thrombocytopenia was the most frequent grade 3/4 toxicity (n=25) and the largest cause of dose-reductions, although counts typically recovered within one week. Only 4 patients could tolerate sustained 250 mg per week throughout their treatment (including one who went on to alternate treatment after 1 cycle) and the median dose/month was 175 mg. Conclusions: Single-agent CCI-779 has substantial anti-tumor activity in relapsed MCL. This study demonstrates that agents, which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The high response rate warrants further studies of this agent in MCL, but the high incidence of hematologic toxicity suggests that a lower dose should be explored. CCI-779 at 25mg is currently being evaluated in MCL through an NCCTG trial

Recent clinical trials have addressed the notion of early treatment of smoldering multiple myeloma (SMM). The results evidence improvement in progression-free survival and, in one study, overall survival. Although the treatment of SMM can be considered under specific circumstances, we propose here that careful interpretation of the clinical trials and the patient-specific data are needed before recommending therapy. In particular, many questions remain regarding the best regimen to be used as well as how to adapt based on the underlying disease biology. Hematologists should have a very thorough understanding of models designed to predict the progression from SMM to multiple myeloma, because their correct interpretation is paramount to establish proper care. Although there is no doubt that treatment should be started before overt end-organ damage, we do not believe that the current data support the widespread treatment of all SMM.