Citations

Abstract Background: Immunoglobulin free light chains (FLC) form the substrate for synthesis of amyloid fibrils in patients with AL amyloidosis. Development of FLC assay (Freelite) has allowed us to better assess the clonal cell burden in patients with AL amyloid. The relationship of the light chain types and their levels in serum to the clinical feature at presentation and the eventual outcome has not been systematically studied. Methods: We identified 730 patients with biopsy proven AL amyloidosis, who were seen at Mayo Clinic between January 1980 and July 2006, who were seen within 90 days of their diagnosis and in whom FLC levels were performed or had stored serum available for analysis. Cardiac biomarkers (cTnT, NT ProBNP) were also performed on stored serum for some of the patients as part of previous studies. Clinical data and follow up status are prospectively collected into the Dysproteinemia database, which was used for the study. Results: The median age of the study population was 63 years (range; 32–90) and 463 patients (63%) were male. The median estimated survival for the entire group was 37 months from diagnosis and the median follow up for the 263 patients (37%) alive at the time of the analysis was 27.8 months (range; 1–177 months). The plasma cell clone was lambda in 528 patients (72%) and kappa in 202 (28%) patients. The median absolute difference between the FLCs was 19.6 mg/dL for the entire group (range; 0.01–2478); for the kappa patients was 29.4 mg/dL (range; 0.01–1359) and for the lambda patients was 18.2 mg/dL (range; 0.03–2478). Kappa AL was associated with more involvement of the GI tract and liver as indicated by higher alkaline phosphatase (1.8 vs. 1.3 fold; P=0.03), higher total bilirubin (0.95 vs. 0.78 mg/dL, P = 0.04) and lower serum carotene (119 vs. 155 ug/dL; P = 0.0002). On the contrary, renal involvement was more in the lambda AL with the 24 hour urinary albumin higher in the lambda AL (2.4 gm vs. 1.4 gm; P = 0.0002) and lower serum albumin (2.77 vs. 2.97 mg/dL; P = 0.001). While there was no difference in the overall survival (OS) between the kappa and lambda AL, the median OS for those without a heavy chain was significantly shorter (12.6 months vs. 29.9 months; P= 0.01) compared to those with a heavy chain identified. There was also a correlation between high FLC difference and degree of organ involvement, especially cardiac. Among the 202 kappa AL patients, the median survival for those with a high FLC difference ( > 29.4 mg/dL) was 13 months vs. 48.8 months for those with low difference (P = 0.001). Similarly among the 528 patients with lambda AL, those with high difference (> 18.2 mg/dL) had a median OS of 9.3 months compared to 33 months for those with low difference (P < 0.0001) (Figure). The FLC difference was independent of the cTnT, NT Pro BNP, uric acid and fold-increase in alkaline phosphatase, all of which were significant in the multivariable analysis. Conclusions: The type of FLC impacts the spectrum of organ involvement, with gastrointestinal involvement observed more frequently with kappa, and renal involvement with lambda FLC. The FLC burden correlates with the degree of organ involvement, and is a significant predictor of overall survival in AL amyloidosis. Lambda FLC exerts similar effect as kappa FLCs, but at lower levels confirming the increased “amyloidogenicity” of lambda FLC. Finally, lack of a chaperone heavy chain is associated with a poorer outcome. Figure 1. Overall survival form diagnosis in patients with high vs. low FLC difference (using median values for cutoffs for kappa and lambda FLC) Figure 1. Overall survival form diagnosis in patients with high vs. low FLC difference (using median values for cutoffs for kappa and lambda FLC)

Abstract Background: The combination of lenalidomide and dexamethasone (Rev/Dex) has been shown to be a highly effective therapy for multiple myeloma (MM). Over half of the patients with newly diagnosed MM achieve a complete response with prolonged therapy. More recently, a phase III trial demonstrated improved survival with use of lenalidomide and low dose dexamethasone with one year survival in excess of 90%. We report the initial results from a phase II trial combining lenalidomide and low dose dexamethasone with cyclophosphamide (CRd) as initial therapy of newly diagnosed MM. Methods: The trial was initiated in July 2006 and completed the target accrual of 33 patients by July 2007. The treatment protocol consisted of lenalidomide given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle. Dexamethasone (dex) was given orally at a dose of 40 mg on days 1, 8, 15, and 22 of each cycle. Cyclophosphamide at a dose of 300 mg/m2 was given on days 1, 8, and 15 of each cycle. Patients also received an aspirin once daily as thromboprophylaxis. Response was defined as a decrease in serum monoclonal (M) protein by 50% or higher and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours, confirmed at least 4 weeks apart. Results: The median age was 63 years (range, 44–79). Eight patients (24%) had ISS stage III disease. At this time, 19 of the 33 patients are evaluable for confirmed responses (i.e., off-study or completed at least 4 cycles of therapy). Of these, 2 achieved VGPR and 13 had a partial response giving an overall response rate of 79%. The response rate was affected by 5 of 19 patients who went off study within three cycles due to toxicities [interstitial nephritis (1 pt), multiple grade 3 toxicities including infection (1 pt) atrial fibrillation and infection (1 pt)] or alternative treatment [no response and possible renal toxicity (1 pt) and progression at 4 cycles (1 pt)]. Overall, hematological toxicity was the most common with grade 4 toxicity seen in 6 patients (20%). Non-hematological grade 3 or higher toxicities included fatigue (4 pts), thrombosis (3 pts) and renal failure (2 pts). One patient with thrombosis came off study for other toxicities, and the other two continued on study with anticoagulation. Thirteen patients (43%) had dose reductions of both cyclophosphamide and lenalidomide, most commonly due to hematological toxicity. So far, 12 patients have gone off study, 6 went to stem cell transplant, 3 due to adverse events, 1 due to disease progression and 2 patients went to alternate treatment. Conclusions: CRd has excellent activity in newly diagnosed myeloma with an estimated overall response rate of 79%. Response evaluation of the entire 33 patients will be presented at the meeting. We believe that the initial use of a 300 mg/m2 dose of cyclophosphamide resulted in 5 of the first 19 pts experiencing early toxicity and withdrawal. As a result, an expansion of the current trial is evaluating lower doses of cyclophosphamide (300 mg fixed dose). Full analysis of this study will be needed to determine if CRd can improve outcome compared to Rd.

Abstract Background: In multiple myeloma (MM), a complete response (CR) is defined by the European Group for Blood and Bone Marrow Transplantation (EBMT) and the International Myeloma Working Group (IMWG) Uniform Response Criteria as absence of monoclonal protein in serum and urine by immunofixation (IFE), and a bone marrow (BM) aspirate/biopsy containing <5% plasma cells (PC). This definition of CR is widely adopted in clinical trials, but there is a high degree of non-compliance with the BM requirement. As a result, differences in CR rates across trials can occur not just as a result of treatment efficacy, but also on how rigorously the BM requirement for CR is implemented. Moreover, requiring BM examinations merely to confirm CR is cumbersome in clinical practice. The goal of this study was to determine the added value of BM examinations in patients who can otherwise be considered to be in CR by virtue of a negative IFE in the serum and urine. Methods: For the purpose of the study, we included only patients with MM who had measurable monoclonal (M) protein levels at baseline (defined as >1 gm/dL in the serum and/or >200 mg/24 hour in the urine) on protein electrophoresis; patients with non-secretory and oligo-secretory MM were excluded. We then identified patients who since 1995 had a negative IFE in the serum and urine and a BM aspirate/biopsy, all done at the same time (within 30 days of each other). Baseline demographics and clinical characteristics; date of diagnosis, last follow up, and follow up status; serum and urine M protein levels at diagnosis; and results of serum and urine IFE, serum free light chain (FLC) ratio and BM aspirate/biopsy within 30 days of complete response were all collected from the existing databases. Results: Ninety-five patients met the criteria for the study, all of whom had measurable disease at baseline and subsequently achieved negative IFE in serum and urine (‘IF- CR’). Of these, only 83 patients (87%) met criteria for CR by the EBMT/IMWG criteria with less than 5% PC in the BM; 13% of patients had 5% or more PC despite the apparent IF-CR on serum and urine IFE. In fact, the BM showed 10% or more PC in 5% of IF-CR patients. We then assessed whether a normal serum FLC ratio in addition to negative serum and urine IFE would eliminate the need for a BM biopsy. The additional requirement of the serum FLC ratio to negative IFE was not fully adequate in eliminating false positive CR’s. Among 34 patients who had IF- CR plus a normal serum FLC ratio, only 88% of patients met CR definition with <5% BM PC; 12% had 5% or more PC, and one patient (3%) had 10% or more PC. We studied the survival (from time of diagnosis) of patients who had true CR’s (negative IFE and <5% PC) versus patients who had IF- CR’s but BM had 5% or more PC. Overall survival from diagnosis between the two groups was 10.7 years versus 5.6 years, respectively, P=0.001 (see Figure 1). Conclusions: BM examination is essential to accurately estimate CR. Up to 13% of patients with negative IFE in serum and urine fail to meet the BM requirement. The addition of a normal serum FLC ratio to negative IFE did not significantly reduce the proportion of patients who fail to meet the BM requirement. Based on this study, we recommend that the CR definition in the EBMT and IMWG criteria should not be revised to eliminate the need for BM examination. Moreover, the consistent collection of BM samples is essential for future strategies to evaluate immunophenotypic CR and molecular CR in MM. Figure 1: Kaplan-Meier curve showing survival benefit (in years) of patients in complete response with less than 5% bone marrow plasma cells. Figure 1:. Kaplan-Meier curve showing survival benefit (in years) of patients in complete response with less than 5% bone marrow plasma cells.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder with a poor survival, especially in patients (pts) with multiple organ involvement. For pts with limited organ involvement, high dose chemotherapy with autologous stem cell (SCT) support is an effective approach. However, the toxicity of SCT limits its widespread use. Melphalan and dexamethasone has been previously shown to be effective in pts ineligible for SCT. Methods: We reviewed our experience with melphalan and dexamethasone for treatment of AL. Eighty one pts were treated between 2001 and 2003; median age at start of therapy was 63 years (range, 38–80) and 56 pts (69%) were males. Among these, 46 pts (57%) had 2 or more major organs (cardiac, renal, hepatic) involved. Intravenous melphalan (IV) was used in 45 pts (56%), 32 (40%) received oral melphalan (PO) and the rest received cycles of both. The most common doses were 16 mg/m2 for IV administration (every 4–6 weeks) and 0.22 mg/kg for PO administration (every 4 weeks). Dexamethasone was usually given at a dose of 40 mg for the first 4 days of each cycle. Results: Patients received a median of 5 cycles (range; 1–17). At the time of analysis, 53 (65%) pts were alive with a median follow up of 10.8 months (range, 1.4–47.1).The estimated median overall survival (OS) was 25.6 months for the entire group, with the number or type of organs involved not impacting survival. Hematological response (HR) was defined by a 50% reduction in either serum M-spike, urine M-spike, or the absolute difference between the involved and uninvolved immunoglobulin free light chains. A HR was observed in 43 pts (67%) of the 64 pts measurable for HR by conventional criteria. Achievement of HR was associated with a superior OS with a median post-therapy OS that was not reached, while non-responders had a median OS of 11.1 months (p<0.0001) (Figure 1). Among these pts, an organ response as defined by conventional criteria, was seen in 14 pts (22%), which was significantly correlated with obtaining a hematological response (33% vs. 5%, p=0.01). A 25% reduction in the difference between the involved and uninvolved FLC strongly predicted prolonged OS, with a median post-therapy OS that was not reached for responders vs. 11.3 months for non-responders (p<0.0001) (Figure 2). A decrease in post-therapy brain natriuretic peptide (BNP) also predicted for a survival improvement, with the median OS not reached for responders vs. a median OS of 17 months for non-responders (p<0.016). Conclusion: Treatment with melphalan and dexamethasone is effective and a significant survival advantage is achieved in patients with a hematological response. FLC and BNP response can help identify patients that are likely to benefit from this therapy. Figure Figure Figure Figure

Abstract Background: High dose melphalan & autologous peripheral blood stem cell (PBSC) transplantation is increasingly utilized for primary systemic amyloidosis (AL). PBSC mobilization with filgrastim is safe in various patient & normal donor populations. While there is a case report of filgrastim-induced fatal pulmonary edema in an AL patient undergoing PBSC mobilization, we elucidate the incidence & magnitude of fluid-related complications in this patient population, describe the management & outcomes, & identify features predictive of risk. Methods: IRB approval & patient consent were obtained prior to review of medical records for all adult Mayo Clinic AL patients who underwent PBSC mobilization with filgrastim 10 mcg/kg once daily from 7/98 – 8/03. Three patient episodes were excluded: 1 refused consent & 2 had a 2nd PBSC mobilization & were included once. A fluid-related complication was defined as documented increased fluid retention (peripheral edema, pleural effusion or ascites) or use of additional therapy (diuretics, albumin or dopamine) to facilitate diuresis. Results: Sixty-three of 123 patients (51%) developed a fluid-related complication. Significant interventions were needed during mobilization & prior to PBSC transplant, including admission to ICU (n=3), hemodialysis to manage fluid status (n=3), paracentesis (n=2), & thoracentesis (n=3), including one requiring chest tube placement & pleurodesis. Patients with complications had more hospitalizations during PBSC mobilization compared to those that did not (24 vs 6; p=0.001); with 20 of 24 directly related to fluid status. While not statistically significant, the complications group was more likely to fail to collect adequate PBSC or have mobilization prematurely discontinued (6 vs 2; p=0.32). One patient in each group died suddenly during mobilization. Characteristics Predictive of Fluid-related Complications Patients with Fluid-Related Complications N (%) p-value AL Organ Involvement 1 vs 2 vs 3 23/58 (40%) 26/45 (58%) 14/20 (70%) 0.01 Kidney: yes vs no 48/85 (57%) 15/38 (40%) 0.08 Heart: yes vs no 41/61 (67%) 22/62 (35%) 0.0004 Baseline edema: yes vs no 47/77 (61%) 16/46 (35%) 0.005 Diuretic: 0 vs 1 vs >1 15/52 (29%) 37/59 (63%) 11/12 (92%) <0.0001 Albumin: ≤ 2 vs > 2 mg/dL 18/24 (75%) 45/99 (45%) 0.009 On univariate analysis patients with complications had increased septal wall thickness (median 13 vs 12 mm, p=0.05), increased total urinary protein (median 3.698 vs 2.9575 g/day, p=0.04), & lower serum albumin (median 2.8 vs 3.3 mg/dL, p=0.005). Via multivariate regression patients with albumin < 2 mg/dL had an OR=3.8 (CI 1.2 – 13.6), those with cardiac AL had an OR=5.5 (CI 2.2 – 15.4), & patients utilizing diuretics at baseline had an OR=12.1 (CI 2.8 – 61.2) for the likelihood of complications. Patients with fluid-related complications during mobilization had a lower survival rate at 100 days (78 vs 92%, p=0.003) & 1 year after PBSC transplantation (65 vs 91%, p=0.003). Conclusions: Over 50% of AL patients who undergo PBSC mobilization with filgrastim 10 mcg/kg once daily develop clinically significant fluid retention & subsequent complications. Cardiac AL, hypoalbuminemia, & diuretic use prior to filgrastim administration were more likely to develop complications. Fluid-related complications during PBSC mobilization are associated with poorer survival after transplantation for AL.

Abstract Background: Primary systemic amyloidosis is an uncommon plasma cell dyscrasia characterized by organ deposition of immunoglobulin light or heavy chain fragments. It is related to the other plasma cell dyscrasias such as multiple myeloma and monoclonal gammopathy of undetermined significance. cIg-FISH on bone marrow plasma cells has become well established in the initial evaluation of myeloma as the t(4;14), t(14;16),13q-, and the 17p- abnormality are of major prognostic value. The corresponding data does not exist in amyloidosis, as there are only three small studies published to date. Methods: Using a prospectively held dysproteinemia database, we reviewed all cases of amyloidosis seen at our institution who had cIg-FISH or cytogenetics performed as part of their routine clinical testing. Three hundred thirty nine patients were identified with amyloidosis and cytogenetic testing. Of these 69 had cIg-FISH testing results. cIg-FISH was performed with fluorescent-tagged antibodies to kappa/lambda immunoglobulin and FISH probes corresponding to the following anomalies: trisomies 3, 7, 9 and 15; del17p/-17; -13/del13q; 14q32 split; and t(11;14). CCND1/IGH. If an IGH rearrangement was detected that did not involve CCNDI, we also evaluated t(4;14) or IGH/FGFR3 and t(14;16) or IGH/c-MAF. These probes constitute the standard screening panel used in MM at our institution. Results: The study population had a median age of 61 years with a male to female ratio of 1.6:1. Median follow up time was 13.5 months. By conventional cytogenetics, 88% of patients had no detectable abnormality. In contrast, only 33% were normal by cIg-FISH. The abnormalities demonstrated were 28% 13-/del13q, 42% IgH translocation, 33% t(11;14), and 3% t(14;16). No patients had a -17/del 17p- or t(4;14). Nine patients had del13q/-13 with an IgH translocation, with 7 of these having t(11;14). Both t(14;16) patients had del 13q. A trend towards increased mortality was seen in patient with any abnormality (p=0.11), but this could not be demonstrated for any single abnormality, likely due to lack of statistical power. There was no correlation between renal involvement or cardiac involvement and cIg-FISH results. Conclusion: The majority of chromosomal abnormalities in amyloidosis are undetected by conventional cytogenetics. With further study, chromosomal abnormalities may carry the same prognostic value in amyloidosis that they currently enjoy in myeloma. This effect may be independent of currently recognized risk factors. Chromosomal abnormalities in Amyloidosis as detected by cIg-FISH Abnormality Amyloidosis % (n=69) Normal 33(23) −13/del13q 28(19) IgH Abnormality 42(29) t(4;14) 0(0) t(11;14) 33(23) t(14;16) 3(2) del 17 0(0) Other 3(2)

Abstract Background: In patients (pts) with newly diagnosed myeloma (MM) eligible for high dose therapy and autologous stem cell transplantation (ASCT), the standard approach is 4–6 months of induction therapy followed by ASCT. The combination of thalidomide and dexamethasone is one of the commonly used induction regimens, and has superior response rates compared to dexamethasone or VAD. Almost all patients undergoing an ASCT relapse at a median interval of 18–24 months. The choice of treatments at first relapse is variable, but re-application of the original induction regimen, if effective is often considered. It is not clear if the responses obtained at the time of induction therapy can be replicated at the time of relapse. We studied the response of thalidomide based regimens when used as first treatment after relapse from an ASCT in patients receiving thalidomide as induction treatment. Methods: Pts who received thalidomide and dexamethasone as induction therapy, and thalidomide ± dexamethasone at first relapse after ASCT were identified for the current study. A group of patients receiving dexamethasone as induction therapy and thalidomide ± dexamethasone at first relapse after ASCT was used as the control group. Results: There were 20 pts in the study group (group 1) and 14 patients in the control group (group 2) identified between 2002 and 2007. There were 15 (75%) males in group 1 and 10 (71%) in group 2. In group 1 there was 1(5%) complete response (CR), 5 (25%) very good partial response (VGPR) and 14 (70%) partial responses (PR) to induction therapy. In group 2 there was 1 (7%)VGPR, 12 (86%) PR and 1 (7%)stable disease following dexamethasone induction. Upon treatment with thalidomide based regimens at first relapse after ASCT, there was a high rate of treatment failures in group 1 as compared to group 2 (no response in 14 out of 20 patients (70%) versus 5 of 14 pts (35%), respectively, p = 0.04). Of the 10 patients with progressive disease in group 1 post transplant, 30% had previously achieved a VGPR and 70% had previously achieved a PR to thalidomide/dexamethasone pre-ASCT. Conclusions: Our study provides evidence toward the lack of efficacy of thalidomide based regimens on post ASCT relapse in patients who had thalidomide responsive disease prior to ASCT. It is possible that this applies to other induction regimens when used at post ASCT relapse and raises the possibility of selection of drug resistant clones with initial therapy. Response rates seen with drug regimens prior to ASCT may not be reproducible at the time of relapse after ASCT.

Abstract Background: The international staging system is a simple, but powerful staging system that is based on two simple and easily available laboratory measurements. The system was developed and validated on a large group pf patients from across the world and has become the standard for patients with newly diagnosed myeloma. While it’s prognostic value is clear in patients with newly diagnosed myeloma, its value at relapse has not been explored. Methods: We examined a uniform cohort of patients relapsing after an autologous stem cell transplant to assess the utility of ISS determined at the time of documented relapse. Relapse was defined using standard EBMTR response criteria. Beta-2 microglobulin and albumin values from within 30 days of the date of relapse were extracted from the medical records. ISS was determined based on the published cut offs. Results: Of the 389 patients evaluated, 132 had values available for B2M and 276 patients had the serum albumin available. Only 131 patients had both the data available and the ISS stage could be determined. Of these patients, 64 patients (49%) were ISS stage I, 50 (38%) were stage II and 17 (13%) were stage III. An albumin < 3.5 mg/dL was prognostic for overall survival post relapse with a median survival of 10.5 months for those with albumin < 3.5 mg/dL compared to 26.3 months for the rest of the group (P < 0.0001). Similarly the median OS from relapse was 15 months for those with B2M > 3.5 mg/dL compared to 23.3 months for those with lower B2M (P = 0.014). The ISS stage predicted overall survival for this group of patients with the OS from relapse estimated at 27.3 mos, 17.8 mos and 12.3 months for ISS stage I, II and III respectively. Conclusions: In a uniform group of patients relapsing after autologous stem cell transplantation, the B2M and albumin maintain their prognostic value and allows the use of the International Staging System for determining prognosis. This supports the use of ISS stage in relapsed trials and will allow comparisons across studies. Results should be validated in a larger dataset that will allow comparisons to other known prognostic factors. Figure Figure

Abstract Background: Recent advances in the therapy of multiple myeloma (MM) have greatly increased the treatment options for this uniformly fatal plasma cell malignancy. It is not clear if introduction of novel therapies and the increased use of high dose therapy (HDT) in the past decade have translated into better outcome for patients (pts) with MM. Methods: We examined the outcome of two cohorts of pts seen at our institution. The first cohort consisted of 387 pts who relapsed after HDT and was examined for potential improvement in survival following relapse after HDT. These pts were divided into two groups; those who relapsed before or after December 31, 2000. The second cohort consisted of 2981 patients with newly diagnosed MM seen between January 1971 and December 2006 and was used to examine the trends in overall survival (OS). Results: Among those relapsing after HDT, there were 245 males (63%); median (range) age at HDT was 57 years (32.8–75.4) and the median time to HDT was 8.1 months (1–90 months) from diagnosis. The median time to relapse was 13.2 months (1.1 months-10.3 years) from HDT. In this cohort, a clear improvement in OS from time of relapse was seen over the past decade, with those relapsing after 2000 having a median OS of 23.9 months (95% CI; 19.8, 27.6) compared to 11.8 months (95% CI; 8.7, 14.9) for the rest (P < 0.001) (Figure 1). In a multivariate analysis, the effect of the date of relapse on survival was independent of other prognostic factors such as relapse <12 months after HDT, abnormal cytogenetics, and B2M > 5.5 mg/dL. Pts who were treated with one or more of the newer drugs (thalidomide, lenalidomide, bortezomib) had longer survival from relapse (30.9 months (95% CI; 23.6, 38.2) compared to 14.8 months (95% CI; 11.3, 18.4); P < 0.001) for others. Among the newly diagnosed MM cohort, the median age at diagnosis was 66 years (20.2 – 97 years), and 1,770 (59.4%) were males. The median follow up for the entire group was 27.4 months (0–29.4 years); and at the time of analysis 558 patients (18.7%) were alive with a median follow up of 32.7 months (0–29.4 years). Pts diagnosed in the last decade had an improved OS (44.8 months) compared to those diagnosed before this period (29.9 months; P < 0.001) (Figure 2). The improvement in survival seen in the last decade among newly diagnosed patients was predominantly among those younger than 65 years (60.3 mos vs. 33.3 mos improvement in median survival); compared to those over 65 at diagnosis (26.5 mos vs. 32 mos). Conclusion: In this study, for the first time, we demonstrate definite proof for improved outcome in patients with myeloma, both in the relapsed setting as well as at diagnosis, a change that is likely to continue with increased use of these drugs. Figure Figure Figure Figure

Abstract Background: Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell proliferative disorder with a high risk of progression to symptomatic multiple myeloma. Identification of risk factors that predict progression of SMM to symptomatic MM could identify higher risk patients who might benefit from chemoprevention or more intensive surveillance. We hypothesized that increased monoclonal free kappa or lambda immunoglobulin light chains in smoldering myeloma (SMM), as detected by the serum free light chain (FLC) assay, indicates an increased the risk of progression to active myeloma. Methods: Of 276 pathologically confirmed SMM patients seen at the Mayo Clinic from 1970 to 1995, baseline serum samples obtained within 30 days of diagnosis were available in 273. Results: At a median follow-up of surviving patients of 12.4 years, transformation to active disease has occurred in 161 (59%) patients. An abnormal FLC ratio was present at baseline in 90% of patients. The best break-point for predicting risk of progression was a FLC ratio less than or equal to 0.125 or greater than or equal to 8 (hazard ratio, 2.3; 95% CI, 1.6–3.2) [Figure 1]. The extent of abnormality of FLC ratio was independent of SMM risk categories defined by number of plasma cells in the bone marrow and size of serum M-proteins (bone marrow plasma cells ≥ 10% and serum M protein ≥ 3 g/dL; bone marrow plasma cells ≥ 10% but serum M protein < 3 g/dL; and serum M protein ≥ 3 g/dL but bone marrow plasma cells < 10%). Incorporating the FLC ratio into the risk model, the division of patients into high-, intermediate-, and low-risk groups is 28, 42, and 30% with 5 year progression rates of 76, 51, and 25%, respectively [Figure 2]. Conclusions: The serum immunoglobulin FLC ratio is an important additional determinant of clinical outcome in patients with SMM. Figure Figure Figure Figure