Negative Immunofixation Research Articles

Long-Term Follow-up of Bendamustine Plus Rituximab Regimen in 69 Treatment Naïve (TN) Patients with Waldenström Macroglobulinemia, a Study on Behalf of the French Innovative Leukemia Organization (FILO)

Background Waldenström macroglobulinemia (WM) is a rare hematological malignancy characterized by the accumulation of IgM-secreting clonal lymphoma cells with a lymphoplasmacytic morphological differentiation. Recently, BTK inhibition has emerged as a promising therapeutic strategy in WM (Buske, JCO 2022; Tam, Blood 2020). However, in real life, a large part of patients(pts) continue to be treated by chemoimmunotherapy (Buske, Lancet Hematol2018) including bendamustine (B)-rituximab (R) in salvage (Tedeschi , Leukemia Lymphoma 2015) or first line MW (Treon, ASH2016). We have previously reported a series of 69 WM pts treated by BR (Laribi, BJH 2018) and demonstrated that this regimen is efficient. However, the follow-up was relatively short and some questions remained unresolved in terms of long-range response and second cancer occurrence. Here we report results of this series with a longer follow-up. Methods Sixty-nine symptomatic previously untreated pts with WM diagnostic criteria according to the second WM Workshop recommendations were enrolled in this retrospective multi-center study between January 2013 and December 2017 in 13 French centers. MYD88L265P and CXCR4 mutations were searched using qPCR and or next generation sequencing. Del(17p) and/or TP53 mutation were investigated in 34 pts. All pts received a BR regimen consisting of 375 mg/m2 of R on day 1 and 90 mg/m2 of B on days 1 and 2, repeated every 4 weeks, with a maximum of 6 cycles. Cumulative incidence of secondary malignancies and high-grade lymphomas were computed, considering death free of malignancies as a competing event. Event-free survival (EFS), time to next treatment (TNT), progression-free survival (PFS) and overall survival (OS) were plotted using the log rank test and Kaplan-Meier graphical comparison. Results Pts median age was 69 years old (yo; range 45-88) at WM diagnosis and 71 yo (range 46-88) at therapy initiation. MYD88 and CXCR4 mutations were present in 45/51 (88%) and 11/44 (25%) of pts, respectively. A complex karyotype was disclosed in 6/44 (14%) pts, and 1/34 (3%) had TP53 alteration. According to the IPSSMW score, 14 (22%) pts were low risk, 32(46%) intermediate, and 32 (46%) high risk. Using consensus response criteria, the overall response rate was 97% (very good partial response [VGPR] with negative immunofixation 19%, VGPR 37%, PR40%, MR 1%) and the major response rate was 96%. Cumulative incidence of VGPR or better was 47.8%, 53.6%, 55%, and 56% at 6, 12, 18, and 24 months, respectively. After a median observation time of 68.5 months (range 23.13-106) post BR, the median OS was not reached (83-NR) , and the median PFS was 82 months (75-NR). Median OS for pts with mutated or WT MYD88 was NR and 72.8 months, respectively (p=0.046). Median OS for pts with mutated or WT CXCR4 was 70.2 months and NR, respectively (p=0.64). Median OS related to disease or treatment was not reached, while median OS related to other causes was 106 months. Sixteen (23.2%) pts relapsed. Fourteen received second line therapy and 2 supportive care. Eight patients received ibrutinib, and 6 chemo-immunotherapy. TNT was 31.55 months (range 2.66-82.43). Median PFS after a second line of treatment (PFS2) was 45 (9.13-NR) or 21 months (range 9.13-NR), for pts receiving ibrutinib or not. Eleven pts developed a second cancer: 9 solid tumors (2 pancreatic, 2 gastric, 1colic, 1 pulmonary, 1 breast, 1 cutaneous), and 2 treatment-related myeloid neoplasms (TRMN). Median EFS, defined as occurrence of death, relapse or second cancer was 82 months (61-NR). The cumulative incidence of second cancer was 2.90%, 5.80%, 10.49%, and 17.6% at 12, 24, 48, and 96 months, respectively (figure 1). Univariate analyses on OS disclosed statistically significant differences for age at diagnosis (p=0.001), age at first therapy (p <0.001), IgM>70g/L (p: 0.018), complex karyotype (p=0.037), and high risk IPSSMW (p<0.01). In multivariate analysis, only IPSSMW remained statistically significant (p<0.001) (table1). Univariate analyses on PFS only singled out age at diagnosis (p=0.03) or at first therapy (p=0.049) as statistically significant. Mutated MYD88 or CXCR4 did not impact OS nor PFS. Conclusion This study demonstrates that the BR regimen is efficient in treatment naïve WM pts, yielding long-term responses. The occurrence of secondary cancers, including TRMN, should be closely monitored in these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax-Targeted Therapy in t(11;14) AL Amyloidosis Patients after Frontline Daratumumab and Cybord: A Retrospective Analysis from the French Amyloidosis Network

Background: Systemic AL amyloidosis is caused by the deposition of misfolded monoclonal immunoglobulin serum free light chains (sFLC) in various organs. Treatment of AL amyloidosis relies mainly on chemotherapy aimed at suppressing the underlying secreting plasma cell clone. Organ responses and survival are greatly influenced by the degree of hematological response evaluated by the decrease in sFLC. Over the last 2 years, anti CD38 monoclonal antibodies (mAb), such as daratumumab (DARA), have emerged as breakthrough targeted therapies for patients (pts) with AL amyloidosis and DARA received approval in combination with CyBorD in frontline pts. Unfortunately, some pts will still not achieve complete response (CR) or ultimately relapse. BCL-2 inhibition represents a promising therapeutic approach in plasma cells dyscrasia and venetoclax (VEN) is an oral BCL-2-selective BH3 mimetic. VEN has shown activity in multiple myeloma (MM) cell lines with t(11;14), partly because of greater BCL-2 co-dependence of such clones. VEN is safe in MM pts with encouraging clinical efficacy. VEN should provide a novel targeted therapy in AL amyloidosis as 50-60% of the pts have a t(11;14). Various retrospective cohorts are now reported with VEN alone or in combination with bortezomib (BOR) and/or DARA, with rapid and deep hematological and organ responses. Objective: To report efficacy of VEN based regimen in AL amyloidosis pts as consolidation or relapsed therapy in frontline AL pts treated with DARA-CyBorD or equivalent. Material & Methods: In this retrospective study, we reviewed charts of 9 pts with AL amyloidosis, from the French Amyloidosis Network, who received VEN as part of their regimen as consolidation (n=3) or for biological progressive disease (n=6) after DARA-CyBorD frontline therapy. Individual data were prospectively and retrospectively collected in the French Amyloidosis database. Pts should have received at least 1 cycle of VEN-containing regimen to be analyzed. Responses were reviewed using current criteria for CR (serum and urine negative immunofixation and normal involved FLC) and for very good partial response (VGPR;differential FLC<40 mg/l). Results: Regarding baseline characteristics (Table 1), pts had a median age of 67 years (IQR:61-71) and all except one had more than 10% bone marrow plasma cells (but no overt MM). Six pts had ≥2 organs involved with heart in 67 % and kidney in 56 %; 6 had MAYO stage 3/4 and median NT-proBNP/troponin levels were 3333 ng/l (IQR:185-9685) and 44 pg/ml (IQR:18-96), respectively. Six pts had FLC only AL amyloidosis. Median dFLC for the whole cohort was 255 mg/l (IQR:140-1060), and 6 pts had baseline dFLC>180 mg/l. All pts had t(11;14) with an additional 11q gain in 3, and 1q gain in 1. Median time from diagnosis to VEN therapy was 6.0 months (IQR: 2.5-7.5). Regarding frontline therapy, 7 pts received DARA-CyborD (median 3 cycles), 1 DARA-CyBorD plus CAEL and 1 pt received DARA-RVD. All pts were DARA exposed, 8 pts had a suboptimal response to DARA and 2 were DARA "refractory". Five pts never reached VGPR or better with DARA-based regimen. VEN (400 mg/day) was given alone in 1 pt or in association with dexamethasone/DEXA (n=1), BOR (n=2), or DARA+BOR (n=5); Median time on therapy was 7.0 months (IQR:3.0-9.5). At data cut-off (06/2022), 6 pts had discontinued therapy because of CR (n=5) and/or GI tract toxicity (n=4). The hematologic response rate was 89%; 78% of pts achieved CR, and 11% partial response (PR) (Figure 1). Among CR pts, all pts achieved dFLC<10 mg/l, and 2 had an iFLC<10 mg/l. Responses were fast and median time to CR was 1 month (IQR:1-3). Regarding VEN monotherapy +/_ DEXA, 50% of pts reached CR; with the addition of BOR, or DARA+BOR, CR was 100, and 80%, respectively. In consolidation pts, all pts achieved CR in 1 month (1-3) with the addition of VEN to DARA-CyBorD. In progressive/relapsed pts, 4/6 (67%) achieved CR and 1 was in stable disease. One pt reached PR and progressed to end-stage renal disease. Finally, both DARA R/R pts reached CR with VEN alone or in association with BOR. Summary & Conclusion: Venetoclax is a promising targeted therapy in AL amyloidosis. Venetoclax can be used in combination with daratumumab and/or bortezomib as consolidation or relapsed therapy after frontline DARA-CyBorD, even in refractory patients, with expected good safety profile. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Normalization of the Serum Free Light Chain Ratio in Patients with Intact Immunoglobulin Multiple Myeloma Who Achieve Less Than Complete Response

BackgroundNormalization of the serum free light chain ratio (rFLC) following achievement of complete response (CR) denotes stringent CR in multiple myeloma (MM) and is associated with favorable prognosis. In contrast, the clinical significance of this phenomenon in patients not achieving CR has not been energetically studied. Only a few studies have reported better progression free survival (PFS) and overall survival (OS) in patients who achieved normalization of the rFLC at their best response than in those who did not. As monoclonal intact immunoglobulin (Ig) and monoclonal FLC are independent biomarkers for the neoplastic plasma cell burden in intact immunoglobulin MM (IIMM), it is not clear whether patients who failed to achieve CR but normalized the rFLC also had improved outcomes. Here, we retrospectively analyzed the prognostic significance of normalization of the rFLC in IIMM patients who did not achieve CR.Patients and methodsConsecutive patients with IIMM diagnosed and treated at the Kameda Medical Center from Jun 2007 to April 2017 were identified. IMWG response criteria were used to assess response. We excluded patients with negative immunofixation for monoclonal M-protein in the serum or urine at diagnosis and those who achieved CR. The FLC assay (FREELITE, The Binding Site, Birmingham, UK) was performed at least monthly as a part of routine clinical management. The following ranges were used for normal FLC values: κ FLC, 0.33-1.94 mg/dL; λ FLC, 0.57-2.63 mg/dL; and rFLC, 0.26-1.65.ResultsThere were 239 patients diagnosed with symptomatic MM, including 191 patients with IIMM and 48 patients with light chain MM (LCMM). Among 191 patients with IIMM, 78 achieved CR by chemotherapy; the remaining 113 patients were included in this analysis. No patient with LCMM achieving less than CR (n = 15) obtained normalization of rFLC during the whole treatment. The median observation period was 21.9 months (m) [range, 0.2-118.9 m] and the median age was 77.0 yr (range, 43.8-90.7 yr). Sixty-four of the 113 patients (56.6%) obtained a normal rFLC during the course of treatment. Patients who achieved a normal rFLC were significantly younger (median age, 75.3 vs 79.2 yr, P = 0.014), more frequently received autologous stem cell transplantation (15.6% vs 0%, P = 0.005), and had better response [very good partial response (VGPR) rate: 57.8% vs 22.4%, P < 0.001] than those who did not. No significant difference was seen between patients with and without normalization of the rFLC with regard to sex, heavy- or light-chain type, ISS category, revised ISS category, albumin, β2 microglobulin, or creatinine levels, hemoglobin concentration, lactate dehydrogenase abnormality, induction regimen, or administration of maintenance therapy. Patients with a normal rFLC had significantly longer PFS and OS than those without on univariate analysis (median PFS, 24.2 vs 6.6 m, P = 0.001; median OS, 59.6 vs 20.2 m, P < 0.001). Normalization of the rFLC retained its prognostic significance for both PFS and OS on multivariate analysis (both P < 0.001). We further examined the impact of achievement of a normal rFLC on PFS and OS in patients with a high or low baseline rFLC. Using receiver operating characteristic curve analysis, the optimal cutoff was 69.8; patients were divided into two groups based on the cutoff. As expected, patients with a higher baseline rFLC who achieved a normal rFLC had longer PFS and OS (median PFS, 29.7 vs 4.3 m, P < 0.001; median OS, 93.6 vs 15.8 m, P < 0.001), but those with a lower baseline rFLC did not (median PFS, 21.4 vs 7.1 m, P = 0.484; median OS, 53.9 vs 34.9 m, P = 0.120). In addition, patients with a lower baseline rFLC were more likely to achieve normal rFLC than those with a higher baseline rFLC, although the difference was not statistically significant (P = 0.074).ConclusionThis study demonstrated that achieving normalization of the rFLC during the course of treatment is robustly predictive for both PFS and OS in patients with IIMM who do not achieve CR. As monoclonal FLC is secreted independently of monoclonal intact Ig from neoplastic plasma cells, normalization of the rFLC also confers improved prognosis of patients with IIMM who had high levels of rFLC. These data indicate that serial measurement of FLC at all levels of response may be a valuable tool for accurate prognostication in IIMM even when achieving only VGPR or worse response to therapy. [Display omitted] DisclosuresKitadate:Fujimoto: Research Funding; Novartis: Research Funding; Kyowa Kirin: Research Funding; Otsuka: Research Funding; Toyama kagaku: Research Funding; Eisai: Research Funding; Asahi Kasei: Research Funding; Chugai: Research Funding; Pfizer: Research Funding.

A simple method to distinguish residual elotuzumab from monoclonal paraprotein in immunofixation assays for multiple myeloma patients

Negative immunofixation electrophoresis (IFE) of serum and/or urine is a diagnostic marker for determining a complete response (CR) after immunotherapy for multiple myeloma (MM). However, residual therapeutic antibodies such as elotuzumab (IgG-κ), can compromise IFE evaluation when the affected immunoglobulins belong to the same IgG-κ subclass. We thus sought to develop a simple and rapid method to treat patient serum before IFE to distinguish the residual elotuzumab. Serum samples from patients receiving elotuzumab were treated with a predetermined amount of soluble signaling lymphocyte activation molecule F7 (SLAMF7) protein and then subjected to conventional IFE testing. We tested our method in samples from 12 patients. The IgG-κ band in IFE disappeared or shifted after elotuzumab treatment in four patients with no bone marrow minimal residual disease and normalized free light chain, whereas seven patients with any sign of residual MM showed a remaining IgG-κ band after treatment. One-hour incubation of samples with 6-9 molar excess soluble SLAMF7 before IFE was sufficient to distinguish residual elotuzumab in 11 of 12 samples. This simple method does not require special reagents, can be performed in most clinical laboratories, and enables differentiation between patients with a CR and those requiring further treatment.

Discordances between Immunofixation (IFx) and Minimal Residual Disease (MRD) Assessment with Next-Generation Flow (NGF) and Sequencing (NGS) in Patients (Pts) with Multiple Myeloma (MM): Clinical and Pathogenic Significance

Discordances between Immunofixation (IFx) and Minimal Residual Disease (MRD) Assessment with Next-Generation Flow (NGF) and Sequencing (NGS) in Patients (Pts) with Multiple Myeloma (MM): Clinical and Pathogenic Significance

Clinical Significance and Biomarkers to Predict Unsustained Complete Remission in Transplant-Eligible Multiple Myeloma

Clinical Significance and Biomarkers to Predict Unsustained Complete Remission in Transplant-Eligible Multiple Myeloma

Assessment of Minimal Residual Disease in a Phase 1b Study of Once-Weekly Carfilzomib Combined with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma

Assessment of Minimal Residual Disease in a Phase 1b Study of Once-Weekly Carfilzomib Combined with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma

Indicators of profound hematologic response in AL amyloidosis: complete response remains the goal of therapy

In AL amyloidosis complete response (aCR) is defined as negative serum and urine immunofixation with normalized free light chain ratio (FLCR). However, achievement of low levels of involved FLC (iFLC) or difference between iFLC and uninvolved FLC (dFLC) are also relevant endpoints for treatment. We divided 434 consecutive patients with AL amyloidosis into five groups according to response 6 months after treatment initiation: aCR, iFLC <20 mg/L, normalized-iFLC, dFLC <10 mg/L, and normalized FLC ratio. Overall survival (OS) was similar (median not reached) in patients in aCR and in those who reached iFLC <20 mg/L, while it was inferior in all other groups (medians ranging from 79 to 91 months). Time to next therapy or death (TNTD) was longer in subjects attaining aCR (median 69 months) than in subjects reaching any FLC endpoint (medians ranging from 18 to 39 months). The ability of discriminating patients who survived more than 2 years among all responders was greater for current definition of aCR compared to combination of negative serum and urine immunofixation with any low-FLC endpoint. Complete response predicts best outcomes in AL amyloidosis and should be the goal of therapy if tolerability allows.

Impact of involved free light chain (FLC) levels in patients achieving normal FLC ratio after initial therapy in light chain amyloidosis (AL).

Achievement of a normal FLC ratio (FLCr) following treatment indicates hematologic response and suggests better outcomes in light chain amyloidosis (AL). We examined if elevated involved free light chain (hiFLC) impacts outcomes in patients achieving normal FLCr. We retrospectively analyzed 345 AL patients who were diagnosed within a 10-year period (2006-2015) and had 2 consecutive normal FLCr values after 1st line treatment. Among these, patients with hiFLC at 1st reading of normal FLCr (hiFLC1; n = 166; 48.1%) were compared to those who did not (n = 179; 51.9%). Patients with AL who have hiFLC1 after initial therapy had higher rates of multi-organ involvement (63.3 vs 46.4%; P = .002) and patients in advanced Mayo stage (42.9 vs 32.2%; P = .04) at diagnosis. The median progression free survival [PFS; 38.2 (95%CI; 26.4, 55.4) vs 67.1 (95%CI; 55.8, 88) months; P = .0002] and overall survival [OS; 94.4 (95%CI; 78, 107.1) vs not reached (NR, 95%CI; 116.1, NR) months; P < .0001] were lower in those who had hiFLC1. A more stringent comparison for patients with 2 consecutive hiFLC (hIFLC2; n = 111; 32.2%) versus not (n = 2234; 67.8%) showed consistent results [PFS; 27.1 (95%CI; 23, 53.8) vs 63.3 (95%CI; 55.4, 77) months; P < .0001 and OS; 78 (95% CI; 54.6, 98.8) vs NR (95%CI; NR, NR); P < .0001]. This poor prognostic impact of hiFLC on survival was independent of serum creatinine, Mayo stage, negative immunofixation status and inclusion of transplant in initial therapy on multivariate analysis. Hence, persistent elevation of iFLC predicts poor prognosis even among patients achieving normal ratio after initial therapy in AL.

Outcomes according to involved free light chain (FLC) levels in patients with normal FLC ratio after initial therapy in light chain amyloidosis (AL).

8049 Background: Complete response in AL is defined as normal FLC ratio with negative serum and urine immunofixation. It is not clear if high involved serum FLC (hIFLC) in a patient with normal ratio may contribute to ongoing amyloid formation and hence affect outcomes. Methods: Data of 1308 patients (pts) with systemic AL seen within 90 days of diagnosis, at Mayo Clinic between 2006-2015, was analyzed retrospectively. Among these, 369 pts had 2 consecutive normal FLC ratio values after 1st line treatment and form the study population. Log rank test was used to estimate survival differences. Results: Among these 369 pts, pts with hIFLC at 1streading of normal FLC ratio (hIFLC1; n=170; 46.1%) were compared to those who did not (n=199; 53.9%). At diagnosis, the median age [61.5 vs 60.8 years (y); p=0.2], proportion of males (62.4 vs 58.3%; p=0.4), percentage of pts with renal involvement (73.5 vs 64.8%; p=0.07), in mayo stage I / II / III / IV (32.9% / 23%/ 27.3% / 16.8% vs 43.6 %/ 22.9% / 18.1% / 15.4%; p=0.1), with bone marrow plasma cells &gt;10% (24.2 vs 30%; p=0.2) and with presence of t(11; 14)(48.4 vs 60; p=0.08) was similar, while cardiac (67.5 vs 53.3%; p=0.006) and hepatic (18.2 vs 9.1%; p=0.01) involvement was higher in hIFLC1 group. The median follow-up from diagnosis was 6.1 y (95% CI; 5.6, 6.8). The median progression free survival (PFS) in pts who had hIFLC1 was lower than for those who did not; 2.6 y (95% CI; 1.9, 4.5) vs 5.2 y (95% CI; 4.6, 6.4), p&lt;0.0001, as was the median overall survival [OS; 6.7 y (95% CI; 4.5, 8.3) vs not reached (NR), p&lt;0.0001]. We performed a more stringent comparison for pts with 2 consecutive hIFLC values (hIFLC2; n=112; 30.4%) versus not (n=257; 69.6%). The median PFS (3.2 y; 95%CI; 2.2, 4.5 vs 5.6 y; 95% CI; 4.7, 7.1; p&lt;0.0001) and OS (7.8 y; 95% CI; 6.4, NR vs NR; 95%CI; 9.5, NR; p&lt;0.0001) were significantly reduced in pts with hIFLC2 versus not as well. A multivariate analysis confirmed an impact of hIFLC1 and hIFLC2 on PFS/OS independent of serum creatinine. Conclusions: In pts with systemic AL, persistent elevation of the involved FLC predicts for poor prognosis (independent of serum creatinine) even among those who achieved normal FLC ratio after 1st line treatment.

Response-Adapted Therapy for Newly Diagnosed Myeloma

Background: Before SWOG S0777 (Durie BGM at al. ASH 2015, abstract #25) it was not clear whether standard upfront regimens VRd (bortezomib, lenalidomide, dexamethasone) or Rd (lenalidomide, dexamethasone) yield different survival outcomes for newly diagnosed myeloma patients (pts.) but it was known that the higher response rate of VRd comes at a higher risk for severe peripheral neuropathy. Since no test predicts who requires the more toxic regimen to avoid adverse myeloma effects we designed a carepath that tailors therapy according to early response endpoints.Methods: Newly diagnosed symptomatic MM patients (pts) with measurable disease who were not eligible for or elected against a clinical trial were advised to begin a 2-drug regimen of lenalidomide (R) and weekly dexamethasone (d) or, if cast nephropathy suspected or R copay too high, bortezomib (V) and dexamethasone (D). Depending on response assessment per IMWG 2011 criteria after each cycle, treatment intensity was to be increased with sequential addition of agents (R or V, cyclophosphamide, and then liposomal doxorubicin) when there was not at least minor response (MR) after the first, or at least partial response (PR) after the second cycle of an administered combination. Once PR was reached, pts. were evaluated for high dose melphalan (HDM) and ASCT or consolidation with their induction regimen followed in either case by lenalidomide or bortezomib maintenance. After IRB approval, pts treated on carepath were identified through our registry and electronic medical records were reviewed.Results: From Oct 2012 to Dec 2015 the carepath was used in 91 pts. Their median age at treatment start was 64 years (34-84), 40 (44%) were ≥ 65, 11 (12%) ≥ 75 years old; at least one cytogenetic risk study (MyPRS®, FISH panel, karyotype analysis) was obtained in 81 (89%) and of them 23 (28.4%) had high risk features (MyPRS® score > 45.2, del17p, 1q amp, t4;14, t;14;16 and non-hyperdiploid karyotype abnormalities), 33 (36%) had ISS stage III and 21 (23%) had serum creatinine ≥ 2mg/dL, 6 (7%) were on dialysis. At median follow up of 20.5 months (1.7-44.6), at least PR was achieved in 84 pts (92%), at least very good partial remission (VGPR) in 63 (69%), with negative immunofixation in blood and urine in 24 (26%) and complete remission (CR) documented by bone marrow exam in 6 (7%). Only one pt (1%) had progressive disease as best response, stable disease and MR were seen in 3 pts. (3%) each. Induction required 2, 3, 4 and 5 drugs in 49 (54%), 33 (36%), 8 (9%), 1 (1%) pts, respectively, and was followed by high dose melphalan and autologous stem cell transplant in 19 (21%). Sixty-three pts. (69%) remain on carepath treatment without progression, while 28 (31%) have experienced progression with skeletal events in 4 (4%) and ARF in 2 pts. (2%). Nine pts. (10%) have died, 4 while in remission of whom 3 suffered a bleed while anticoagulated for DVT or pre-existing A-fib and died 1 after transition to hospice; the remaining 5 died after progression, of infection (3), secondary plasma cell leukemia (1), or after transition to hospice (2). No patient developed shingles or second primary malignancies so far; mild peripheral neuropathy (PNP) occurred in 27 pts (30%), severe or painful PNP in 4 (4%) and 8 pts. (9%) suffered venous thromboembolism (9%) on DVT prophylaxis with aspirin.Conclusions: Carepath therapy required only two drugs during induction in over 50% of patients to achieve an overall response rate of 92% with ≥ VGPR in 69% in a real-world setting without exclusion of patients on dialysis. Reduction in costs and side effects compared to upfront use of VRd for everyone were accompanied by promising early Kaplan-Meier estimates for progression-free and overall survival (Fig. 1) supporting the carepath principle and future randomized comparison of response-adapted therapy to fixed regimens like the new SWOG S0777 defined standard triplet VRd. [Display omitted] DisclosuresReu:Novartis: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Signal Genetics: Consultancy. Valent:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Faiman:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Takeda: Consultancy. Hamilton:Takeda: Speakers Bureau. Smith:Celgene: Honoraria; Spectrum: Honoraria; Genentech: Honoraria; Abbvie: Research Funding.

RASSF4 functions as a tumor suppressor in Multiple Myeloma

of over-represented TCR Vbeta than CD4+ T cells. Most of the patients (22out of 23) showed at least oneTCRVbeta over-represented in CD8+ T cells suggesting an enrichment compared to the general population. As shown in Figure 1, the most common over-represented TCR Vbeta were 13.1, 5.3 and 17. In this study, 70% of the long survivors showed an oligoclonal band in serum immunofixation, different from original monoclonal myeloma paraprotein. Among them, 19% over-expressed 4 or 5 different TCR Vbeta while patients with negative immunofixation displayed less diversity in their repertoire. The most frequent over-represented TCR Vbeta 13.1 and 17 were found among the patients with oligoclonal humoral immune response. In contrast, other TCR Vbeta such as 13.2 seemed to be higher in patients who did not show oligoclonal bands. Conclusions: Characterization of TCR repertoire of the long survivors indicates a higher involvement of the CD8+ T cells compared to CD4+ T cells. Patients with oligoclonal bands showed a higher diversity of TCR Vbeta over-represented, preferentially 13.1 and 17, suggesting a potential oligoclonal expansion of the CD8+ T cell response.

Utility of Serum Free Light Chain Measurements in Multiple Myeloma Patients Not Achieving Complete Response

![Graphic][1] Background: Normalization of serum free light chain ratio (FLCr) following achievement of a complete response (CR) to therapy denotes a stringent CR in multiple myeloma, and is associated with improved overall survival (OS). However, its value in patients achieving less than a CR is not clear. We hypothesized that patients in whom FLCr normalizes with the initial anti-myeloma therapy will have an improved outcome, even in the absence of a CR. Methods: We analyzed the medical records of patients with MM who were evaluated at Mayo Clinic, Rochester, MN between January 2004 and December 2011, seen within 90 days of diagnosis. We selected patients with measurable disease on serum protein electrophoresis, defined as a serum M-spike ≥1 g/dl at the time of diagnosis. Then, we excluded all patients with negative immunofixation for monoclonal M-protein in serum and urine at their first response as well as those who did not have serum FLC results available from the time of their first best response. M protein measurements were collected serially from the time of diagnosis until the time of the first relapse or last follow up date if no relapse was recorded. Progression-free survival (PFS) and OS were analyzed using the Kaplan-Meier method. Results: Out of the 1354 MM patients seen at our institution during this period, a total of 453 patients were included in our study. The median age of the cohort at the time of diagnosis was 65 (range, 29-91); 49% were older than 65 years and 284 (63%) were male. The estimated median follow up for the whole cohort was 66 months (95% CI; 61, 71); 241 patients were alive with a median follow up of 4.7 years (range, 0.4 to 10). Three hundred and seventy three (82%) patients had relapsed following the initial therapy with a median time to progression (TTP) of 19.5 months (95% CI; 18, 22) and PFS of 19 months (95% CI; 17, 20). The median OS for the entire cohort is 67 months (95% CI; 59, 73). The median time to the best first response was 6.9 months (range: 0.3-83 months). At the time of the best first response 154 patients (34%) had normal FLCr. Patients with normal FLCr had a longer PFS (29 vs. 16 months, P< .0001) and OS (91 vs. 58 months, P= .0002). We then examined the impact of FLCr normalization on survival outcomes according to their IMWG response categories. We found that FLCr normalization had a favorable impact on PFS in each of the three groups [very good partial response (VGPR), Partial response (PR), and Stable disease (SD)], However, when looking at the OS, only patients with PR had a better OS associated with a normal sFLC κ/λ ratio ( Table 1) . Conclusions: Obtaining a normal sFLC ratio appears to confer a more favorable prognosis irrespective of the depth of the response, suggesting an important role for serial-sFLC measurements in disease monitoring even in patients who achieve only a PR to therapy as their best response. This supports the inclusion of sFLC at all levels of response included in the current International Myeloma Working Group (IMWG) criteria. | | SD | PR | VGPR | | --------------------------- | ------------- | ----------- | ----------- | ------------- | | Normal FLCr | Abnormal FLCr | p-value | Normal FLCr | Abnormal FLCr | p-value | Normal FLCr | Abnormal FLCr | p-value | | Number of patients | 7 | 70 | | 62 | 157 | | 85 | 60 | | | PFS, month, median (95% CI) | 27 (14, 36) | 7 (5, 12) | < .02 | 26 (20, 36) | 17 (13, 20) | .0005 | 29 (23, 32) | 21 (18, 26) | .03 | | OS, months, median (95% CI) | 68 (49, 68) | 41 (31, 61) | > .1 | NR (65, NR) | 61 (50, NR) | .004 | 74 (67, 107) | 73 (59, NR) | > .9 | Abstract 3427. Table 1 Effect of FLCr normalization according to IMWG response categories • Abbreviations: NR; statistically not reached •• Progressive disease (PD) was not included because none of the 12 patients achieved a normal FLCr. Disclosures No relevant conflicts of interest to declare. [1]: /embed/inline-graphic-2.gif

Comparison of Waldenstrom Macroglobulinemia Responses Using Immunoglobulin Heavy / Light Chain Analysis and Conventional Electrophoresis Techniques

Background. Waldenstrom’s macroglobulinaemia (WM) is a B cell lymphoproliferative disorder which is characterised by the production of monoclonal IgM (m-IgM). Response assessment is reliant upon reductions in the m-IgM as measured by serum protein electrophoresis (SPEP) or nephelometric/turbidimetric total IgM (tIgM) measurements alongside lymphadenopathy / splenomegaly assessment. Response assessment guidelines include reductions of <25% m-IgM (stable disease, SD), 25-50% (minor response, MR), 50-90% (partial response, PR), >90% (very good partial response, VGPR), 100% with negative immunofixation (complete response, CR) with progressive disease being described as a >25% increase in m-IgM. However, quantitation of m-IgM is not without limitations. The pentameric form of IgM has a molecular weight of >900 kDa, which may be responsible for its tendency to self-aggregate which causes issues in the accuracy of quantitation by SPE. tIgM values are systematically greater than measurement by SPEP densitometry and unable to discriminate between m-IgM and polyclonal IgM as serum concentrations approach the normal range (~2 g/L). Recently novel immunoassays quantifying the heavy / light chain partnership for IgM (IgMκ / IgMλ) have become available, here we report on the performance of the assay in a population of Waldenstrom’s patients.Methods. Diagnostic serum was available for 78 WM patients (48IgMκ / 30IgMλ); longitudinal samples were available for 25 patient (median 9 samples, range 3-20), median 1146 days (min 62, max 2220). Sera were analysed retrospectively using the IgM Hevylite immunoassay (Binding Site, UK) on a SPAPLUS (Binding Site, UK) analyser. Results were compared to SPEP / Immunofixation (Sebia, Hydrasys II), tIgM (Binding Site, UK) and established normal ranges (IgMκ: 0.19-1.63 g/L; IgMλ: 0.12-1.01 g/L; IgMk/IgMl ratio: 1.18-2.74; total IgM: 0.5-2 g/L). dHLC (monoclonal isotype IgM HLC – uninvolved isotype IgM HLC) was used as an assessment of m-IgM. Substantial equivalence was assessed by Weighted Kappa (WK, >0.81 considered to be agreement between methods)Results. At presentation all WM patients had an abnormal IgMκ / IgMλ ratio (IgMκ median 140, range 9-2850; IgMλ median 0.1, 0.001-0.9), 2/48 IgMκ and 9/30 IgMλ patients were not quantifiable by SPEP and 4 patients had m-IgM within the normal tIGM normal range. There were considerable differences in the m-IgM concentration as measured by the three tests. IgMκ SPEP (median 13.52g/L, range 0-52.0g/L), tIgM (18.15g/L, 3.28-65.4g/L) and IgMκ HLC (21.2g/L, 2.82-126g/L); IgMl SPEP (median 10.62/L, range 0-39.88/L), tIgM (11.30/L, 1.40-65.40/L) and IgMl HLC (13.4g/L, 0.77-67.4g/L). However, responses assigned by the test during follow-up were remarkably consistent (see table 1) SPEP v dHLC WK 0.84 (s.e. 0.045 95% c.i. 0.75-0.93), tIgM v dHLC WK 0.86 (s.e. 0.04 95% c.i. 0.78-0.94),. Interestingly, IgMκ / IgMλ ratios indicated residual disease in 5/25 patients in whom electrophoresis indicated a CR, in 2/5 of these patients the abnormal ratio was driven by a suppression of the uninvolved HLC IgM. Furthermore, in 7/25 patients tIgM values fell within the normal range during monitoring, and IFE was required to confirm m-IgM. In 7/7 patients IgMκ / IgMλ ratios remained abnormal.Conclusion. Quantification of m-IgM can be problematic not assisted by the poor agreement between methods and method specific limitations. To adequately evaluate patients SPEP, IFE and tIgM are all required to overcome these issues; in our study these could be replaced using IgM HLC. Furthermore the sensitivity to detect residual disease appeared to be greater when looking at IgMκ / IgMλ ratios than when using electrophoretic techniques. This may be due isotype matched pair suppression which has been shown to be prognostic in other B cell disorders including MGUS and Multiple Myeloma. Further studies are required to thoroughly evaluate the role of IgM HLC and pair suppression in WM. [Display omitted] DisclosuresLeblond:Roche: Honoraria, Speakers Bureau.

The Role of CD27, CD40 and CD117 in the Diagnosis and Prognosis of Multiple Myeloma Established by Flow Cytometry

Multiple myeloma (MM) is a clonal disease characterized by an increased number of malignant plasma cells (M-PCs) that accumulate in bone marrow (BM). High dose of chemiotherapy followed by autologous peripheral blood stem cell transplantation produces a high rate of complete remissions; however the duration of such responses does not usually exceed three years due to the persistence of residual tumor cells, known as minimal residual disease (MRD), responsible for tumor relapse. The aetiology of malignancy remains unknown, although the BM microenvironment plays a critical role in the genesis by stimulating the proliferation of M-PCs and inhibiting the apoptosis.The aim of this study is to analyse and compare the phenotype of M-PCs with that of normal PCs as well as to correlate it with clinical outcome of MM patients in order to identify significant phenotypic differences able to 1) contribute to the differential diagnosis of monoclonal gammopathies by clearly identifying and characterizing M-PCs; 2) identify new prognostic markers; 3) evaluate MRD and monitor treatment efficacy; 4) identify new potential specific markers of M-PCs suggesting antibody-based targeted therapies.A total of 45 patients (pts) were enrolled in the study and their BM samples collected at the diagnosis: 15 patients with active MM, 10 with non-active MM, 10 with MGUS and 10 controls. The BM samples of MM patients were prospectively collected following each course of therapy, and in particular at time +100 after HDT/ASCT, as well as at the time of relapse or progression. At each consultation a multiparametric flow cytometric immunophenotype evaluation was performed using the following monoclonal antibodies: CD56, CD19, CD138 (CD38), CD45 and immunoglobulin κ and λ light chains to identify PCs . The CD117, CD40 and CD27 antibodies were used to distinguish distinct populations of PCs. A direct 8-color method was applied to study the immunophenotype of PCs, utilizing a Navios Cytometer (Beckaman Coulter), and analysing with Kaluza software. Immunophenotype data were compared with them of immunofixation (IMF) and polymerase chain reaction (PCR) approaches. The study was approved by the local Ethics Committee and all patients provided their informed consent in accordance with the Declaration of Helsinki.Significant immunophenotype changes were found in the marrow infiltration of M-PCs, and, mainly, in the aberrant expression of CD27 and CD40/CD117. Almost all patients (93,3%) with active MM showed the characteristic immunophenotype of M-PCs with aberrant expression of CD56 and concomitantly lack of CD19 and CD27. When the expression of CD27 was evaluated in M-PCs following the therapy and compared with both IMF and PCR data seemed to be modulated by disease relapse/progression or disease treatment (fig.1) resulting a significant increased (P=0.006) in pts with complete response (CR) (IMF and PCR negative) as compared with them relapsed and lost with myeloma progression. An inverse correlation was observed by evaluating the expression of CD40 and CD117 that seemed be modulated by disease treatment. Following the therapy the simultaneous expression of CD40/CD117 was observed in almost pts (86%) with negative IMF and positive PCR. Conversely this characteristic immunophenotype fingerprint was absent in all pts with CR. However the expression of CD117 in CD38+CD138+ cells was greater in MGUS or non-active MM pts than in pts in CR (p<0,01).In the present study, we assumed that the contribution of different antigens assessed simultaneously would give more information to diagnosis of MM pts and to better stratify for risk of relapse/progression in order to initiate the most appropriate treatment, and to monitor treatment efficacy. CD19 and CD27 together resulted in optimal accordance with IMF and PCR approaches. Conversely CD40/CD117 showed a good accordance with disease response to the treatment. Our next goal will be to enrol more patients in order to generate a model of forecasting that evaluates simultaneous all three antigens assigning each one a specific weight in the contribution of diagnosis/prognosis. This will be useful to identify a immunophenotype fingerprint on which to design antibody-based targeted therapies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Utility of Serum Free Light Chain Measurements in Multiple Myeloma Patients Not Achieving Complete Response

▪Background: Normalization of serum free light chain ratio (FLCr) following achievement of a complete response (CR) to therapy denotes a stringent CR in multiple myeloma, and is associated with improved overall survival (OS). However, its value in patients achieving less than a CR is not clear. We hypothesized that patients in whom FLCr normalizes with the initial anti-myeloma therapy will have an improved outcome, even in the absence of a CR.Methods: We analyzed the medical records of patients with MM who were evaluated at Mayo Clinic, Rochester, MN between January 2004 and December 2011, seen within 90 days of diagnosis. We selected patients with measurable disease on serum protein electrophoresis, defined as a serum M-spike ≥1 g/dl at the time of diagnosis. Then, we excluded all patients with negative immunofixation for monoclonal M-protein in serum and urine at their first response as well as those who did not have serum FLC results available from the time of their first best response. M protein measurements were collected serially from the time of diagnosis until the time of the first relapse or last follow up date if no relapse was recorded. Progression-free survival (PFS) and OS were analyzed using the Kaplan-Meier method.Results: Out of the 1354 MM patients seen at our institution during this period, a total of 453 patients were included in our study. The median age of the cohort at the time of diagnosis was 65 (range, 29-91); 49% were older than 65 years and 284 (63%) were male. The estimated median follow up for the whole cohort was 66 months (95% CI; 61, 71); 241 patients were alive with a median follow up of 4.7 years (range, 0.4 to 10). Three hundred and seventy three (82%) patients had relapsed following the initial therapy with a median time to progression (TTP) of 19.5 months (95% CI; 18, 22) and PFS of 19 months (95% CI; 17, 20). The median OS for the entire cohort is 67 months (95% CI; 59, 73). The median time to the best first response was 6.9 months (range: 0.3-83 months). At the time of the best first response 154 patients (34%) had normal FLCr. Patients with normal FLCr had a longer PFS (29 vs. 16 months, P< .0001) and OS (91 vs. 58 months, P= .0002).We then examined the impact of FLCr normalization on survival outcomes according to their IMWG response categories. We found that FLCr normalization had a favorable impact on PFS in each of the three groups [very good partial response (VGPR), Partial response (PR), and Stable disease (SD)], However, when looking at the OS, only patients with PR had a better OS associated with a normal sFLC κ/λ ratio (Table 1).Conclusions: Obtaining a normal sFLC ratio appears to confer a more favorable prognosis irrespective of the depth of the response, suggesting an important role for serial-sFLC measurements in disease monitoring even in patients who achieve only a PR to therapy as their best response. This supports the inclusion of sFLC at all levels of response included in the current International Myeloma Working Group (IMWG) criteria.Abstract 3427. Table 1Effect of FLCr normalization according to IMWG response categoriesSDPRVGPRNormal FLCrAbnormal FLCrp-valueNormal FLCrAbnormal FLCrp-valueNormal FLCrAbnormal FLCrp-valueNumber of patients770621578560PFS, month, median (95% CI)27 (14, 36)7 (5, 12)< .0226 (20, 36)17 (13, 20).000529 (23, 32)21 (18, 26).03OS, months, median (95% CI)68 (49, 68)41 (31, 61)> .1NR (65, NR)61 (50, NR).00474 (67, 107)73 (59, NR)> .9- Abbreviations: NR; statistically not reached-- Progressive disease (PD) was not included because none of the 12 patients achieved a normal FLCr. DisclosuresNo relevant conflicts of interest to declare.

Clinical analysis of 36 multiple myeloma patients with extramedullary plasmacytoma invasion of the spinal canal

Few physicians are familiar with extramedullary plasmacytoma (EMP) invasion of the spinal canal in multiple myeloma (MM) patients, and little information about this rare disease is available. The purpose of the present study was to investigate the clinical features, prognosis and treatment of MM patients with EMP invasion of the spinal canal. We evaluated 36 MM patients with EMP invasion of the spinal canal. EMP invasion was confirmed by magnetic resonance imaging, computed tomography and/or histopathological analysis of bone marrow biopsy samples. Patients underwent surgery followed by chemotherapy or received chemotherapy alone. Chemotherapy consisted of bortezomib-containing regimens and other combination therapies. The patients' median age was 58.6 years (range, 31-78 years). Eight patients had negative immunofixation electrophoresis results, and nine patients had a bone marrow plasma cell infiltration rate of less than 5%. Of the 36 MM patients with EMP invasion of the spinal canal that we identified, 19 had thoracic spinal cord involvement, 10 had lumbar spinal cord involvement, 2 had sacral spinal cord involvement and 5 had both lumbar and thoracic spinal cord involvement. The findings of our study, which is the largest study in MM patients with EMP spinal canal invasion conducted to date, suggest the importance of the early detection of spinal invasion in MM patients. Extramedullary disease was resistant to conventional treatments but responded well to regimens containing novel drugs such as bortezomib. In patients with symptoms of nerve root involvement, the tumour should be resected as soon as possible to relieve spinal cord compression.

Prognostic Value Of Deep Sequencing Approach For Minimal Residual Disease (MRD) Detection In Multiple Myeloma Patients

Background and AimMost multiple myeloma (MM) patients will experience relapse due to the persistence of residual tumor cells, or MRD. We compared the prognostic value of traditional response criteria with MRD measured by three different methods: a sequencing-based method, termed the LymphoSIGHT™ platform, multiparameter flow cytometry (MFC) and ASO-PCR of Ig genes in a cohort of 133 uniformly-treated MM patients from the Spanish Myeloma Group trials. MethodsBone marrow samples were obtained from 133 patients at diagnostic and post-treatment time points on GEM clinical trials (GEM00 and GEM05). All 133 patients were either in CR or VGPR at the post-treatment time point. Using the sequencing assay, we identified clonal rearrangements of immunoglobulin (IGH-VDJ, IGH-DJ, and IGK) genes in diagnostic samples. We then assessed MRD in follow-up samples, analyzing concordance between: sequencing, MFC and ASO-PCR of Ig genes MRD results, and comparing the prognostic value of each method with traditional response criteria. ResultsThe sequencing assay detected the presence of a myeloma-specific gene rearrangement in diagnostic samples from 121 of 133 (91%) patients. We tested MRD in follow-up time points in 109 of the 121 patients.Of the 109 patients, 79 were positive by sequencing at MRD levels of 10-5 or higher and 30 were MRD negative. The Time to Tumor Progression (TTP) and Overall Survival (OS) were significantly longer in the MRD negative group compared with the MRD positive group by sequencing (TTP, median 80 vs. 31 months, p<0.0001; and OS, median not reached vs. 80 months p=0.02) (Figures 1A and 1B). All patients in VGPR, with the exception of 4 cases, were MRD positive by sequencing (92%). Three of the 4 cases with MRD negative and positive immunofixation became immunofixation negative after maintenance treatment. When restricting the analysis to the 61 patients that were in conventional CR (negative immunofixation), 35 of 60 patients were positive by sequencing at MRD levels at 10-5 and higher and 26 were MRD negative. There was a significantly improved TTP in the MRD negative group compared with the MRD positive group (median 131 vs. 35 months, p=0.001) (Figure 1C).A high correlation between MFC and sequencing MRD results was observed (r2=0.87); as well as between ASO-PCR of Ig genes and sequencing (r2=0.89). Discordant results between FCM and sequencing (SEQ) included: 14 cases who were positive by SEQ and negative by FCM, and 5 cases negative by SEQ but positive by FCM; while the remaining cases were concordant: 63 cases were positive by both methods and 16 were negative by both methods. Correlation between ASO-PCR and SEQ was possible in 45 patients: 10 were discordant (9PCR-SEQ+ and 1 PCR+SEQ-) while 35 were concordant (20 PCR+SEQ+, 15 PCR-SEQ-). [Display omitted] ConclusionsThe sequencing applicability for MRD studies in MM is 91%, which is essentially equivalent with that of MFC (96% Rawstron AC et al, JCO 2013). There is a high correlation between MRD levels by sequencing, ASO-PCR and MFC. Based on these results, MRD assessment by sequencing is a useful method for patient risk stratification and can be used to determine molecular CR in MM. Disclosures:Pepin:Sequenta, Inc.: Employment, Equity Ownership. Weng:Sequenta, Inc.: Employment, Equity Ownership. Faham:Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Minimal Residual Disease in Multiple Myeloma

Minimal Residual Disease in Multiple Myeloma

An Intact Immunoglobulin IgAλ Multiple Myeloma Patient Exhibiting Light Chain Escape

AbstractAbstract 5008A 48 year old man was referred to the Institute of Hematology and Transfusion Medicine, Warsaw, Poland in April 2008 with anemia (Hemoglobin; 10. 4 g/dl) and mild renal impairment (eGFR; 75. 4 mL/min/1. 73m2). An initial diagnostic monoclonal protein screen (serum protein electrophoresis (SPE), serum immunofixation electrophoresis (IFE) and serum free light chain (FLC) analysis) revealed an IgAλ monoclonal protein (0. 8g/dL) with monoclonal serum FLC and an abnormal serum FLC κ/λ ratio (0. 0001; RI, 0. 26–1. 65). A bone marrow biopsy at that time confirmed 60% involvement of monoclonal λ - restricted plasma cells; a bone survey did not detect any osteolysis. The patient was diagnosed with multiple myeloma (MM) (ISS stage I, Durie and Salmon stage IA) and was initially treated with 6 cycles of vincristin, doxorubicin and dexamethasone (VAD). The patient responded well to the induction treatment and subsequently underwent a successful autologous stem cell transplantation (ASCT).The patient was monitored for 3 years subsequent to the ASCT with both serum and urine electrophoresis, serum FLC analysis (Freelite) and heavy chain/light chain (HLC) immunoassays (Hevylite). Sixteen months following the ASCT the dFLC (involved λ FLC– uninvolved κ FLC) concentration began to increase, the FLC κ/λ ratio became abnormal with a trace of λ Bence Jones protein (BJP) detected by urine IFE. However, both SPE and IFE were normal and the HLC ratio (IgAλ/IgAκ) was within the normal range. During the next 9 months the dFLC continued to increase and a λ BJP could now be clearly detected on the urine IFE. 27 months following the ASCT the patient sustained a pathological fracture of the tibiae and was referred to our centre 4 months later. At this point, the dFLC concentration was highly elevated (3168 mg/L) with a λ BJP detectable by both serum and urine IFE. However, there was no detectable monoclonal intact immunoglobulin by serum IFE or HLC analysis, indicating disease relapse by a separate FLC clone; referred to as light chain escape (LCE). A bone marrow biopsy revealed 15% involvement of λ restricted plasma cells; this time a bone survey identified osteolysis. The patient was diagnosed with progression of multiple myeloma and received 6 cycles of bortezomib, cyclophosphamide and dexamethasone (VCD regimen). He responded well to treatment and 3 years following the ASCT achieved a CR as indicated by a normalized κ/λ FLC ratio, negative immunofixation with 1–3% bone marrow plasma cells. The patient is now well and able to continue with normal life.In this case study the increase in the dFLC levels was the first indication of disease progression and highlights the importance of monitoring intact immunoglobulin MM patients with serum FLC immunoassays for early detection of LCE. Disclosures:Endean:The Binding Site Group Ltd: Employment. Harding:Binding Site: Employment.