Responses Assigned Using Heavy+Light Chain Assessments Have Better Clinical Correlation with Outcome Than Those Using Current IMWG Criteria for Multiple Myeloma

Abstract Introduction: Stratification of multiple myeloma patient responses by reductions in monoclonal component is based upon reliable, historic outcome data. With the introduction of novel agents, a greater number of patients are achieving hitherto unthought-of responses, with many expecting to meet the requirement for VGPR or greater. Multiple factors can impact the quantification and assessment of response in patients achieving deep responses including the influence of IgG recycling, accuracy of quantitation against an increasing polyclonal background and the presence of monoclonal immunotherapies. Alternative strategies for monoclonal protein measurement include heavy+light chain (HLC) immunoassays. Here for the first time we compare the consistency of response assignment between the two methods and evaluate the clinical impact of discordance. Methods: Sera from 509 newly diagnosed intact immunoglobulin multiple myeloma (IIMM) patients enrolled onto IFM-2009 trial were available (median age was 59 (range: 33-66) years, follow-up 30 (3-56) months). Two patients arms were treated with RVDx3+ASCT+RVDx2 or RVDx8, followed by 12 months Lenalidomide maintenance. Responses were assigned at the end of consolidation therapy according to IMWG criteria using changes in monoclonal protein concentrations measured by either SPE or dHLC (clonal - non clonal). Complete response (CR) was assigned by either method by the absence of monoclonal protein on IFE or a normal HLC ratio (HLCr), respectively, and <5% BM plasma cells. HLC-pair suppression was defined as levels of the non-clonal HLC (e.g. IgGλ in an IgGκ patient) below the reference range (IgGκ <3.84g/L; IgGλ <1.91g/L; IgAκ <0.57g/L; IgAλ <0.44g/L). Minimal residual disease (MRD) was assessed by 7-color flow cytometry at the end of consolidation therapy. Results: IFE and HLCr concordantly identified clonality in 99% patients. In 463 patients followed until the end of consolidation we found moderate agreement in response assignment between the two tests. HLC gave similar response assignments to electrophoretic tests in patients with poor response (≤PR, 76/96; 79%) or complete response (≥CR, 130/142; 92%). However in patients achieving VGPR there was considerable discordance between methods for response assignment (102/225; 45%). Having identified discordant results for VGPR we sought to assess the clinical accuracy of the responses assigned within this group. Of the 225 patients with standard VGPR, HLC response assignment varied (PR (18/225), VGPR (102/225) and ≥CR (105/225)). Median PFS for patients achieving standard VGPR was 34.5 months; responses by HLC further described these patients into those with poorer PFS (PR, median PFS=21.3 months (95%CI: 9.0-33.7)); VGPR (PFS=28.9 months (95%CI: 25.1-32.6)), and those with improved outcomes (CR, median PFS not reached); p<0.0001 (Figure 1). This suggested that the response assigned by electrophoresis could be refined by HLC analysis. By contrast, responses assigned by electrophoretic methods offered no added clinical value in patients achieving VGPR (log-rank: p=0.724) or ≥CR (log-rank: p=0.402) by HLC assessment. Furthermore, an abnormal HLCr post-consolidation had a greater concordance with MRD+ assessment (78% positive) compared to IFE (51% positive); whereas both a normal HLCr and negative IFE displayed similar agreement with MRD- assessment (88% and 94% negative, respectively). Finally we assessed the clinical impact of recovering polyclonal immunoglobulin levels after consolidation therapy. In 142 patients with complete responses, HLC-pair suppression (n=15, median PFS=35.1 months (95%CI: 20.9-49.2) and severe suppression (n=7, median PFS=22.9 months (95%CI: 16.6-29.2)) were associated with poorer outcomes (p=0.060 and p=0.004, respectively). Conclusions: In patients achieving a poor or exceptional response there was good agreement between HLC and standard response assignment. For patients achieving a VGPR we suggest that HLC response assignment may be beneficial, therefore overall the assessment could be used to augment or replace electrophoresis. The prognostic significance of HLC responses seems to be partly dependent in the patient's ability to recover their immune system, as determined by normalisation of non-clonal HLC levels. Figure 1 Figure 1. Disclosures Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Attal:sanofi: Consultancy; janssen: Consultancy, Research Funding; amgen: Consultancy, Research Funding; celgene: Consultancy, Research Funding. Moreau:Novartis: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Avet-Loiseau:janssen: Consultancy; sanofi: Consultancy; amgen: Consultancy; celgene: Consultancy.

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Consolidation with Bortezomib, Thalidomide and Dexamethasone After High Dose Therapy Is Feasible, Safe and Effective In De Novo Multiple Myeloma Patients Who Already Received New Drugs Containing-Induction Regimen

Blood ◽

10.1182/blood.v116.21.3041.3041 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3041-3041 ◽

Cited By ~ 2

Author(s):

Murielle Roussel ◽

Gaëlle Dörr ◽

Willy Vaillant ◽

Anne Huynh ◽

Michel Attal

Keyword(s):

Multiple Myeloma ◽

Research Funding ◽

Residual Disease ◽

Complete Response ◽

New Drugs ◽

High Dose ◽

Consolidation Therapy ◽

High Dose Therapy ◽

Induction Regimen ◽

Immunophenotypic Analysis

Abstract Abstract 3041 High dose therapy (HDT) with autologous stem cell transplantation (ASCT) is a standard treatment option for frontline myeloma patients (pts). However, after a single or a double transplantation, almost all pts ultimately relapse. Thus, new strategies are required to control the residual disease after HDT. Consolidation therapy, given early after HDT, could enhance the depth of response and further improve progression free survival (PFS) and overall survival (OS). The IFM (Intergroupe Francophone du Myélome) previously reported that either Thalidomide or Lenalidomide, administered after HDT, was able to reduce this residual disease (IFM 99-02 and 2005-02 trials, Attal M et al. Blood 2006 and ASCO 2010). Ladetto M et al. (JCO 2010) also reported a major shrinking of residual tumor cell burden in myeloma pts undergoing early consolidation with Bortezomib, Thalidomide and Dexamethasone (VTD) after ASCT. None of these pts had previously received treatment with Thalidomide and/or Bortezomib during induction. The aim of this study was to evaluate the feasibility, safety and efficacy of early consolidation therapy in pts who had received new drugs containing-induction therapies before ASCT. Patients and Methods: In this prospective monocenter study,patients were eligible if they had the following: 1) at least partial response (PR) after HD melphalan (HDM), 2) no grade ≥ 2 peripheral neuropathy (PNY). The consolidation therapy with vTD had to be started within 3 months from ASCT for a total of 2 cycles. Each 4-week cycle consisted of: a) Bortezomib: 1mg/m2 as an IV injection twice weekly (on days 1, 4, 8, 11); b) oral Thalidomide: 100 mg/day; c) oral Dexamethasone 40 mg/day once a week (on days 1, 8, 15 and 22). Pts did not receive maintenance therapy after vTD consolidation. A systematic prophylactic anticoagulation therapy was given either by aspirin or low molecular weight heparin. Pts also received systematic anti herpes zoster prophylaxis with valacyclovir. Toxicities were graded according to the CTAECv4 at each cycle. Response was assessed according to modified European group for Blood and Marrow Transplantion criteria including very good partial response (VGPR), 1 month after the last cycle of vTD. As no immunophenotypic analysis was available routinely in our institute, we did not evaluate stingent complete response. Results: From August 2008 to May 2010, 90 newly diagnosed multiple myeloma pts under 65 received HDM followed by ASCT in the Toulouse's hospital bone marrow transplant unit, FRANCE. Forty-six pts were eligible for this study and started on consolidation. Two pts are ongoing their treatment and 41 received the whole planned treatment. Two pts withdrawn thalidomide and 1 pt did not receive the second cycle of consolidation because of toxicities. Forty-four pts were excluded mainly because of PN (27%). Initial characteristics were: age=58 years (range,44-65); ISS: 1= 50%, 2= 23%, 3=18%, NA= 9%; DS stage: I=4,5%, II=4,5%, III=91%; median beta-2microglobulin=2,9 mg/l (1,3-11,3); FISH analysis: t(4-14) and/or del 17p= 4/29 evaluable pts. The induction regimen was: Bortezomib/Dexamethasone (82%), vTD (11%), or another regimen (7%). Before consolidation therapy, response rates were: PR=16%, VGPR=48%, near complete response (nCR)=14% and CR=23%. In an Intend to treat basis, 17 pts (39%) improved their responses after consolidation with vTD: 3 pts (7%) from PR to VGPR, 8 pts (18%) from VGPR to nCR, and 6 pts (14%) from VGPR to CR. Response improvement was also reported in the 5 pts who already received induction therapy with vTD; three pts (60%) improved their response: 1 pt from PR to VGPR and 2 pts from VGPR to nCR. As immunophenotypic analysis was not avalaible, response improvement might be underestimate for CR pts. Overall, consolidation therapy with 2 cycles of vTD was efficient; 16 pts (36%) acheived CR, 30 pts (68%) CR+nCR and 40 pts (91%) VGPR or better. Considering the safety profile, there was no toxic death or grade 3/4 hematological toxicity. Non-hematological toxicities reported were: fatigue=18%, PNY (all grades)= 9%, pneumonia=7%, vertigo= 7%, constipation= 6%, and deep-vein thrombosis= 4,5%. Conclusions: Early consolidation with vTD in pts who already received Thalidomide and/or Bortezomib as induction therapy is feasible, safe and effective. Response rates improved in almost 40% of pts. Disclosures: Roussel: Janssen: Consultancy, Research Funding, orator; celgene: Consultancy, Orator, Research Funding. Off Label Use: bortezomib and thalidomide as consolidation therapy after High Dose Melphalan. Attal:celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding.

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An Intact Immunoglobulin IgAλ Multiple Myeloma Patient Exhibiting Light Chain Escape

Blood ◽

10.1182/blood.v120.21.5008.5008 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5008-5008

Author(s):

Maria Kraj ◽

Barbara Kruk ◽

Krzysztof Warzocha ◽

Andrzej Szczepinski ◽

Kelly Endean ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bone Marrow Biopsy ◽

Light Chain ◽

Plasma Cells ◽

Induction Treatment ◽

Mild Renal Impairment ◽

Multiple Myeloma Patient ◽

Monoclonal Protein ◽

Serum And Urine

Abstract Abstract 5008 A 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.

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Mass Spectrometry to Measure Response in Immunoglobulin Light Chain Amyloidosis (AL)

Blood ◽

10.1182/blood-2018-99-119969 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4502-4502

Author(s):

Angela Dispenzieri ◽

Surendra Dasari ◽

Bonnie Kaye Arendt ◽

Mindy Kohlhagen Kohlhagen ◽

Taxiarchis Kourelis ◽

...

Keyword(s):

Board Of Directors ◽

Light Chain ◽

Research Funding ◽

Complete Response ◽

Serum Samples ◽

Advisory Committees ◽

Monoclonal Protein ◽

Maldi Tof ◽

Monoclonal Proteins ◽

Tof Ms

Abstract INTRODUCTION: Our group has demonstrated that MASS-FIX is a quick, inexpensive, and accurate means to diagnose and monitor the serum and urine of patients with plasma cell disorders. Screening can be done with a MALDI-TOF MS and samples reflexed to microflow liquid chromatography coupled with electrospray ionization (ESI) and Q-TOF MS (microLC-ESI-Q-TOF MS). Because this technique provides a mass/charge (m/z) for a given patient's monoclonal protein, this method can provide greater sensitivity and specificity to monitor for complete response (CR), especially in patients receiving therapeutic monoclonal antibodies. Our goal was to assess the performance of miRAMM in patients with AL who have been classified as complete response using conventional means. METHODS: We identified 77 patients with AL who had both documented CR by immunofixation (Seibia) of the serum (SIFE), urine IFE (UIFE), and serum free light chain (FLC; The Binding Site) and paired serum samples to test by MALDI-TOF and ESI-TOF. No urine samples were available to test. Paired serum samples from baseline and approximately one year post-therapy were immunoaffinity purified using nanobodies targeting kappa, lambda, alpha, gamma and mu as previously described. For the MALDI-TOF (Bruker Microflex, LT), a range of 9,000 to 32,000 m/z was acquired. The m/z distribution was then visually inspected for the presence of a peak that was distinct from the polyclonal background in both the M+1 and M+2 light chain mass ranges. For the ESI-TOF, spectra were also collected on an TripleTOF 5600 quadrupole time-of-flight mass spectrometer (ABSciex, Vaughan ON, CA) in ESI positive mode with a Turbo V dual ion source with an automated calibrant delivery system. TOF MS scans were acquired from m/z 600−2500 with an acquisition time of 100 ms. RESULTS: Median age of the cohort was 58 (range 42, 81). Fifty-eight percent were male. No test was 100% sensitive at baseline with positive results as follows: abnormal FLC ratio, 82%; positive SIFE, 70%; 73% positive UIFE; positive serum MASS-FIX, 71%; and ESI-TOF, 79% . There was light chain isotype agreement in all cases, except for 2 patients for whom the SIFE and the FLCr disagreed. Of the 56 patients with baseline positive MASS-FIX, there was evidence of the original monoclonal protein in 5 patients (see figure for example of spectra illustrating same m/z before and after therapy). Of the 63 patients who had baseline positive ESI-TOF, there was evidence of the original monoclonal protein in 8 patients. Small unrelated monoclonal proteins were seen both by SIFE and by mass spectrometry techniques. With the spectrometry techniques, however, these transient oligoclonal bands could be distinguished from the original monoclonal protein when they shared the same isotype based on the difference in m/z. DISCUSSION: At baseline, the MALDI was able to identify the baseline monoclonal protein in a comparable number of patients as SIFE, UIFE, and FLC. Approximately 10% of patients thought to be in CR using routine screening tests were found to have persistence of their original clone by MALDI and by ESI-TOF. Small post-therapy unrelated monoclonal proteins were also seen both by IFE and by MALDI, but either the presence of a different isotype or in the case of MALDI, a different m/z, made it clear that the monoclonal protein was not related to the original clone. The sensitivity of the assay will improve significantly when we formalize the introduction of free light chain magnetic beads to capture the serum FLCs. Routine use of MASS-FIX of the urine will also increase performance characteristics. Figure. Figure. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Prothena: Honoraria; celgene: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Physicians Education Resource: Consultancy; annexon: Consultancy; Apellis: Consultancy; Alnylam: Honoraria; Medscape: Consultancy; Amgen: Consultancy; janssen: Consultancy; Research to Practice: Consultancy; Abbvie: Consultancy; Ionis: Honoraria. Kumar:Novartis: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership.

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Serum free light chain measurements to reduce 24-h urine monitoring in patients with multiple myeloma with measurable urine monoclonal protein

American Journal of Hematology ◽

10.1002/ajh.25215 ◽

2018 ◽

Vol 93 (10) ◽

pp. 1207-1210 ◽

Cited By ~ 1

Author(s):

Marcella Tschautscher ◽

Vincent Rajkumar ◽

Angela Dispenzieri ◽

Martha Lacy ◽

Morie Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Light Chain ◽

Free Light Chain ◽

Serum Free ◽

Monoclonal Protein ◽

Serum Free Light Chain

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High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis

Blood ◽

10.1182/blood-2007-01-067728 ◽

2007 ◽

Vol 110 (3) ◽

pp. 827-832 ◽

Cited By ~ 132

Author(s):

Frits van Rhee ◽

Vanessa Bolejack ◽

Klaus Hollmig ◽

Mauricio Pineda-Roman ◽

Elias Anaissie ◽

...

Keyword(s):

Multiple Myeloma ◽

Light Chain ◽

Prognostic Significance ◽

Complete Response ◽

High Serum ◽

Free Light Chain ◽

Response To Therapy ◽

Rapid Reduction ◽

Serum Free ◽

Serum Free Light Chain

Abstract Serum-free light chain (SFLC) levels are useful for diagnosing nonsecretory myeloma and monitoring response in light-chain–only disease, especially in the presence of renal failure. As part of a tandem autotransplantation trial for newly diagnosed multiple myeloma, SFLC levels were measured at baseline, within 7 days of starting the first cycle, and before both the second induction cycle and the first transplantation. SFLC baseline levels higher than 75 mg/dL (top tertile) identified 33% of 301 patients with higher near-complete response rate (n-CR) to induction therapy (37% vs 20%, P = .002) yet inferior 24-month overall survival (OS: 76% vs 91%, P < .001) and event-free survival (EFS: 73% vs 90%, P < .001), retaining independent prognostic significance for both EFS (HR = 2.40, P = .008) and OS (HR = 2.43, P = .016). Baseline SFLC higher than 75 mg/dL was associated with light-chain–only secretion (P < .001), creatinine level 176.8 μM (2 mg/dL) or higher (P < .001), beta-2-microglobulin 297.5 nM/L (3.5 mg/L) or higher (P < .001), lactate dehydrogenase 190 U/L or higher (P < .001), and bone marrow plasmacytosis higher than 30% (P = .003). Additional independent adverse implications were conferred by top-tertile SFLC reductions before cycle 2 (OS: HR = 2.97, P = .003; EFS: HR = 2.56, P = .003) and before transplantation (OS: HR = 3.31, P = .001; EFS: HR = 2.65, P = .003). Unlike baseline and follow-up analyses of serum and urine M-proteins, high SFLC levels at baseline—reflecting more aggressive disease—and steeper reductions after therapy identified patients with inferior survival.

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Serum Free Light Chain Analysis Improves Monitoring of Multiple Myeloma Patients Receiving First-Line Therapy with the Combination of Velcade, Doxil, and Dexamethasone (VDD).

Blood ◽

10.1182/blood.v110.11.2736.2736 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2736-2736

Author(s):

Daniel Lebovic ◽

Tara Kendall ◽

Christine Brozo ◽

Amanda McAllister ◽

Malathi Hari ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Disease Progression ◽

Light Chain ◽

Residual Disease ◽

Clinical Information ◽

Complete Response ◽

Response To Therapy ◽

Controlled Clinical Trial ◽

Serum Free

Abstract Introduction: Serum free light chains (sFLC) have a short 2–6hr serum half-life compared with up to 3 weeks for intact immunoglobulins (Ig). sFLC analysis (Freelite™, The Binding Site Inc) therefore provides earlier therapeutic information for Intact Ig Multiple Myeloma (IIMM) patients producing monoclonal FLC. Also, it may be a more sensitive method than urinary Bence Jones protein (BJP) analysis for monitoring light chain MM (LCMM) patients. We assessed the benefits of monitoring sFLC in addition to serum and urine M-protein in previously untreated MM patients receiving combination therapy with Velcade, Doxil, and Dexamethasone (VDD). Methods: 38/40 patients enrolled in a Phase II clinical trial received up to six 3-week VDD cycles (Velcade: 1.3 mg/m2IV; Days 1, 4, 8, 11, Doxil: 30 mg/m2 IV; Day 4, and Dexamethasone: 20 mg PO; Days 1, 2, 4, 5, 8, 9, 11, 12. During the first cycle, Dexamethasone was given at 40 mg per dose, with the first 10 patients receiving Dexamethasone at 40 mg PO on Days 1 – 4). Responses were determined based on uniform response criteria (URC, Durie et al. (2006) Leukemia20, 1467). 31/38 patients had IIMM (16 IgGκ, 8 IgGλ, 5 IgAκ, 2 IgAλ). 7/38 patients had LCMM (3 κFLC, 4 λFLC). 8/31 IIMM and 2/7 LCMM patients had sFLC levels <10mg/dL at baseline, too low to define measurable disease according to the URC. Results: sFLC and intact Ig response was similar in 16/31 IIMM patients (at least partial response (PR), 4/16 had baseline sFLC levels <10mg/dL). In 7/31, the difference between involved and uninvolved sFLC levels fell to <50% of baseline one cycle or more earlier than intact Ig levels indicated at least PR (for 3/7, intact Ig levels indicated stable disease). In 1 patient, intact Ig levels fell to <50% of baseline before sFLC. 2/31 patients displayed probable light chain escape during treatment, with a third patient’s disease progression indicated earlier by sFLC than intact Ig. In 4/31 patients, sFLC analysis provided no useful information. sFLC ratios normalised in 6/31 IIMM patients, supportive of a stringent complete response. 16/31 IIMM patients had no significant BJP; in 15/31 with BJP, changes in sFLC and BJP levels were similar. Changes in sFLC and BJP levels agreed in 5/7 LCMM patients. 2/7 became negative for BJP while continuing abnormal sFLC levels suggested residual disease (in both these patients, baseline sFLC levels were <10mg/dL). Conclusion: Analysing sFLC in addition to intact Ig generated clinically relevant detail in 10/31 (32%) IIMM patients, with earlier response identified in 7 patients and probable disease progression in 3 patients. sFLC analysis provided a more sensitive means of monitoring response to therapy and identifying residual disease in 2/7 (29%) LCMM patients. No clinical information would have been lost by replacing BJP with sFLC analysis when monitoring either IIMM or LCMM. Our data suggests that the URC 10mg/dL baseline sFLC cut-off may not always be appropriate, as sFLC analysis of some patients with <10mg/dL was informative. Furthermore, sFLC analysis can be used in assessing stringent complete response. This analysis of data from a controlled clinical trial shows that sFLC can be used not only as a useful tool to monitor initial therapy of multiple myeloma, but also as a possible replacement for 24-hr BJP analysis.

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T-Bird (thalidomide, clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], Dexamethasone) Therapy for Upfront Use in Symptomatic Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.1861.1861 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1861-1861

Author(s):

Tomer Mark ◽

Morton Coleman ◽

David S Jayabalan ◽

Roger Pearse ◽

Faiza Zafar ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Event ◽

Partial Response ◽

Skin Rash ◽

Research Funding ◽

Study Drug ◽

Complete Response ◽

Median Number ◽

Median Response ◽

Dexamethasone Therapy

Abstract Abstract 1861 Poster Board I-886 Background: BiRD therapy (clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], dexamethasone) for use as upfront therapy in symptomatic multiple myeloma in 72 patients yielded impressive results: over 90% achieved at least a partial response (PR), with nearly 40% in complete response (CR). We hypothesized that we could safely increase the immunomodulatory benefit of the BiRD combination with the addition of low-dose thalidomide to the regimen, since these drugs have non-overlapping toxicities. A trial of T-BiRD (thalidomide, clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], dexamethasone) therapy for use in up-front treatment of symptomatic multiple myeloma (MM) was initiated to test safety and efficacy. Methods: Eighteen patients were enrolled in a single-institution trial of T-BiRD therapy for symptomatic MM. The T-BiRD regimen consists of clarithromycin 500mg twice daily, dexamethasone on days 1,8,15,22 of a 28-day cycle, and lenalidomide 25mg for days 1–21 of a 28-day cycle. Thalidomide is given at a dose of 50mg daily for the first week and thereafter at 100mg daily. Thromboprophylaxis with aspirin (162 mg once weekly, 81mg on subsequent days) was used for all subjects. Serum protein electrophoresis/immunofixation as well as free light chain determinations were done monthly. Bone marrow biopsy and either skeletal imaging were done at to confirm disease progression or CR. This protocol continues to accrue with a planned enrollment of 25 patients. Results: The median number of T-BiRD cycles was 5.5 (range 1–6). Twelve patients (67%) had achieved at least a partial response (PR) by cycle 1, compared to a median response time of 2 cycles for BiRD. Mean percent drop in M-protein for evaluable patients at each cycle is as follows: Cycle 1 – 61%, Cycle 2 – 77%, Cycle 3 – 79%, Cycle 4 – 81%, Cycle 5 – 93%, Cycle 6 – 92%. For 9 subjects who received 5 cycles of therapy, the overall response rate was 100%, with all but one subject achieving a VGPR or better. On an intent to treat basis, the VGPR or better rate was 55% because of patient withdrawal due to toxicity. A total of 10 subjects (56%) experienced an adverse event (AE), some study-drug related (RAE) during treatment. Seven subjects (39%) withdrew from the study due to drug toxicity: 2 had grade 2 skin rash prior to initiation of full-dose thalidomide (RAE), 1 patient had grade 4 skin rash (Stevens-Johnsons syndrome, SJS) during cycle 1 of T-BiRD (RAE), 1 had a TIA in cycle 2, 1 developed renal failure in cycle 1, 1 developed chest pain in cycle 3. Other toxicities include 1 patient with Grade 2 steroid myopathy (RAE), 1 patient with DVT of the leg (RAE), and 1 patient with atrial fibrillation. 1 subject died of progressive myeloma prior to completion of 1 cycle. Conclusions: T-BiRD is a highly effective first-line regimen for rapid and profound treatment response of multiple myeloma. Toxicity from T-BiRD may preclude its long-term use since many of the enrolled patients experienced an adverse event. Disclosures: Mark: Celgene: Research Funding, Speakers Bureau. Zafar:Celgene Corp: Speakers Bureau; Millenium: Speakers Bureau. Crann:Milllennium: Membership on an entity's Board of Directors or advisory committees. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Proteolix: Consultancy, Research Funding.

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Changes in Serum Free Light Chain Rather Than Intact Monoclonal Immunoglobulin Levels Predict Outcome with Therapy in Patients with Light Chain Amyloidosis.

Blood ◽

10.1182/blood.v114.22.747.747 ◽

2009 ◽

Vol 114 (22) ◽

pp. 747-747

Author(s):

Shaji Kumar ◽

Morie A Gertz ◽

Martha Q. Lacy ◽

Suzanne R. Hayman ◽

Francis Buadi ◽

...

Keyword(s):

Overall Survival ◽

Light Chain ◽

Research Funding ◽

Amyloid Fibrils ◽

Multivariable Analysis ◽

Free Light Chain ◽

Term Outcome ◽

Long Term Outcome ◽

Monoclonal Protein ◽

Hematological Response

Abstract Abstract 747 Background: Light chain amyloidosis is a monoclonal plasma cell proliferative disorder characterized by multiorgan deposition of monoclonal light chain derived amyloid fibrils. The diffuse organ infiltration by the amyloid fibrils leads to various AL related clinical features. Therapy of AL has been primarily aimed at elimination or control of the monoclonal plasma cells, thus decreasing the light chain available for amyloid formation. Assessment of response to therapy has been grouped into hematological response demonstrating elimination or reduction of the monoclonal population and organ response demonstrating actual improvement in its structure or function. Given the potentially long delay in observing organ improvement, hematological response has been the surrogate short term marker for long term outcome given the relatively rapid decline seen in the monoclonal protein with effective therapy, as well as studies showing improved long term outcome with a hematological response, especially complete response. However, conventional hematological response criteria give priority to the intact monoclonal protein rather than the light chain, which is the amyloidogenic protein. We hypothesized that a light chain response will correlate better with outcome than changes in the intact monoclonal protein levels. Methods: We identified 348 patients who had undergone stem cell transplant (SCT) for AL from among a large group of patients undergoing different treatments for AL, and in whom serial tests results were available. We identified the lowest value attained following SCT for various hematological response parameters (intact serum M-protein [MP], the difference between involved and uninvolved serum free light chain [FLC-diff], and urine M-protein [UP]) before an alternate therapy was instituted. We first estimated the best cutoff for the degree of change in each parameter that predicted 5-year survival from SCT. Cox proportional hazards model was used for multivariable analysis of factors influencing overall survival (OS). Results: We first examined the relative contribution of the MP and the FLC-diff on the overall survival following transplant. The best cutoff for reduction in FLC-diff to predict OS at 5 years from SCT was 88% if all patients were considered and 90% if only those with a baseline FLC diff > 7.5 mg/dL were considered. The best cutoff for MP reduction was 40% for 5 year survival for all patients and 67% for those with a baseline MP > 1.0 gm/dL. We then looked at the impact of FLC reduction and MP reduction in a multivariable analysis using OS as endpoint. For all patients, FLC reduction, but not MP reduction significantly impacted outcome, and results were similar when considering patients with MP>1.0 gm/dl and FLC-diff > 7.5 mg/dl at baseline. Among those with a baseline FLC-diff >7.5 mg/dL (n=125), the overall survival was 35 mos from SCT for those with less than 90% decrease in FLC-diff (45 pts) compared to not reached for those with at least 90% decrease (80 pts); P < 0.001 (Figure). Conclusions: The current study supports the notion that reductions in the free light chain parameters represent a more useful measure of hematological response that translates into better overall survival and possible better chance at organ improvement. A reduction in the FLC difference of 90% appears to correlate best with prolonged survival. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:celgene: Research Funding.

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Bortezomib with Dexamethasone in Newly Diagnosed Patients with Primary Systemic Light Chain Amyloidosis or Multiple Myeloma-Associated AL Amyloidosis

Blood ◽

10.1182/blood.v120.21.5036.5036 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5036-5036 ◽

Cited By ~ 1

Author(s):

Beihui Huang ◽

Juan Li ◽

Junru Liu ◽

Dong Zheng ◽

Mei Chen ◽

...

Keyword(s):

Multiple Myeloma ◽

Side Effects ◽

Light Chain ◽

Conflicts Of Interest ◽

Complete Response ◽

Al Amyloidosis ◽

Newly Diagnosed ◽

Hematologic Response ◽

Best Response ◽

Organ Response

Abstract Abstract 5036 Objective: To assess the efficacy and tolerability of bortezomib with dexamethasone for patients with primary systemic light chain (AL) amyloidosis or multiple myeloma-associated AL amyloidosis. Methods: Twelve newly diagnosed patients with primary systemic AL amyloidosis and six patient with multiple myeloma-associated AL amyloidosis were treated with a combination of bortezomib (1. 3 mg/m2 d1, 4, 8, 11) and dexamethasone (20 mg d1–4). Results: Sixteen patients was evaluable. 12/16 had a hematologic response and 6/16 (37. 5%) a hematologic complete response. Median cycles to response was 1 cycle and median cycles to best response was 2 cycles. In patients with primary AL amyloidosis, 8/10 (80. 0%) had a hematologic response and 5/10 (50. 0%) a hematologic complete response. In patients with myeloma-associated AL amyloidosis, 7/10 (70. 0%) had a hematologic response and 1/6 (16. 7%) a hematologic complete response. Twelve patients (75. 0%) had a response in at least one affected organ, in which 7 in patients with primary AL amyloidosis and 5 in myeloma-associated AL amyloidosis. Person correlation between hematologic response and organ response was 0. 667 (p=0. 005). Fatigue, diarrhea and infection were the most frequent side effects. Three patients developed herpes zoster and had to stop chemotherapy. Conclusions: VD produces rapid and high hematological responses in the majority of patients with newly diagnosed AL regardless of primary or associated with myeloma. It is well tolerated with few side effects. This treatment may be a valid option as first-line treatment for newly diagnosed patients with primary systemic AL amyloidosis and multiple myeloma-associated AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

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Sequence Impact Of Pomalidomide and Carfilzomib On Treatment Response In Relapsed Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.1954.1954 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1954-1954 ◽

Cited By ~ 1

Author(s):

Tomer M Mark ◽

John N. Allan ◽

Angelique Boyer ◽

Adriana C Rossi ◽

Roger N Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Salvage Chemotherapy ◽

Advisory Committees ◽

Effective Response ◽

Disease Response ◽

Prior Therapy

Abstract Background Pomalidomide and Carfilzomib (Cfz) are two recently approved agents for the treatment of multiple myeloma (MM) that has relapsed after prior therapy including an IMiD and bortezomib. The sequencing of these agents to achieve maximum tumor reduction is thus far not known. We have previously reported response data from the combination clarithromycin, pomalidomide, dexamethasone (ClaPD) for relapsed or refractory MM. (Mark et al, ASH 2012). We examined the subset of these patients that had received a Cfz-based regimen prior to ClaPD as well as the subset of patients that received a Cfz-based regimen after ClaPD to determine whether the sequence of agents had any impact on response. Methods One hundred nineteen patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPD. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1-21, and dexamethasone 40mg on days 1,8,15,22 of a 28-day cycle. Two subsets of patients were compared: 1) Subjects that had received treatment with a Cfz-based prior to ClaPD (CP) and 2) Subjects that had received a Cfz-based therapy after progression on ClaPD (PC). Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Results Fourteen patients comprised CP and 20 in PC. Patients in the CP group were more heavily pre-treated with a median of 6 (range 3-15) lines of therapy, as compared to 5 lines (range 3-10) for PC. Responses are shown in Table 1. Median cycles of ClaPD and Cfz received in PC was 6.5 (range 2-16) and 5 (1-14), respectively. Median cycles of Cfz and ClaPD in the CP group was 8 (1-19) and 5 (1-23), respectively. CR complete response; VGPR: very good partial response; PR: partial response; SD: stable disease; PD: progressive disease; ORR: overall response rate Conclusions ClaPD and a Cfz-based regimen appear to have equally effective response regardless of sequence in salvage chemotherapy. Somewhat deeper responses are seen with ClaPD after Cfz as compared to Cfz after ClaPD, which is intriguing given that the CP group had more prior lines of treatment than PC. Longer follow-up to analyze duration of the response is needed prior to concluding which sequence (PC vs CP) is more effective. This data supports the use of pomalidomide after carfilzomib failure and vice-versa as potent salvage therapeutic options. Disclosures: Mark: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Zafar:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx: Speakers Bureau. Pekle:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Niesvizky:Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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