Transplantation for Immunoglobulin Light Chain Amyloidosis. A Statistical Analysis of Factors Predicitng Outcome In Over 400 Patients

Abstract Abstract 3557 Introduction: Autologous stem cell transplantation for patients with amyloidosis results in high reported hematologic and organ response rates compared with conventional chemotherapy. Patients: Four-hundred and thirty-four patients have undergone transplantation between March 8, 1996, and April 13, 2010 Table 1. Clinical parameters seen in patients with amyloid are given in Table 2. The overall day-100 mortality seen in this group of patients is 44 of 434 patients (10%). Results: The most important determinant of outcome is stage defined by BNP and troponin levels. Figure 1 demonstrates the survival for patients for all 3 cardiac stages. Troponin <.035; NT-proBNP <332. Stage 1 both low, Stage 3 both elevated. The survival of all patients based on whether they achieved a complete response, a partial response (>50%), or no response was analyzed. Median survival has not been reached for the complete response group, is 107 months for the partial response group, and is 32 months for the no response group (p<0.0001). Figure 2, divides the patients at the median dFLC level of 13.5 mg/dL demonstrating that for patients with a higher level of free light chain, the median survival is 87.6 months and has not been reached for those with a lower level of free light chain. A proportional hazards model for variables that impact on survival was done in all patients, and the only relevant predictor of outcome was stage (p<0.0001). When the same analysis was performed using a landmark of 6 months, the only predictor of outcome was stage (p=0.0005). When best response was incorporated into the landmark model, it was the strongest predictor of survival. The amyloid stage predicted survival (p= 0.0005), and the best response to therapy (p <0.0001). When the same analysis was performed in the entire group of 434, stage and best response each remained significant (p<0.0001). Discussion: There is a high response rate associated with high-dose therapy that was not observed in the melphalan and prednisone era. For eligible patients who can be transplanted safely, high-dose melphalan is an effective therapy for many patients with amyloidosis. Best response and stage at diagnosis are the best predictors of overall survival. Disclosures: Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

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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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Defining Complete Response in Multiple Myeloma: Role of the Serum Free Light Chain Assay and Multiparameter Flow Cytometry.

Blood ◽

10.1182/blood.v110.11.1479.1479 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1479-1479 ◽

Cited By ~ 1

Author(s):

Roger G. Owen ◽

J. Anthony Child ◽

Andy C. Rawstron ◽

Sue Bell ◽

Kim Cocks ◽

...

Keyword(s):

Flow Cytometry ◽

Light Chain ◽

Plasma Cells ◽

Complete Response ◽

Free Light Chain ◽

Multiparameter Flow Cytometry ◽

High Dose ◽

Reference Laboratory ◽

Serum Free ◽

Serum Free Light Chain

Abstract It is becoming increasingly clear that the use of immunofixation (IF) to define complete response (CR) in MM has its limitations. Paraprotein concentration is not a direct measure of tumour bulk and maximal responses may take many months to achieve which inevitably underestimate CR rates in therapeutic schedules that contain the sequential use of different agents. The purpose of this study was to prospectively assess the applicability and value of the serum free light chain (SFLC) assay and multiparameter flow cytometry (MFC) to assess CR in the intensive pathway of the MRC Myeloma IX Trial. In this trial patients are initially randomised to induction with CVAD or CTD and patients with stable disease or better proceed to high dose melphalan (HDM) with stem cell support. There is a second randomisation to maintenance thalidomide or no further therapy. SFLC as well as standard serum and urine paraprotein assessments were performed in a central reference laboratory at the following time points: presentation, end of induction, day 100 post HDM and 3 monthly until relapse. Similarly MFC in which neoplastic plasma cells are identified and differentiated from normal plasma cells on the basis of CD19 and CD56 expression was evaluated (again in a central laboratory) at presentation, end of induction and day 100 following HDM and annually until relapse. An initial analysis of 207/1114 randomised patients was performed and the results are detailed below - End of induction Day 100 post HDM IF negative 16.3% 49.4% SFLC normal 46.1% 78.6% MFC negative 10.2% 50.7% The SFLC assay was informative in 95% of patients and provided for a more rapid assessment of response than conventional methods. A normal SFLC assay at the end of induction appeared to predict for attainment of an IF-neg CR at day 100 (70% IF-neg CR if SFLC normal vs 30% when SFLC abnormal at the end of induction). It should however be noted that 58% of patients who failed to achieve an IF-neg CR at day 100 had a normal SFLC assay. MFC provides for a direct assessment of residual neoplastic plasma cells. The assay was informative in 96.7% of patients and has a reproducible sensitivity of 0.01%. The majority of patients (89.8%) had detectable disease at the end of induction with a median of 0.7% neoplastic plasma cells (range 0.01–14%). Further cytoreduction was provided by the HDM such that 49.3% had flow detectable disease at day 100 with a median of 0.26% neoplastic plasma cells (range 0.02–8%). 30% of patients with IF-neg CR had detectable disease while 21% of patients with a persistent paraprotein had no detectable disease in their marrow. The majority of the latter patients had IgG paraproteins and it is postulated that many of these pts will ultimately achieve an IF-neg CR. We would conclude that given the kinetics of paraprotein clearance in MM it may be more appropriate to define CR on the basis of a normal SFLC assay and the absence of minimal residual disease by MFC. In this way it should be possible to more accurately define the CR rate achieved by individual components of multi-agent sequential regimens.

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Immunoglobulin Heavy/Light Chain Measurements During Monitoring Provide Prognostic Information of Relapse After Therapy in Myeloma Patients

Blood ◽

10.1182/blood.v120.21.3964.3964 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3964-3964 ◽

Cited By ~ 1

Author(s):

Mark T Drayson ◽

Oscar Berlanga ◽

Tim Plant ◽

Nicola J Newnham ◽

Philip Young ◽

...

Keyword(s):

Partial Response ◽

Light Chain ◽

Progressive Disease ◽

Residual Disease ◽

Complete Response ◽

Maximum Response ◽

High Dose ◽

Cell Transplant ◽

Normal Ranges ◽

Normal Ratio

Abstract Abstract 3964 Introduction: Monitoring multiple myeloma (MM) patients is required to help guide therapy and assess response. Currently the most commonly employed tests to monitor MM patients include serum protein electrophoresis (SPEP), immunofixation (IFE), 24hr urine and serum free light chain (FLC) analysis. Whilst electrophoretic tests are adequate for IgG MM, they may be inadequate for IgA MM where the monoclonal immunoglobulin co-migrates with other serum proteins (∼60% of cases). Recently the inclusion of FLC testing to identify patients in stringent complete response (sCR) has been recommended. Novel nephelometric reagents have become available that can quantify IgA kappa and IgA lambda immunoglobulins (HLC) in serum. Here we assess the use of these tests at maximum response to detect residual disease and comment on the prognostic value of sCR. Patients, materials and methods:196 IgA MM patient samples recruited from the MRC IX trial were assessed at maximum response. Briefly, patients were randomised on to intensive (I: induction therapy with CVAD or CTD followed by high-dose melphalan and ASCT) and non-intensive (NI: clodronate or zoledronic with MP or CTDa) arms. Median age was 59 years (range: 37–71) and 74 years (range: 65–89) for patients in the I and NI arms, respectively. 31% patients in the I arm and 39% in the NI arm presented with stage III disease. Samples were taken 3 months after autologous stem cell transplant or maximum response and analysed nephelometrically using serum FLC and HLC immunoassays. Ratios for both FLC and HLC were compared to normal ranges (FLC normal ratio= 0.256–1.65, IgAkappa/IgAlambda normal ratio=0.8–2.04). Additionally, isotype-matched immunoparesis was described as <0.48 g/L IgAkappa and <0.36g/L IgAlambda. Results were compared to SPEP, IFE and total immunoglobulin assays (where immunoparesis was described as <6g/L IgG and <0.4g/L IgM). 2-year progression free survival (PFS) was determined using Kaplan Meier analysis (SPSS v 19.0). Results: 3 months post-therapy, patient responses were: I arm: progressive disease (PD): n=1(<1%); minimal response (MR): n=1(<1%); partial response (PR): n=10(8%); very good partial response (VGPR): n=35(29%); complete response (CR): n=13(11%); sCR: n=58(48%); for two patients no data was available; NI arm: progressive disease (PD): n=3(4%); stable disease (SD): n=5(7%); MR: n=10(13%); PR: n=31(41%); VGPR: n=16(21%); CR: n=11(15%). Within the 2-year follow up, 41% patients in the I arm and 46% in the NI arm relapsed. Median PFS was not significantly different between the two arms (not reached v 7 months, p=0.65). Response (3VGPR) was not associated with PFS in either arm (I, p=0.717; NI, p=0.236). By contrast, achievement of a sCR (p=0.013) was significantly associated with longer PFS in the I arm and tended towards significance in the NI arm (p=0.063). An abnormal HLC ratio was associated with shorter PFS in both arms (I, p=0.002; NI, p=0.032). In all patients achieving a 3VGPR, an abnormal HLC ratio was associated with shorter PFS (p>0.0001). Similarly, in patients achieving a 3CR an abnormal HLC ratio was also associated with shorter PFS (p=0.04). Furthermore, patients achieving a CR where both FLC and HLC ratios were normal had a significantly longer PFS than those with an abnormal FLC or HLC ratio (median PFS not reached v 18 months, p=0.007). Isotype-matched immunoparesis was associated with shorter PFS in all patients achieving a CR (p=0.061). By contrast, systemic immunoparesis of either IgG or IgM immunoglobulins were not associated with PFS (p=0.525 and p=0.964, respectively). Discussion: Novel therapies have dramatically improved MM patient outcomes, however improvements in the assessment of those outcomes has not followed a similar trajectory. Here we present data suggesting immunoglobulin HLC ratios may be better markers of residual disease than electrophoretic methods. In addition a response category based on normalisation of both FLC and HLC ratios may be more valuable than sCR. Finally, the identification of isotype matched immune reconstitution as a marker of outcome suggests a preferential suppression of immunoglobulin production not previously reported. Conclusion: Normalisation of the FLC and HLC ratio at maximum response is a better assessment of disease than IFE. Further work is required to validate these results and to assess FLC and HLC ratios against multi-parametric flow cytometry. Disclosures: Young: Binding Site: Employment.

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Outcomes of Patients with Relapsed/Refractory (R/R) B-Cell Acute Lymphocytic Leukemia (ALL) Post Blinatumomab Failure

Blood ◽

10.1182/blood.v126.23.1335.1335 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1335-1335 ◽

Cited By ~ 1

Author(s):

Jenny Dahl ◽

Hagop M. Kantarjian ◽

Musa Yilmaz ◽

Tapan Kadia ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

B Cell ◽

Median Survival ◽

Median Duration ◽

Salvage Therapy ◽

Research Funding ◽

Clinical Characteristics ◽

Complete Response ◽

Best Response ◽

Duration Of Response

Abstract Introduction: Blinatumomab is a first-in-class Bispecific T-cell engaging (BiTE) antibody targeting CD19-positive malignant cells and CD3-positive T cells. It has shown activity in both R/R B-cell ALL and with persistent minimal residual disease (MRD). However, despite a 50% response rate with blinatumomab, the duration of response is very short with many pts experiencing relapse. The goal of this study is to assess the outcome of patients with R/R B-cell ALL post blinatumomab failure. Methods: We reviewed 40 patients with R/R ALL treated with blinatumomab at our institution between 1/2012 and 1/2015. Of the 40 patients treated, 30 were either refractory (n=18) or lost their response (n=12) after initially achieving a complete response or complete response with incomplete count recovery (CRi). We analyzed the clinical characteristics and survival of these 30 patients who failed blinatumomab. Results: Clinical characteristics of the 30 patients with blinatumomab failure are summarized in Table 1. Best response to blinatumomab was CR in 9 pts and CRi in 3 with a median duration of response of 3 months (range, 1-8 months). After a median follow-up of 6.8 months (range 4.8- 31 months) from blinatumomab failure, 8 patients (27%) remain alive. The median overall survival was 6.4 months and the estimated 12-month survival rate was 36%. The median survival was 3 and 11 months for patients refractory to blinatumomab and those who relapsed after a previous response, respectively (p=0.179). Furthermore, there was a trend for better outcome post blinatumomab failure if the drug was administered as first, second, or third and beyond salvage therapy with a median survival of 19, 11, and 5 months, respectively (p= 0.248). Following blinatumomab failure, 11 patients received inotuzumab ozogamicin salvage therapy as a single agent in 5 or in combination with mini-hyper-CVD in 6 [Jabbour E et al; EHA 2015]. Eight patients responded for an overall response rate of 73% for a median duration of 6 months (range, 1.2-30 months). Overall, 9 patients underwent allogeneic stem cell transplant (allo-SCT), 5 of them post salvage therapy with inotuzumab. Seven of them remain alive in CR at the last follow-up. The 1-year survival rates were 83% and 11% for patients who received an allo-SCT and those who did not, respectively (p<0.001). Conclusions: Overall, the outcome of patients with R/R ALL post blinatumomab failure is poor with a median survival of 6.4 months. Inotuzumab ozogamicin is a good salvage therapy option allowing patients with refractory disease to proceed with allo-SCT that remains the only curative approach for these patients. Table 1. Clinical Characteristics of Patients with Blinatumomab Failure N=30 Parameter N (%)/Median [Range] Age (years) 29 [19-76] Sex (Male) 23 (77) Performance Status 1 [0-2] Cytogenetics Diploid 9 (30) t(4;11) 1 (3) Miscellaneous 15 (50) t(9;22) 1 (3) Insufficient Metaphase 4 (14) WBC at start (x 109/L) 2.75 [0.4-24] % PB blasts at start 8 [0-98] % BM Blasts at start 80 [10-98] WBC at failure (x 109/L) 3.4 [0-224] % BM Blasts at failure 69 [2-98] # Prior therapies, median 3 [1-6] # Blinatumomab courses 2 [1-5] Best response to blinatumomab CR 9 (30) CRi 3 (10) Median duration of response (months) 3 [1-8] Follow up, median (months) 6.8 [4.8-31] Disclosures Cortes: Teva: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

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Role of Second Stem Cell Transplant in Patients with Amyloidosis Who Are Refractory or Relapsing.

Blood ◽

10.1182/blood.v106.11.5469.5469 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5469-5469

Author(s):

Morie Abraham Gertz ◽

Martha Q. Lacy ◽

Angela Dispenzieri ◽

Suzanne R. Hayman ◽

Shaji K. Kumar ◽

...

Keyword(s):

Stem Cell ◽

Light Chain ◽

Stem Cell Transplant ◽

Complete Response ◽

Free Light Chain ◽

High Dose ◽

Cell Transplant ◽

High Dose Therapy ◽

Single Organ

Abstract Introduction: Stem cell transplant is an increasingly widely applied technique for managing amyloidosis. As in multiple myeloma, the treatment would not be expected to be curative and patients would be expected to relapse in most instances. In addition, approximately one-third of patients fail to respond to initial therapy. The role of second transplantation in treatment failures or patients who relapse is reviewed. Patients: Of 242 patients undergoing high dose conditioning and stem cell transplantation for amyloidosis (AL) at the Mayo Clinic, 6 subsequently underwent a second transplant. Results: Patient 1, who had single organ renal amyloid nephrotic syndrome responded and relapsed at 73 months, received a second stem cell transplant achieving a hematologic complete response with normalization of a markedly elevated pre transplant free light chain (59 to 1.9 mg/dL) and is alive at 12 months. Patient 2 relapsed 42 months after transplant for single organ renal amyloidosis; the second stem cell transplant, has normalized his free light chain ratio reduced his urinary protein loss from 5450 to 1482 mg/day and he is alive 21 months following his second transplant (63 months overall). Patient 3 relapsed 34 months after a response of renal and cardiac amyloidosis. After transplant two, he failed to achieve a 50% reduction in his free light chain, began hemodialysis 7 months post transplant and died one year post transplant. Patient 4 with single organ cardiac involvement relapsed 30 months following his first transplant and died on day +5 of his second transplant of an acute pulmonary embolus. Patient 5 was a response failure after his first transplant, had a second transplant 35 months later, having failed Dexamethasone followed by Melphalan/Dexamethasone therapy, and died 3 months later of progressive disease. Patient 6 had single organ vascular involvement manifest by calf and thigh claudication and failed to respond with his first transplant with a persistently elevated free light chain. The second transplant was performed six months after the first without further free light chain reduction and persistent claudication at 11 months. Conclusion: Patients who failed to achieve a hematologic response after a first transplant appear not to benefit from a second course of high dose therapy. Among 4 patients who were previously responsive and relapsed, one achieved a hematologic complete response, one achieved a hematologic partial response, and two died. The two patients achieving a second hematologic response had the longest response duration (73 and 42 months) following their first transplant, and the second response presumably reflects favorable (indolent; non proliferative) biology of the underlying plasma cell dyscrasia. High dose therapy and stem cell transplant may be an effective salvage regimen for patients who responded to a first transplant and whose response lasted greater than 36 months.

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Standard Oral Melphalan Chemotherapy for AL Amyloidosis Revisited Using the Serum Free Light Chain Assay.

Blood ◽

10.1182/blood.v106.11.3495.3495 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3495-3495 ◽

Cited By ~ 2

Author(s):

Mark Offer ◽

Ashutosh D. Wechalekar ◽

Hugh J.B. Goodman ◽

Julian D. Gillmore ◽

Helen J. Lachmann ◽

...

Keyword(s):

Partial Response ◽

Light Chain ◽

Nyha Class ◽

Single Agent ◽

Complete Response ◽

Free Light Chain ◽

Al Amyloidosis ◽

Serum Free ◽

Haematological Response ◽

Serum Free Light Chain

Abstract Treatment of systemic AL amyloidosis (AL) remains difficult, especially in older and sicker patients in whom dose intensive therapies are often associated with unacceptable morbidity and mortality. Many such patients continue to be treated with oral melphalan ± prednisone (MP) despite early trials having shown only very modest clinical efficacy, presumably encouraged by its perceived low toxicity. The recent advent of the sensitive nephelometric serum free light chain (sFLC) assay has for the first time enabled the typically subtle underlying clonal disease to be monitored in an effective quantitative manner in the majority of patients with AL. We report here sFLC responses and clinical outcome of patients with AL who received MP first-line and underwent serial evaluations at the UK National Amyloidosis Centre. The 90 patients comprised 46 males and 44 females with a median age of 68yrs (range 43–83). Median number of organs involved was 3 (1–4), including kidneys in 72%, heart in 56%, and liver in 29%. 16 (17%) had ≥ NYHA class III heart failure. Median ECOG performance status was 1. Median follow-up was 2.3 yrs (0.3–14). 60 patients received oral melphalan with prednisone, and 30 received single agent melphalan. Patients received a median of 6 cycles of treatment (range 1– 26), and the sFLC assay was scheduled following each cycle after availability of the assay and retrospectively on stored sera for earlier patients. Haematological response data using sFLC assay were evaluable in 54 (60%). Responses were defined as complete response (CR) - sustained normalisation of sFLC ratio, partial response (PR) - sustained ≥50% reduction in pre-treatment clonal isotype. There was a haematological response in 22 (40%) of evaluable patients. 4 (7%) had a complete response, 18 (33%) had a partial response and 32 (59%) did not respond. 42% of patients treated with single agent melphalan responded compared with 39% of those treated with melphalan and prednisone (p=0.8). Responders received a median 6 cycles of treatment, and complete responders received a median of 14 cycles. Non-responders received a median of 5 cycles of treatment. The median time to commencing further chemotherapy was 5 months. The median overall survival (OS) was 5.8yrs, but most patients received further salvage treatments and the influence of MP treatment on OS could not be ascertained. Toxicities during MP were seen in 13 (14%) cases, including myelodysplasia in 2 patients. There were no treatment related deaths. In conclusion, use of the sFLC assay confirms that response of the underlying clonal plasma cell disease to standard oral melphalan and prednisone is poor in AL amyloidosis, and that response is usually very delayed even among patients who respond completely. Encouragingly however, toxicity was low among this relatively old and sick cohort of patients. These findings support frequent sFLC measurements in AL patients receiving MP to enable rational treatment decisions to be made at the earliest opportunity.

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GMMG MM5 Trial In Newly Diagnosed Multiple Myeloma To Evaluate PAd Vs VCD Induction Prior To High Dose Treatment Followed By Lenalidomide Consolidation and Maintenance – Final Analysis On Induction Therapy

Blood ◽

10.1182/blood.v122.21.3369.3369 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3369-3369 ◽

Cited By ~ 2

Author(s):

Hartmut Goldschmidt ◽

Jan Duerig ◽

Uta Bertsch ◽

Christina Kunz ◽

Thomas Hielscher ◽

...

Keyword(s):

Partial Response ◽

Induction Therapy ◽

Research Funding ◽

Treatment Strategies ◽

Response Rates ◽

Complete Response ◽

Disease Stage ◽

Induction Treatment ◽

High Dose ◽

Good Partial Response

Abstract Background The MM5 phase III trial of the German-Speaking Myeloma Multicenter Group (GMMG) was designed to address two independent primary objectives: 1.) demonstration of non-inferiority of VCD (bortezomib, cyclophosphamide, dexamethasone) induction compared to PAd (bortezomib, adriamycin, dexamethasone) induction therapy with respect to response rate (very good partial response or better). 2.) determination of the best of four treatment strategies with respect to progression-free survival (PFS). The four treatment strategies were defined by PAd vs. VCD induction treatment, high dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) as well as consolidation and maintenance treatment with lenalidomide for 2 years vs. lenalidomide until complete response (CR). Methods 504 patients were included in the trial between July 2010 and October 2012. A non-inferiority analysis of VCD compared to PAd with respect to response rates after induction treatment with a non-inferiority margin of 10% for the difference in response rates (VGPR and better; first primary endpoint) and a safety analysis were performed. During the induction phase the patients were treated with 3 cycles of PAd or VCD. PAd was dosed as bortezomib 1.3 mg/m2, days 1, 4, 8, 11, doxorubicin 9 mg/m2, days 1-4, dexamethasone 20 mg, days 1-4, 9-12, 17-20 (repeated every 28 days). VCD consisted of bortezomib 1.3 mg/m2, days 1, 4, 8, 11, cyclophosphamide 900 mg/m2 day 1, dexamethasone 40 mg, days 1-2, 4-5, 8-9, 11-12 (repeated every 21 days). The route of administration for bortezomib was changed from intravenously to subcutaneously in all study arms by a protocol amendment in February 2012 after inclusion of 314 patients. The non-inferiority analysis was based on intention-to-treat (ITT) population (502 evaluable patients) and per-protocol (PP) population (473 evaluable patients). Responses were assessed according to the response criteria of the International Myeloma Working Group (IMWG). Results In the ITT population, patients treated with PAd or VCD were equally distributed for ISS and Durie-Salmon disease stage, LDH, kidney function and the cytogenetic abnormalities translocation t(4;14), deletion 17p13 and gain 1q21. In the PAd group, the median age of the patients was higher (59.4 vs. 58.7, p=0.04). 229 of 251 patients (91.2%) in the PAd group and 241 of 251 patients (96.0%) in the VCD group completed induction treatment. Observed response rates (PAd vs. VCD) were 4.4% vs 8.4% for complete response, 34.3% vs. 37.0% for ≥ very good partial response and 72.1% vs. 78.1% for ≥ partial response. Non-inferiority of VCD compared to PAd was shown (two-sided p=0.0026). Similar results were obtained in the PP analysis. The proportion of patients with any adverse event (AEs) was comparable in PAd vs. VCD (61.3% vs. 64.0%, p=0.58), but more serious adverse events (SAEs) were observed during PAd induction (32.7% vs. 24.0%, p=0.037). VCD led to a significantly higher proportion of leukopenia and neutropenia CTCAE grade 3 and 4 (PAd: 11.3% vs. VCD: 35.2%; p<0.001). There was no significant difference in the number of infections (≥ CTCAE grade 2) during PAd induction compared to VCD induction (24.6% vs. 22.4%; p=0.60). Interestingly, compared to the infection rate (≥ CTCAE grade 2) of 49% during PAD (dexamethasone 40 mg days 1-4, 9-12, 17-20) in the HOVON65/GMMG-HD4-trial, a reduction in MM5 during induction was observed. In the PAd arm more deaths were observed compared to the VCD arm (6 vs. 1). Conclusion PAd and VCD are well tolerated with more than 90% of the patients receiving all three planned induction cycles. Non-inferiority of VCD compared to PAd was shown in ITT and PP analysis. In conclusion, VCD was found to be a valid alternative to PAd with comparable efficacy and a favourable toxicity profile. Disclosures: Goldschmidt: Celgene: Consultancy, Honoraria, Research Funding; Chugai: Research Funding; Janssen Cilag: Consultancy, Honoraria, Research Funding. Duerig:Janssen Cilag: Honoraria; Celgene: Honoraria. Schmidt-Wolf:Janssen: Honoraria; Novartis: Honoraria. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Scheid:Janssen Cilag: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Salwender:Janssen Cilag: Honoraria; Celgene: Honoraria.

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Early Serum Free Light Chain Response after High-Dose Melphalan and Stem Cell Transplantation Predicts Hematologic Response in AL Amyloidosis

Blood ◽

10.1182/blood-2020-138500 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 26-26

Author(s):

Vanessa Fiorini Furtado ◽

Dina Brauneis ◽

Shayna Sarosiek ◽

Karen Quillen ◽

Vaishali Sanchorawala

Keyword(s):

Light Chain ◽

Research Funding ◽

Amyloid Fibrils ◽

Advisory Board ◽

Free Light Chain ◽

Light Chains ◽

High Dose ◽

Al Amyloidosis ◽

Serum Free Light Chain ◽

High Dose Melphalan

Introduction Immunoglobulin light chain (AL) amyloidosis is a rare disease caused by a clonal plasma cell dyscrasia producing monoclonal light chains that misfold and form amyloid fibrils which can deposit in a variety of tissues and organs. This deposition of amyloid fibrils can lead to progressive organ impairment, multi-organ failure, and death if left untreated. High-dose melphalan and autologous stem cell transplantation (HDM/SCT) is known to improve patient outcomes with hematologic complete responses (CR) rates of 25-67%. Hematologic CR is currently defined as the absence of monoclonal protein in serum and urine by immunofixation electrophoreses and normal serum free light chain ratio (FLCR). Studies have shown that even among patients achieving a normal FLCR after initial therapy with HDM, persistent elevation of the involved FLC (hiFLC) predicts poor prognosis. Serum half-life of FLCs is approximately 2-6 hours, even with diminished glomerular filtration rates, and could be a tool for early treatment response evaluation. We sought to determine the extent to which early FLC responses after HDM/SCT predict hematologic complete response (CR) at 6 months. Methods We analyzed patients with AL amyloidosis who underwent HDM/SCT from 2012-2019 at Boston Medical Center. Exclusion criteria included death within 100 days, lack of FLC data at any time point, pre-SCT normal FLC concentrations and ratio, and chronic renal insufficiency (serum creatinine >1.3 mg/dL) with a normal FLC ratio. All subjects received a total of 140-200 mg/m2 melphalan IV in equally divided doses on days -3 and -2. Stem cells were infused on day 0. FLC measurements were obtained early in the peri-SCT period (< 1 month), at 6 months, and at 12 months after HDM/SCT. The patients were evaluated for response according to the consensus response criteria at 6 months. Statistical analysis to compare CR at 6 months and early post-SCT free light chain levels was performed by Chi-square with significance considered at p<0.05. Results Of the 113 patients with AL amyloidosis treated with HDM/SCT during the specified time period, 32 were excluded (4 died within 100 days of SCT, 15 had normal FLCs pre-SCT, 5 lacked data, and 8 had chronic renal insufficiency (Cr >1.3 mg/dL) with normal FLCR. A total of 81 subjects (females=30) were analyzed. Median follow-up from SCT was 27.6 months (range, 6-145). Median time of early post-SCT FLC measurement was 8 days (range, 7-30). Median age at diagnosis was 58 years (range 30-79) and the iFLC was lambda in 81.5% (n = 66) of patients. Median number of bone marrow plasma cells was 10% (range, 1-50). The mean absolute involved FLC was 196 mg/L ±221 prior to SCT, 60 mg/L ± 77 in the early post-SCT period, 92 mg/L ± 152 at 6 months post-SCT. In early post-SCT period, 39.5% (n=32) had iFLC <20 mg/L, 28% (n=16/57) had dFLC<10 mg/L, and 84% (n=48/57) had normal FLCR. Early post-SCT dFLC <10 mg/dL and early post-SCT iFLC <20 mg/L were statistically associated with prediction of hematologic CR at 6 months (p=0.025 and p=0.001, respectively). However, early post-SCT normal FLCR was not associated with predicting hematologic CR at 6 months. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of early post-SCT iFLC <20 mg/L, dFLC <10 mg/L and normal FLCR to predict hematologic CR at 6 months are presented in table 1. Conclusion This study concludes that achievement of dFLC <10 mg/L and iFLC <20 mg/L in the early post-SCT period is associated with prediction of hematologic CR at 6 months. Early post-SCT dFLC <10 mg/L could be considered a tool for early evaluation of treatment response following HDM/SCT in AL amyloidosis. Key words: immunoglobulin light chains; AL amyloidosis, HDM/SCT Disclosures Sarosiek: Spectrum: Research Funding. Sanchorawala:Caelum: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Oncopeptide: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Janssen: Research Funding.

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The importance of bone marrow examination in determining complete response to therapy in patients with multiple myeloma

Blood ◽

10.1182/blood-2009-01-198788 ◽

2009 ◽

Vol 114 (13) ◽

pp. 2617-2618 ◽

Cited By ~ 30

Author(s):

Cheng E. Chee ◽

Shaji Kumar ◽

Dirk R. Larson ◽

Robert A. Kyle ◽

Angela Dispenzieri ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Light Chain ◽

Plasma Cells ◽

Complete Response ◽

Free Light Chain ◽

Response To Therapy ◽

Serum Free ◽

Serum Free Light Chain ◽

Serum And Urine

Abstract The current definition of complete response in multiple myeloma includes a requirement for a bone marrow (BM) examination showing less than 5% plasma cells in addition to negative serum and urine immunofixation. There have been suggestions to eliminate the need for BM examinations when defining complete response. We evaluated 92 patients with multiple myeloma who achieved negative immunofixation in the serum and urine after therapy and found that 14% had BM plasma cells more than or equal to 5%. Adding a requirement for normalization of the serum-free light chain ratio to negative immunofixation studies did not negate the need for BM studies; 10% with a normal serum-free light chain ratio had BM plasma cells more than or equal to 5%. We also found that, on achieving immunofixation-negative status, patients with less than 5% plasma cells in the BM had improved overall survival compared with those with 5% or more BM plasma cells (6.2 years vs 2.3 years, respectively; P = .01).

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Overall and Progression Free Survival from the Mcrn-003/Myx.1 Trial: A Single Arm Phase II Study of High-Dose Weekly Carfilzomib Plus Cyclophosphamide and Dexamethasone in the Treatment of Relapsed Multiple Myeloma

Blood ◽

10.1182/blood-2019-122637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1871-1871 ◽

Cited By ~ 1

Author(s):

Christopher P Venner ◽

Richard Leblanc ◽

Irwindeep Sandhu ◽

Darrell J White ◽

Andrew Belch ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Phase Ii ◽

Light Chain ◽

Research Funding ◽

Free Light Chain ◽

High Dose ◽

Advisory Committees

Background: Carfilzomib is effective in the treatment of relapsed and refractory multiple myeloma (RRMM). Questions remain regarding optimal dosing strategies and combinations. The MCRN-003/MYX.1 single arm phase II clinical trial of high-dose once weekly carfilzomib in combination with dexamethasone and cyclophosphamide (wCCD) in RRMM met its primary endpoint with an overall response rate (ORR) ≥ 80% after 4 treatment cycles [Venner, Blood 2018 132:1984]. This abstract focuses on previously unreported protocol specified secondary and exploratory endpoints including progression free (PFS) and overall survival (OS). Methods: This multi-centre clinical trial is run through the Myeloma Canada Research Network (MCRN) with support from the Canadian Cancer Trials Group (CCTG). Patients who had 1-3 prior lines of therapy and without proteasome inhibitor (PI) refractory disease were eligible. Treatment consists of carfilzomib (20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28-day cycle, plus weekly oral dexamethasone 40 mg and cyclophosphamide 300 mg/m2 capped at 500 mg. Treatment continues until progression or intolerance, except for cyclophosphamide which is discontinued after 12 cycles. Secondary endpoints included toxicity, depth of response, PFS and OS as defined by International Myeloma Working Group Uniform Response Criteria (2016). Exploratory endpoints included the impact of cytogenetics (CG) and prior PI or lenalidomide exposure on efficacy, and the novel endpoint of serum free light chain (sFLC) escape, defined as a > 25% change in the difference of involved to uninvolved light chain with the absolute rise > 100mg/L, in individuals with disease previously measurable by serum or urine protein electrophoresis. This analysis is based on the locked database of 19 June, 2019. Results: Of 76 patients accrued, 75 were included in the analysis. One was ineligible due to prior bortezomib refractoriness. Thirty-nine percent received 1 prior line, 44% two prior lines and 17% three prior lines of therapy. High-risk cytogenetics (t(4;14), t(14;16) and/or del P53, considered positive at any level above local accepted threshold) were identified in 32%. Twenty percent had ISS stage III disease. The majority of participants were previously exposed to PI (87%) and lenalidomide (83%). The median duration of follow-up was 25 months. The ORR at any time was 85% (1 patient achieved a response after 4 cycles) with ≥ VGPR achieved in 68% and ≥ CR in 29%. The presence of high-risk CG conferred a worse ORR (75% vs 97% respectively, p = 0.013). Thirty-one patients have died with a median OS and median PFS of 27 months and 17 months respectively (figure 1). High risk CG conferred a worse median OS (18 months vs NR, p = 0.002) and a trend toward a worse median PFS with high risk CG (14 months vs 22 months, p = 0.06; figure 1). For patients with prior PI exposure the median OS and PFS were 27 and 17 months respectively. For patients with prior lenalidomide exposure median OS and PFS were 26 and 16 months respectively. Free light chain escape events were noted in 11 patients (15%) but was the only progression event in 3 (4%). For the remaining 8 patients the sFLC rise was a harbinger of traditional relapse by electrophoresis. The median PFS when sFLC escape was included as a progression event was 17 months. With updated toxicity data the most common ≥ grade 3 non-hematologic events were infection (40%), cardiac (15%, including 5 dyspnea and 1 pulmonary edema) and vascular (17%, including 7 with hypertension and 3 with thrombotic microangiopathy). To date 57 (76%) patients have discontinued carfilzomib, including 34 due to disease progression and 14 due to toxicity. Conclusion: This phase II trial demonstrates that wCCD remains a safe and effective regimen for RRMM. The survival data presented here is comparable to current phase II and III studies examining the weekly dosing strategy. No new toxicity signals are observed but cardiovascular risks remain an important factor in the use of carfilzomib-based therapies. Using sFLC escape does not negatively affect PFS outcomes but likely better characterizes progression as a harbinger of more traditional events detected by electrophoresis. This regimen will be a useful triplet-based option for RRMM especially in patients refractory to lenalidomide and otherwise ineligible for the carfilzomib-lenalidomide-dexamethasone combination. Disclosures Venner: J&J: Research Funding. Leblanc:Amgen: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sandhu:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; gilead: Honoraria. White:Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Reece:Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Louzada:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bayer: Honoraria. McCurdy:Janssen: Honoraria; Celgene: Honoraria. Hay:Janssen: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Kite: Research Funding; Takeda: Research Funding; Roche: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; MorphoSys: Research Funding; Gilead: Research Funding. OffLabel Disclosure: While Carfilzomib is approved for use in relapsed and refractory myeloma the combination with cyclophosphamide is not approved.

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