The Utility of the Follow-up with Serum Free Light Chain After Autologous Stem Cell Transplantation in Multiple Myeloma Patients with Measurable M-Protein.

Abstract Abstract 4878 Introduction According to international uniform response criteria for multiple myeloma suggested in 2006, the response assessment for patients with oligo- and non-secretory multiple myeloma (MM) can be evaluated by the serum free light chain (FLC) assay. Although the FLC response criteria are not applicable in MM patients with measurable disease, there were several reports suggesting that serial measurement of serum FLC may detect relapse earlier than protein electrophoresis studies. We, therefore, investigated the preceding changes in serial serum FLC assay until progressive disease was confirmed by the international uniform response criteria in post-ASCT patients with measurable disease. Patients and Method We included patients from the AMC MM transplant registry, who met the following (1) undertook ASCT for measurable disease (2) showed, at least, two serial response assessment of stable disease or complete response before progression or relapse by serum or urine M-protein, (3) had periodic serum FLC assay simultaneously tested with serum and/or urine protein electrophoresis at each response assessment. Progressive disease (PD) was defined by increase of ≥ 25% from baseline in serum M-protein (the absolute increase must be ≥ 0.5mg/dL) and/or urine M-component (the absolute increase must be ' 200mg/24h) according to international uniform response criteria. In this investigation, significant increase in the difference between involved and uninvolved FLC (dFLC) and in the involved FLC (iFLC) was defined by increase of ≥ 25% from baseline. The positive predictive value of three cutoff levels for absolute increase, 10mg/L, 20mg/L, 100mg/L, were evaluated for both dFLC and iFLC provided serum FLC ratio was abnormal. Each patient was followed up with 1-3 month intervals according to the protocol for MM patients after ASCT. Result A total 29 patients of 138 patients in the AMC MM transplant registry satisfied above criteria. When the cut-off level for absolute increase was defined as 100mg/L, the significant increase of iFLC in 12 patients (41%) and dFLC in 11 patients (38%) preceded or accompanied with the time of progressive disease observed by M-protein. The median value of preceding time was 2 month (range -5 - 0). When the cut-off level was defined as 20mg/L, the sustained significant increase of iFLC in 21 patients (72%) and dFLC in 17 patients (59%) preceded or accompanied with the time of progressive disease with median of 2 month (range -9 - 0) and 2 month (range, -5 – 0), respectively. At the cut-off level of 10mg/L, the sustained significant increase of iFLC in 23 patients (79%) and dFLC in 21 patients (72%) preceded or accompanied with the time of progressive disease observed by M-protein. The median of preceding time was 2 month (range -11 - 0) and 1 month (range, -11 - 0), respectively. Twenty-eight dFLC values were observed as negative values out of a total 123 data from 29 patients. Of these values, 12 were below normal iFLC concentration, 14 within normal range of iFLC (kappa 8.5 - 23.7 mg/L, lambda 9.5 - 23.5 mg/L), and 2 above normal iFLC concentration. Conclusion In this study, about 70% of patients showed sustained significant increase of iFLC that preceded or accompanied the time of progressive disease observed by M-protein by a median of 2 months at a cut-off absolute increase of 20mg/L. Although there is a subtle difference in prediction rates according to defined cut-off levels, serial follow up of iFLC and sustained increase by 25% during follow-up seems to have a utility in the prediction of progression after ASCT. In addition, interpretations of dFLC may be difficult as it is frequently observed as negative value in post-ASCT MM patients. Therefore, the serial and sustained increase of iFLC may be useful in lower iFLC concentrations. However, there should be more validation with large patients' population. Disclosures No relevant conflicts of interest to declare.

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Carfilzomib-Pomalidomide-Dexamethasone (KPD) in Relapsed/Refractory Multiple Myeloma Patients - an Institutional Retrospective Analysis

Blood ◽

10.1182/blood-2019-131674 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5572-5572

Author(s):

Pallavi Mehta ◽

Neha Yadav ◽

Mohan Bhaarat ◽

Sumeet Prakash Mirgh ◽

Vishvdeep Khushoo ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Progressive Disease ◽

Conflicts Of Interest ◽

Haematological Toxicity ◽

Response Assessment ◽

Median Number ◽

Entire Cohort ◽

Response Status

Introduction Multiple myeloma has relished the emergence of various novel agents in last few decades. Unfortunately,relapses are still an inevitable part and at each relapse, treatment choice becomes a complex decision making process as these patients usually have exhausted conventional therapeutic regimens.Carfilzomib is a second-in class Proteosome Inhibitor (PI) and has been approved for patientsrefractory to minimum 2 lines of prior therapies. We are, hereby, presenting our initial experience with this novel combination (KPD)in RRMM patients at our centre. Methodology Retrospective study of RRMM patients who received KPD therapy from August 2017 till October 2018. Responses were assessed as per International Myeloma Working Group. Study was approved by Institutional Review Board. Results Total 39 patients were treated with KPD regimen during study period. Median age was 56 (32-74 years) with male ratio of 51.2% (n=20). At baseline presentation, bone disease {n=32 (82%)} was the most common presenting complaint followed by anemia {n=21 (53.8%)} and renal failure {n=16 (41%)}. Most common ISS staging was ISS-3 {n=18(46.1%)} and subtype was Light chain myeloma {n=15 (38.3%)} followed by IgG {n=13 (33.3%)}.Fluorescence In Situ Hybridization (FISH) was available in {n= 10 (25%)} and it was positive for del13q (n=1/10) and del17p (n=1/10) and t(11;14) (n=1/10). (Table-1) Median number of prior lines of chemotherapy was 3(1-15). Thirty-six (91%) patients were relapsed/refractory to both bortezomib and lenalidomide whereas n=3(9%) were relapsed/refractory to bortezomib only. Eleven (30.5%) patients underwent SCT pre KPD therapy including 2/11 patients received double SCT. Pre KPD 25 (64.1%) patients had progressive disease (PD), 10 (25%) had relapse and 4 (11.1%) patients had stable disease (SD). Median number of KPD cycles were 3(1-8). Median number of KPD cycles after which response assessment was donewas 3 (2-8). Median time to treatment response was 3 (2-7) months. ORR was 51.2% {CR-n=5 (12.8%); VGPR-n=5 (12.8%), PR-n=10 (25.6%)} whereas 2 (5.1%) patient had SD and 10 (25.6%) patients had PD at 2-8 cycles. Two (5.1%) patients are yet to be assessed. (Table-1) Common hematological toxicities seen were anemia (n=8), thrombocytopenia (n=13){grade-3/4=30.7%; n=4/13} and neutropenia(n=14){grade3/4=21.4%; n=3/14}.Non haematological toxicity such as cardiac toxicity was not observed in our patients. Pre KPD 2D-ECHO was available for 13 patients and which was normal in all patients. Post 2-4 cycles of KPD, 2D-ECHO was available for 7 patients and all patients had normal ECHO. Carfilzomib induced hypertension was seen in 20 patientsand could be well controlled with antihypertensives. Peripheral neuropathy (grade1/2) was seen in 10 patients. We also observedCarfilzomib induced hyponatremia in one patient.Febrile neutropenia(bacterial =6, viral=4, possible fungal=5) was seen in 14 patients.(Table-2) Twelve (20.5%) patients proceeded to either maintenance therapy or autologous stem cell transplantation (ASCT). Eight patients opted only for maintenance (carfilzomib=5, pomalidomide-dexamethasone=2 and pomalidomide =1). Remaining n=4/12(16%) patients received SCT. Pre SCT response status was VGPR n=2; PR n=1 and SD=1. Post SCT response status was VGPR (n=3) &PR (n=1). Post SCT, 3 patients were started on maintenance therapy as Bortezomib/pomalidomide=1, Pomalidomide/dexamethasone=2. One patient has been continued on KPD as a consolidation therapy. At a median follow-up of 10 months (1-14 months), relapse rate was 12.8% (n=5). Ten (25.6%) patients had PD.Mortality rate was 8.3% (n=3), commonest cause being progressive disease. The estimated mean PFS, OS and EFS of entire cohort was 11.9 months (95% C.I. 10.8- 13 months) (figure-1 a), 13 months (95% C.I. 11.9-14 months) (figure-1 b) and 7.9 months (95% C.I. 6.5-9.3 months) (figure - 1 c) respectively. Conclusion KPD is a well-tolerated regimen for patients with RRMM who have exhausted frontline myeloma regimen, however at the cost of significant side effects like infections and hypertension. It seems to be a convincing regimen as a bridge to ASCT but warrants further studies with longer follow-up to validate our results. Disclosures No relevant conflicts of interest to declare.

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Evaluation of Serum Free Light Chains In Chinese Multiple Myeloma Patients

Blood ◽

10.1182/blood.v116.21.5011.5011 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5011-5011

Author(s):

Chengcheng Fu ◽

Shiqiang Qu ◽

Wu Depei

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Light Chain ◽

Elevated Level ◽

Response Assessment ◽

Myeloma Cells ◽

Serum Free ◽

Β2 Microglobulin ◽

Measurable Disease

Abstract Abstract 5011 Purpose: Serum Free-Light Chain (sFLC) Assay is a sensitive tool recently used for diagnosis and response assessment of plasma cell disorders, especially in light chain multiple myeloma, nonsecretory multiple myeloma and primary amyloidosis. According to assemble analysis of multiple large-scale clinical research results, guideline of sFLC analysis was introduced by IMWG in 2008. But sFLC assay has not been routinely used in China and the clinical significance of the item has been explored in this study. Patients and Methods: Serum specimens from 36 cases of MM patients identified by IFE were analyzed. The median age was 56.2(36-74). 24(66.7%) patients were male. The M protein type was IgG in 50%, IgA in 22%, IgD in 3%, light chain in 25%. According to D-S staging, 11% pts was inIIA, 58% in IIIA, 31% in IIIB. 8% patients was in±of ISS staging, 17% inII and 75% in III. Normal range for FLC measurements is as follows: κ3.3–13.1 mg/L, λ5.7–26.3 mg/L, and κ/λ ratio of 0.26–1.65. Results: Abnormal rFLCs were detected 100% in 14 newly-diagnosed patients. 86% patients had measurable disease. In κ-MM patients, levels of sFLC-κ were (553.1±471) mg/L; sFLC-λ were (14.2±4) mg/L; the median of rFLC was 32.62. In λ-MM patients, levels of sFLC-κ were (5.3±2.67) mg/L; sFLC-λ were (2503±1043) mg/L; the median of rFLC was 0.002. 22 MM patients were detected during the follow up after treatment. Abnormal clonal rFLC could be found 100% in 3 PD patients, 66.7% in 12 PR/SD patients and 0 in 7 ≥VGPR patients. There was no statistical significance between sFLC and sTLC (p≥0.05). The value of iFLC in ≥VGPR group was statistical different from other response assessment groups (p<0.05). In 24 patients with measurable disease (9 with κ-MM,15 with λ-MM), an elevated level of iFLC was associated with increased myeloma cells in bone marrow and β2-microglobulin, but not with ALB, LDH. Conclusions: sFLC assay is a highly sensitive diagnostic and response monitoring tool for multiple myeloma. An elevated level of iFLC was associated with increased myeloma cells in bone marrow and β2-microglobulin, but not with ALB, LDH in measurable disease. More patients and longer follow-up are needed to further evaluate the diagnostic and prognostic significance of this judgment parameter. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v124.21.3427.3427 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3427-3427

Author(s):

Muhamad Alhaj Moustafa ◽

S. Vincent Rajkumar ◽

Angela Dispenzieri ◽

Francis K Buadi ◽

Morie A Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Complete Response ◽

M Protein ◽

P Value ◽

Serum Free ◽

Serum Free Light Chain ◽

Best Response ◽

First Response

Abstract 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 1 Effect of FLCr normalization according to IMWG response categories 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 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.

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A Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.4774.4774 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4774-4774

Author(s):

James R. Berenson ◽

Laura V. Stampleman ◽

Alberto Bessudo ◽

Peter J. Rosen ◽

Leonard M Klein ◽

...

Keyword(s):

Multiple Myeloma ◽

Progressive Disease ◽

Liposomal Doxorubicin ◽

Phase 1 ◽

Single Agent ◽

Pegylated Liposomal Doxorubicin ◽

Great Promise ◽

Phase 2 ◽

Grade 3

Abstract Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

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Bortezomib (Velcade™) + Adriamycin™ + Thalidomide + Dexamethasone (VATD) as an Effective Regimen in Patients with Refractory or Relapsed Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v104.11.2399.2399 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2399-2399 ◽

Cited By ~ 17

Author(s):

Klaus Hollmig ◽

Julie Stover ◽

Giampaolo Talamo ◽

Athanasios Fassas ◽

Choon-Kee Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Platelet Count ◽

Stable Disease ◽

Progressive Disease ◽

Single Agent ◽

Patient Characteristics ◽

M Protein ◽

Ambulatory Care Setting ◽

Pet Scans

Abstract Velcade™ (Vel) has shown promising activity as single agent and, more recently, in combination with other antimyeloma agents (dexamethasone, thalidomide) in relapsed or refractory multiple myeloma. We have now explored the efficacy and safety of adding Adriamycin™ 2.5–10.0mg/m2 continuous infusion on days 1–4 and days 9–12 to Velcade™ 1.0 or 1.3 mg/m2 administered on days 1, 4, 9 and 11; thalidomide 50 or 100 mg days 1–12; and dexamethasone 20 or 40 mg days 1–4 and 9–12 (VATD). The treatment was administered in an out-patient, ambulatory care setting to 20 patients. Of the 20 patients evaluable for toxicity, 14 are also evaluable for response. Patient characteristics are outlined in Table 1. Prior resistance to Velcade™-based treatment was demonstrated in 19 patients, with progressive disease in 13 and stable disease in 6. All patients have received systemic therapy immediately prior to the initiation of VATD, which included Vel + thal (7), VTD (5), DT-PACE (4), Revlimid (3), and dex + thal (1). Hematologic toxicities were dependent on the pre-VATD platelet count and WBC levels, as outlined in Table 2. Out of 14 evaluable patients, partial response (≤ 75% of serum M protein reduction, ≤ 75% of urinary M excretion) was obtained in 7 (50%); none had a complete response. Serum M protein decreased by a median of 57% (21–90%) and urine M decreased by a median of 93% (21–90%). Bone marrow follow-up examinations were available in 13 patients and revealed a median reduction in monoclonal plasmacytosis of 50% (range 33–94%); none had a normal bone marrow. Pre-VATD PET scans showed evidence of disease in 10 patients. Post VATD PET scans showed improvement in 5, stable disease in 1 and progressive disease in 4 patients. Our results are promising and demonstrate that administration of Adriamycin™ can be safely added to VTD, and that this addition does overcome the resistance to Velcade-based therapy even in metronomic doses. This approach is now being formally evaluated in a randomized trial comparing VTD alone versus added Adriamycin™ 2.5 mg/m2 on days 1–4 and 9–12 as a salvage protocol in patients with recurrent or progressive MM. Patient Characteristics Velcade 1.0 mg/m² Velcade 1.3 mg/m² Parameter Total Adria 2.5 mg/m² Adria 5 mg/m² Adria 10 mg/m² Adria 5 mg/m² 1: Autotransplant; 2: Thalidomide; 3: Velcade; 4: Velcade; Thalidomide, Dexamethasone N 20 7 10 1 2 % Age ≥ 65 14 14 60 100 0 % Abn Cytogen 55 43 60 100 50 % Prior Autotx1 85 86 80 100 100 % Prior Thal2 100 100 100 100 100 % Prior Vel³ 95 100 90 100 100 % Prior VTD[sup4] 45 71 20 100 50 % LDH > 190 U/l 55 57 60 100 0 Hematologic Toxicities Pre-Treatment Median WBC Nadir Platelet Count WBC < 2,000 WBC > 2,000 WBC < 2,000 WBC > 2,000 > 100k (n=6) 1 5 .65 2.07 50k-100k (n=9) 3 6 .94 1.73 < 50k (n=4) 1 3 1.98 3.44 Median Platelet Nadir > 100k 46,000 51,000 50K–100k 11,000 20,000 < 50K 36,000 47,000

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Safety and Efficacy of Bortezomib (VELCADE™) in 104 Patients with Relapsed and/or Refractory Multiple Myeloma Who Have Received at Least Two Previous Lines of Therapy: Impact of Cytogenetics on Response from a Canadian Cohort.

Blood ◽

10.1182/blood.v108.11.5118.5118 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5118-5118

Author(s):

Joseph R. Mikhael ◽

Donna E. Reece ◽

Andrew Belch ◽

Nizar J. Bahlis ◽

Deepa Sharma

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Poor Prognosis ◽

Progressive Disease ◽

Karnofsky Performance Status ◽

Performance Status ◽

M Protein ◽

Cytogenetic Abnormalities ◽

Refractory Multiple Myeloma ◽

The Impact

Abstract Background: Bortezomib (VELCADE™) is a reversible proteasome inhibitor that has been shown to be safe and efficacious in patients (pts) with relapsed and/or refractory multiple myeloma (MM) using a dose of 1.3 mg/m2 on days 1, 4, 8 & 11 of a 21-day cycle. Certain cytogenetic abnormalities are associated with poor prognosis in MM, including deletion 13, t(4;14) and the p53 deletion.(Stewart et al, JCO2005; 23(26):6339–44). Bortezomib has demonstrated the ability to overcome the poor prognosis associated with deletion 13 (Jagannath, JCO2005; 23(16S) 6501). The impact of bortezomib on a broader range of cytogenetic abnormalities, such as t(4;14) has yet to be determined. Methods: In this multicentre, open-label, non-randomized, phase 3b study, pts with MM across 13 centres in Canada, who had received at least 2 previous lines of therapy and who were refractory to or had relapsed after their last therapy were enrolled. Pts received up to eight 3-week cycles of bortezomib on days 1, 4, 8 & 11. Dexamethasone 20 mg PO was administered on each day of and day after bortezomib administration if the pts either experienced progressive disease after receiving at least 2 treatment cycles of bortezomib or had no change in disease status from baseline after receiving at least 4 treatment cycles of bortezomib. Results: 104 pts were enrolled; the mean age in this cohort was 60.7 years, and 65 (62.5%) were male. Approximately 30% of pts had a Karnofsky performance status of 70 or less at baseline. 71 pts (68.3%) had received prior thalidomide therapy, 32 (30.8%) had received a prior autotransplant and 4 (3.8%) had received prior bortezomib treatment. 74 (71.2%) received 3 or more lines of prior MM therapy. During the study, mean number of bortezomib cycles completed was 4.6 (range, 0–11 cycles), and the number of pts that completed 8 cycles of therapy was 36 (34.6%). 15.2% of pts received dexamethasone at cycle 3 and 19.2% at cycle 5. Cytogenetic analysis was performed on approximately half of the pts. Response data for cycle 5 is currently available for 69/99 (69.7%) of evaluable pts (see Table 1). Overall, 76.9% of the pts experienced Grade 3 & 4 adverse events. Safety profile observed is similar to past trial results with bortezomib. Conclusion: In this large Canadian cohort of extensively pre-treated patients with mulitple myeloma, bortezomib demonstrated good response, consistent with previous studies. Analysis correlating cytogenetic profile and response rate is ongoing and will be available at the time of conference. In addition, a detailed safety analysis and impact of prior treatment on response will be analyzed and made available at the time of conference. Table 1. Response to Bortezomib Category of Response* No. of Patients (%) *Modified SWOG: CR 100% M-protein reduction; R 75–99%; PR 50–74%; MR 25–49%; SD<25%, PD increasing M-protein Any Response (CR + VGPR + PR + MR) 47 (68.1) ---Complete Response (CR) + Very Good Partial Response (VGPR) ---22 (31.9) ---Partial Response (PR) + Minimal Response (MR) ---25 (36.2) Stable Disease 10 (14.5) Progressive Disease 12 (17.4)

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Treatment Patterns & Survival In Multiple Myeloma Patients Sequentially Exposed To Thalidomide, Bortezomib & Lenalidomide In a UK Single Centre

Blood ◽

10.1182/blood.v122.21.5380.5380 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5380-5380 ◽

Cited By ~ 5

Author(s):

Julie L Tarant ◽

John Ashcroft ◽

Sylvia Feyler ◽

Roger G Owen ◽

Christopher Parrish ◽

...

Keyword(s):

Multiple Myeloma ◽

Progressive Disease ◽

Response To Therapy ◽

High Dose ◽

Second Line ◽

Single Centre ◽

Line Therapy ◽

Wide Range ◽

Duration Of Response

Abstract Background In recent years, the introduction of the immunomodulatory drugs (IMiDs) thalidomide & lenalidomide & the proteasome inhibitor (PI) bortezomib has substantially improved the therapeutic options & prolonged survival of patients (pts) with multiple myeloma (MM). Current treatment strategies involve sequential exposure to these agents, though the most effective sequencing of exposure has yet to be determined. MM is still, for the majority of pts, a relapsing & incurable disease with poor survival outcomes & alternative treatment approaches in relapsing disease after exposure to currently available novel agents is an on-going unmet need. We report the results of extended follow-up in this patient cohort. Objectives We examined outcomes in pts with progressive disease following sequential exposure to thalidomide, bortezomib & then lenalidomide, to assess responses to these & subsequent therapies in a “real-life” single centre setting. Methods Pts were eligible for this retrospective study if they had received sequentially thalidomide-, bortezomib- then lenalidomide-based combination therapy (LenCom) for MM as per The National Institute for Health & Care Excellence (NICE) guidance. Case records were examined for diagnostic details, depth & duration of response to PI treatment & regimens employed. T0 was defined as the time point at which LenCom was discontinued, whether for progressive disease (PD) or intolerance (I). Response to therapy subsequent to T0& Progression Free Survival/Overall Survival (PFS/OS) were assessed & factors predicting outcome analysed (e.g. ISS stage at diagnosis, age, previous therapies received, previous depth & length of response to treatment). Results Between Jan’07-Sept’12, 55 pts (27 Male & 28 Female) were enrolled. Median age at diagnosis was 59 yrs (range 33-89);ISS scores were: 20% stage I, 28% stage II & 28% stage III (23% unclassified). The median number of lines of therapy prior to LenCom was 3 (range 2-6). First line therapy was thalidomide-based in 64%; 36% underwent ASCT & 4 pts underwent tandem ASCT/RIC AlloSCT. Second line therapy was bortezomib-based in 42% & 53% pts received lenalidomide as > 4th line. Median time from diagnosis to commencing LenCom was 52.5mns (range 4-146). 43 pts (77%) had reached T0 (PD n=29, I n=14). At a median of 66 mns follow up (range 12-162 mns), a median of 9 cycles (range 1-32) of LenCom were administered to all pts & 7 cycles (range 1 -32) to those who had discontinued LenCom. Dexamethasone was discontinued after median 12 cycles in pts reaching T0, being stopped in 28% (median 6 cycles before T0). Median PFS from commencement of LenCom was 16.2 mns. At 4 mns median follow-up post T0, a total of 26 pts have received therapy after T0, of whom 3 received lenalidomide-based treatment (11.5%) & 3 received bortezomib-based treatments (11.5%). Thalidomide based treatment was received by 13 pts (combined with Bendamustine in 3 & bortezomib in 2). Post-T0 pts also received clinical trial therapies (3 pts on SRT501 trial, 1 pt on pomalidamide companion study & 1 pt on KW2478 – a heat shock protein 90 inhibitor), thalidomide-based treatment (10 pts, 2 with bortezomib), & high dose dexamethasone. 13 pts (50%) demonstrated PD as maximum response to first post-T0 therapy. Duration of response was generally very limited (median 0 mns, range 0-6 mns). Second line post T0 treatments, including pomalidomide, were received by 12 pts with only 2 pts pts achieving a PR or better to Thalidomide & bortezomib based regimens. Third line post T0 treatments were given to 2 pts with 1 pt achieving a further brief PR to DT-PACE. With a median follow-up of 6.4mns (1-37), 31 pts have died (PD n=18, infection n=6, other n=7). Median OS from diagnosis & commencement of LenCom were 100 mns & 18.4 mns, respectively. Median OS from T0 was 3.9mns (range 0-33 mns), influenced by the b2-microglobulin at T0 (<vs.³ 3.0 mg/L: 9 vs. 4.8 mns, p=0.027). The depth of response to LenCom correlated with PFS (P<0.001) but not post-T0OS (p=0.68). Conclusion Pts with MM who have relapsed after sequential exposure to thalidomide, bortezomib & lenalidomide have very limited treatment options. At present, a wide range of treatments are used, including re-challenging with lenalidomide, bortezomib & trial based treatments. However, few pts achieve a meaningful response to therapy & survival is consequently extremely poor. Disclosures: No relevant conflicts of interest to declare.

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Continued monoclonal protein response beyond day 100 after auto-transplantation for multiple myeloma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8587 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8587-8587

Author(s):

Wilson I. Gonsalves ◽

Morie Gertz ◽

Yi Lin ◽

Martha Lacy ◽

Angela Dispenzieri ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Response ◽

M Protein ◽

Disease Assessment ◽

Maximal Response ◽

Solitary Plasmacytoma ◽

Bone Marrow Plasma ◽

Smoldering Myeloma ◽

Protein Response

8587 Background: Patients (pts) undergoing an auto-transplant (ASCT) for multiple myeloma (MM) have disease assessment approximately 100 days later. This result may direct decisions of further therapy versus observation. However, some pts continue to experience a decline in their serum or urine monoclonal (M) - protein after day 100 without more therapy. Little is known about the prevalence and significance of this phenomenon. Methods: We identified 903 MM pts who underwent ASCT within 12 months (mos) of diagnosis (Dx) at our institution. Their day 100 post-ASCT M-protein from serum and urine electrophoresis with immunofixation as well as serum free light chains were compared to subsequent values during follow-up. The IMWG criteria were used to evaluate response. Results: Of the pts included, 510 (56%) were male and median age at ASCT was 59 (range 28-76). Median follow up from Dx and ASCT was 82 mos (95% CI; 75 - 86) and 74 mos (95% CI; 70 - 79) respectively. There were 453 (50%) pts seen in follow-up who had not achieved a CR at Day 100 nor initiated on maintenance therapy. Of these pts, 167 (37%) had a further decrease in their M-protein after day 100 at a median of 9.4 mos (95% CI; 8 – 10) post-ASCT. Given the time taken for maximal response, we assessed patients’ clinical response at one year post-ASCT. Compared to patients who did not have further clinical response between day 100 and 1 year, pts experiencing further response had a longer time to next therapy (TTNT) (43 mos vs. 17 mos, P < 0.001) as well as overall survival (OS) (96 mos vs. 62 mos, P < 0.001). Positive predictors for continued response included having an IgG isotype, evolution from a pre-existing MGUS, smoldering myeloma or solitary plasmacytoma and a Day 100 bone marrow plasma cell < 3%. In a multivariate analysis, elevated creatinine at Dx and lack of continued response predicted for shorter TTNT and OS post-ASCT. Older age and high-risk MM by FISH also predicted a shorter OS. Conclusions: In MM pts undergoing ASCT, continued M - protein response was seen in a third of the pts lacking a CR at day 100. This phenomenon appears prognostic and must be considered when interpreting studies evaluating post-ASCT response and the need for further therapy.

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Tracking Daratumumab Clearance Using Mass Spectrometric Approaches: Implications on M Protein Monitoring and Reusing Daratumumab

Blood ◽

10.1182/blood-2021-153209 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2707-2707

Author(s):

Nadine Abdallah ◽

David L Murray ◽

Angela Dispenzieri ◽

Prashant Kapoor ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Univariate Analysis ◽

M Protein ◽

Urine Protein ◽

Advisory Committees ◽

Plasma Cell Disorders

Abstract Background: MASS-FIX is a screening method for serum and urine monoclonal proteins in multiple myeloma and related plasma cell disorders, which uses immunoglobulin enrichment coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). In addition to superior sensitivity over conventional gel-based techniques, MASS-FIX can distinguish therapeutic monoclonal antibodies (MoAb) from patient's M protein. As the utilization of therapeutic MoAbs increases, it is essential to understand the persistence pattern of these therapeutic antibodies in the serum. We designed this study to evaluate the duration of daratumumab detection by MASS-FIX in the serum of treated patients. Methods: We used a prospectively maintained database at Mayo clinic to identify patients with multiple myeloma and related plasma cell disorders who were treated with a daratumumab-containing regimen anytime during their disease course and had serial MASS-FIX data available after discontinuation of daratumumab. A univariate analysis was performed to assess for factors that may impact the clearance of daratumumab. Results: We included 125 patients with plasma cell disorders who received daratumumab as first or subsequent line of treatment between March 15 th, 2016, and March 4 th, 2020. The median age was 60.2 years and 57% were male. The most common diagnoses were multiple myeloma (70%) and light chain amyloidosis (18%). Daratumumab-based treatments were initiated after a median of 28.8 (IQR: 6.4-76.3) months from initial diagnosis. The most common regimen used was daratumumab, bortezomib and dexamethasone (23%); 26% underwent transplant after daratumumab-based induction. The median duration of treatment with a daratumumab-based regimen was 208 (IQR: 99-479) days. The median follow-up from the time of daratumumab discontinuation was 457 (95% CI: 346-NR) days. By last follow up, daratumumab was not detected by MASS-FIX in 93 (74%) patients but remained detectable in 32 (26%) patients. The median time from daratumumab discontinuation to disappearance of daratumumab by MASS-FIX was 160 (IQR: 107-233) days. On univariate analysis, the presence of ≥0.5 grams of urine protein was associated with earlier disappearance of daratumumab on MASS-FIX [risk ratio (RR): 2.0, P=0.02). The median time from daratumumab discontinuation to disappearance of daratumumab on MASS-FIX was 116 (95%CI: 76-160) days in patients with urine protein ≥0.5 grams and 203 (95%CI: 162-216) days in patients with urine protein <0.5 grams (P=0.02). There was no association between the time to disappearance of daratumumab by MASS-FIX and old age ≥70 (RR: 0.9, P=0.81], male gender (RR: 0.9, P=0.60), eGFR <60 (RR: 1.0, P=0.98), daratumumab schedule (every 1/2 weeks vs >2weeks) (RR: 1.0, P=0.97), treatment duration (<200 days vs ≥200 days) ( RR: 1.0, P=0.95), or transplantation status (RR: 1.0, P=0.98). Conclusion: The therapeutic monoclonal antibody daratumumab remains detectable in the serum of treated patients by MASS-FIX for several months after discontinuation and the duration varies between individual patients. This data has implications for diagnostic and monitoring testing and may provide guidance for reuse of daratumumab in clinical trials and practice. Proteinuria is associated with earlier disappearance of daratumumab by MASS-FIX and may have implications in patients with amyloidosis and monoclonal immunoglobulin deposition disease (MIDD). Further studies are needed to identify additional factors associated with the timing of disappearance. Disclosures Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

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Multiple Myeloma Oligosecretory Relapse, a Non-Negligible Phenomenon. Frequency, Clinical Characteristics and Outcomes in a Single Center

Blood ◽

10.1182/blood-2021-151255 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3772-3772

Author(s):

Itai Zamir ◽

Tamir Shragai ◽

Svetlana Trestman ◽

Tomer Ziv Baran ◽

Efrat Luttwak ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Clinical Characteristics ◽

M Protein ◽

Advisory Committees ◽

Monoclonal Protein ◽

Disease Characteristics ◽

Comparator Group ◽

Measurable Disease

Abstract Introduction: Multiple myeloma (MM) is malignancy of plasma cells, which secrete monoclonal antibodies that are detectable in the patient's (pt) serum and/or urine. Infrequently, MM may present as an oligosecretory disease, where monoclonal protein (M-protein) and involved free light chain (iFLC) are either not detected (=non-secretory) or are both below the threshold for measurable disease (=oligosecretory) as defined by International Myeloma Working Group (IMWG). The incidence of non-secretory MM at presentation has been estimated at 1-2% [Chawla, Eur J Haematol 2015], yet data regarding the frequency and clinical phenotype of oligosecretory relapse is lacking. These pts are typically excluded from most clinical trials. Methods: Pt's MM was classified as oligo-secretory, in the absence of measurable disease according to the IMWG criteria (M-protein≥1 gr/dL, or U-PEP > 200 mg/24 hrs or involved free light chain≥ 100 mg/L). Relapse was defined according to IMWG criteria, based on changes in monoclonal protein in the serum or urine, bone or extramedullary lesions on imaging, bone-marrow plasmacytosis, serum hemoglobin, creatinine and calcium levels. Pts treated at our center for MM, who had secretory (i.e., measurable disease) MM at diagnosis, and relapsed (secretory or non-secretory relapse) between January 2016 to July 2020, were included. MM baseline pt and disease characteristics, disease characteristics at relapse, treatment regimens and outcomes were documented. The first oligosecretory relapse (OSR) that any given pt experienced was defined as the index OSR for that pt. For each pt with an OSR, we identified the first 4 pts with a secretory relapse (SR) in the dataset, who matched the pt by the relapse index number and calendar year of relapse, to form a SR comparator group. We compared pt and disease characteristics, therapy patterns and outcomes between the OSR and SR groups. Results: One hundred and seventy-seven pts with relapse were identified; 8 (4.5%) had oligo-secretory disease at MM diagnosis and were excluded; 152 of the 169 pts who were secretory at presentation (89.9%) had secretory MM at all relapses; 17 (10.0%) had an OSR (4 non-secretory and 13 oligosecretory), the SR comparator group included 67 pts. Pts with OSR had similar characteristics compared to SR pts at MM presentation, in terms of demographics, FISH cytogenetics, ISS, levels of M-protein and involved FLC, frequency of extramedullary disease, target organ involvement; Treatment pattern and response to upfront therapy were comparable (Fig1 A). Oligosecretory disease was more frequent at relapse compared to newly diagnosed MM (10% vs 4.5%), proportion of OSR among pts with previously secretory MM increased in later relapses. The proportion of OSR from total 3 rd or 4 th relapses, was high as 20% and 17.6%, respectively (Fig 1B). OSR pts had a higher rate of new plasmacytoma (53% vs 9%, p<0.001) as the criteria for relapse, and a trended towards increase in LDH, and higher rate of extramedullary disease (17% vs 4.4%, p=0.09) whereas increase in monoclonal protein was more frequent in the SR group as a criterion for relapse. Overall response rate to therapy of the index relapse was similar between groups among evaluable pts (58% vs 64%), however, in 5/17 (29%) of the OSR, response was non evaluable from available documentation. Median follow up was 10.2 months [Q1 4.1- Q3 16.7]. Twelve-months progression free survival was 82.4% vs 73.8% (p=0.76), and 12-months overall survival was 60.2% vs 64.75% (p=0.60) in RS and OSR, respectively. Conclusions: Oligosecretory disease was more frequent in relapsed MM, compared to its rate at MM presentation, reaching 10% of the pts with relapsed MM and increasing in more advanced relapses. Pts with OSR and those with SR had similar clinical characteristics of their MM at presentation as well as comparable outcomes, but pts with OSR had higher rates of new skeletal and extramedullary lesions. As identification of the OSR may be challenging in the absence of serum and urine biomarkers, awareness and clinical alertness are warranted to avoid end organ damage. We suggest inclusion of OSR pts in clinical trials should be considered, despite some challenges in following their therapy response, as they comprise a non-negligible proportion of pts, in particular in the advanced relapse setting. Figure 1 Figure 1. Disclosures Avivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Cohen: Neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karophram: 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, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: 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.

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