Disease monitoring with quantitative serum IgA levels provides a more reliable response assessment in multiple myeloma patients

AbstractUnlike IgG monoclonal proteins (MCPs), IgA MCP quantification is unreliable due to beta-migration of IgA MCPs on serum protein electrophoresis (SPEP). The utility of nephelometric quantitative IgA (qIgA) to monitor IgA multiple myeloma (MM) is unclear. We retrospectively studied disease response kinetics using qIgA versus MCPs by SPEP, and developed and validated novel qIgA disease assessment criteria in 491 IgA MM patients. The SPEP MCP nadir occurred a median of 41 (IQR 0–102) days before the qIgA. The median time to achieve a partial response (PR) was shorter using standard IMWG versus qIgA response criteria (32 vs 58 days, p < 0.001). Stratification by qIgA criteria, unlike IMWG criteria, led to clear separation of the progression-free survival curves of patients achieving a PR or very good PR. There was a consistent trend toward earlier detection of disease progression using qIgA versus IMWG progression criteria. In conclusion, monitoring IgA MM using MCP-based IMWG criteria may be falsely reassuring, given that MCP levels on SPEP decrease faster than qIgA levels. The qIgA response criteria more accurately stratify patients based on the progression risk and may detect disease progression earlier, which may lead to more consistent measurement of trial endpoints and improved patient outcomes.

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Assessing the utility of monitoring IgA multiple myeloma patients with quantitative serum IgA levels.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e20515 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e20515-e20515

Author(s):

Alissa Visram ◽

Abdullah S. Al Saleh ◽

Harsh V Parmar ◽

David L Murray ◽

David Dingli ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Median Time ◽

Treatment Initiation ◽

Progression Free Survival ◽

Organ Damage ◽

Bone Lesions ◽

Disease Response ◽

Kaplan Meier ◽

Monoclonal Proteins

e20515 Background: IgA monoclonal proteins (MCPs), unlike IgG MCPs, often migrate in the beta region on serum protein electrophoresis (SPEP) which can lead to underestimation of their size due to the co-migration with physiologic proteins. In IgA multiple myeloma (MM), the utility of quantitative IgA levels in assessing disease response in comparison to SPEP is not well studied. Methods: We retrospectively analyzed 304 IgA MM patients, diagnosed between 2004 and 2018, with available serial MCP and quantitative IgA levels. Kaplan Meier analysis was used to estimate the median progression free survival (mPFS) using the IMWG criteria and our study definition of IgA progression (2 consecutive IgA values that are > 25% above the nadir IgA value and above upper limit of normal (ULN) of 356 mg/dL, and a detectable IgA MCP on serum immunofixation). The mPFS was defined as the time from treatment initiation until disease progression or death. Results: IgA MCP migrated in the beta region in 134 (44%) patients, and in the gamma region in 150 (56%) patients. At diagnosis the median MCP was 3 (IQR 1.9-4) g/dL and the median IgA was 3240 (IQR 2008-4420) mg/dL. The median time from treatment initiation to MCP nadir was 80 (IQR 42-144) days and median time to IgA nadir was 154 (IQR 90-238) days. At MCP nadir 40% of patients had an IgA above the ULN. All complete responders (n = 104) had normal IgA levels, with a median IgA of 54 (IQR 27-88) g/dL. A ≥90% decrease in IgA between treatment initiation and IgA nadir, compared to a < 90% decrease, was associated with a longer mPFS (34 vs. 20 months, p = 0.006) and overall survival (97 vs. 33 months, p = 0.003). Patients with serial MCP and IgA levels available prior to progression (n = 195) were used to compare the mPFS using the IMWG and IgA progression criteria. The mPFS using the IgA criteria was 32 (95% CI 29-39) months, versus 39 (95% CI 33-45) months using IMWG criteria. Overall, 92 (47%) patients progressed by both IMWG and IgA criteria. At the time of progression using the IgA criteria compared to at IMWG progression, the median hemoglobin was higher (13.3 vs. 11.6 g/dL, respectively, p < 0.001) and fewer patients had new symptomatic bone lesions (2% vs. 33%, respectively, p < 0.001). Conclusions: In IgA MM patients, monitoring quantitative IgA levels predicts disease response and allows for earlier detection of disease progression, prior to the development of end organ damage.

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Bortezomib Consolidation Following Upfront ASCT for Multiple Myeloma Deepens Disease Response and MRD-Negative Rate without Compromising Response to Subsequent Bortezomib Salvage: Results of a Phase II Study

Blood ◽

10.1182/blood.v128.22.4508.4508 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4508-4508 ◽

Cited By ~ 2

Author(s):

Oliver C Cohen ◽

Neil Rabin ◽

Nicholas Counsell ◽

Roger G Owen ◽

Bilyana Popova ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Phase Ii ◽

Salvage Therapy ◽

Progression Free Survival ◽

Patient Choice ◽

High Dose ◽

Cell Transplant ◽

Second Line ◽

Disease Response

Abstract Background: Consolidation after high dose therapy and autologous stem cell transplant (ASCT) for multiple myeloma (MM) can improve response depth and prolong progression free survival (PFS), but it is important to ensure good quality of life (QoL) and responsiveness to further salvage therapy. We conducted a single-arm Phase II weekly bortezomib consolidation trial (BCT) to assess outcomes in MM patients receiving upfront ASCT. Methods: Bortezomib-na•ve patients with at least stable disease at 3-4 months post-high dose melphalan 200mg/m2 with ASCT received up to 8 cycles of bortezomib (1.3mg/m2 days 1,8,15,22 in a 4-week cycle), 17 intravenously (IV) and 23 subcutaneously (SC). The primary endpoint was disease response (IMWG) at 6 and 12 months post-ASCT. Other endpoints were MRD by multiparametric flow cytometry (patient 15 onwards) at 6 and 12 months post-ASCT, toxicity, PFS, overall survival, osteoblast function and Qol (EORT-QLQ-C30). Serum basic alkaline phosphatase (bALP) and ostocalcin (OC) were measured by ELISA. Results: The study recruited 40 patients between December 2009 and March 2014 at a median of 3.4 months post-ASCT. The median age was 61 years (range 43-69); 55% male; isotypes were: 22 (59%) IgG, 9 (24%) IgA, 1 (3%) IgD, 5 (14%) light chain only, 1 non-secretory and 2 unknown. Induction regimens pre-ASCT were thalidomide (33, 87%), idarubicin and dexamethasone (5, 13%). and unknown in 2. One patient was withdrawn prior to commencement (unfit for treatment) and 3 patients stopped trial treatment after 1 cycle (2 toxicity, 1 disease progression). Of 36 patients who completed >1 cycle of bortezomib, 10 stopped treatment early (5 toxicity, 4 patient choice, 1 disease progression); median number of cycles received was 8. Eleven (28%) patients experienced a total of 15 grade 3 adverse events (AE); 6 (neuropathy, 3 in IV group, 18% cf 3 in SC group, 13%), 4 (infection), 1 (fatigue), 2 (haematological), 2 other. One patient had a grade 4 infection (cycle 1, treatment discontinued) and 1 grade 4 back pain. EORTC-QLQ-C30 scores for global health status and physical, emotional and social functioning did not change significantly throughout treatment. After a median follow up of 44.4 months, 18 (45%) are alive without progression, 20 (50%) are alive with progression and 2 (5%) died after progression. BCT improved response depth in assessable patients who completed >1 cycle (n=34). Disease response at trial entry: 4 (12%) sCR/CR, 19 (56%) VGPR, 10 (29%) PR, 1(3%) SD, cf. response at 12 months post-ASCT: 7 (21%) sCR/CR, 22 (65%) VGPR, 4 (12%) PR, 1(3%) PD. Biochemical response depth improved in 12 patients. 19 patients had MRD testing at 3 (where available) or 6 months post-ASCT and again at 12 months, 10 were MRD+ at the earlier time point, of whom 4 converted to MRD- at 12 months. Of the 9 MRD- patients, all remained negative at 12 months. 15 patients (44%) had improvement in biochemical and/or MRD response at 12 months. Median PFS was 38.5 months (95%CI 29.1-47.9)(Figure). Patients who were MRD- at 12 months had median PFS of 49.2 months (95%CI 35.3-63.2) compared with 22.0 months (95%CI 21.5-22.6) in MRD+ patients (p=0.03). Of the 22 patients who relapsed, 12 received bortezomib-based salvage regimens, 5 received carfilzomib-based regimens and 5 have not started second-line therapy. Disease responses in patients receiving bortezomib salvage was 8 (67%) VGPR, 4 (33%) PR. Four patients went on to have a 2nd ASCT. In the 17 patients receiving salvage, median 2nd PFS from start of second line was 14.8 months (95%CI 8.2-18.0). At 3 months post-ASCT, levels of the osteoblast markers bALP and OC were significantly higher in CR/VGPR patients, compared to patients with PR or less (p=0.04 and 0.03, respectively). Neither marker changed significantly following BCT. Conclusions: For patients with MM, consolidation with weekly bortezomib post-ASCT is well tolerated and deepens disease response and MRD negativity without compromising the response to subsequent bortezomib-based salvage therapy. Patients who are MRD- at 12 months enjoy a median PFS of 4 years. This low intensity post-ASCT strategy deserves further study in the context of current and evolving protocols for newly diagnosed patients. Figure Figure. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.

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Tumor Reduction in Multiple Myeloma: New Concepts for New Therapeutics

Frontiers in Oncology ◽

10.3389/fonc.2021.800309 ◽

2022 ◽

Vol 11 ◽

Author(s):

Rafael Alonso ◽

Juan José Lahuerta

Keyword(s):

Multiple Myeloma ◽

Residual Disease ◽

Imaging Techniques ◽

Prognostic Significance ◽

Response Assessment ◽

Tumor Burden ◽

Response Criteria ◽

Disease Response ◽

Tumor Reduction ◽

Novel Therapeutic Strategies

The development of new resources for a more accurate diagnosis and response assessment in multiple myeloma has been a long process for decades, mainly since the middle of the 20th century. During this time, the succession of technical advances has run parallel to the better knowledge of disease biology and the availability of novel therapeutic strategies. The cornerstone of standardized criteria to uniformly evaluate the disease response in myeloma dates back to the 1990s when the key role of complete remission was established. Since then, different updates have been implemented according to available scientific evidences not always without certain controversies. The progressive improvements in survival results of myeloma patients and the growing quality of responses due to the novel therapies have led to the need of developing new tools for better monitoring of tumor burden. In this way, the concept of minimal residual disease and its key value based on the prognostic significance and the clinical relevance has been consolidated during the last years, overcoming the value of conventional response criteria or classical adverse prognosis markers. Nevertheless, its precise role in the clinical management of myeloma patients to detect early treatment failure and trigger early rescue strategies is still pending to be defined. In this review, we revisit the major milestones in the understanding of tumor reduction in multiple myeloma until the most recent imaging techniques or liquid biopsy approaches, including a critical view of conventional response criteria, whose backbone has remained unchanged during the last 20 years.

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ClaPD (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.77.77 ◽

2012 ◽

Vol 120 (21) ◽

pp. 77-77 ◽

Cited By ~ 9

Author(s):

Tomer M Mark ◽

Angelique Boyer ◽

Adriana C Rossi ◽

Manan Shah ◽

Roger N Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Disease Progression ◽

Research Funding ◽

Response Rate ◽

Progression Free Survival ◽

Tolerability Profile ◽

Disease Response ◽

Immunomodulatory Agent

Abstract Abstract 77 Background: The addition of clarithromycin has been reported to enhance anti-myeloma activity of lenalidomide+dexamethasone in the upfront treatment of multiple myeloma (MM). Pomalidomide is a distinct IMiD® immunomodulatory agent with a significant response rate in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We have shown initial results that clarithromycin may similarly enhance the activity of pomalidomide + dexamethasone in patients with RRMM after prior lenalidomide therapy (Rossi et al, ASCO 2012). We now report updated results from a phase 2 trial of large group of patients treated with ClaPD in RRMM. Methods: One hundred patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPD. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1–21 of a 28-day cycle, and dexamethasone 40mg on days 1,8,15,22. All subjects had thromboprophylaxis with 81mg aspirin daily. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression. Results: Ninety-seven patients had completed at least 1 cycle of ClaPD and were eligible for disease response and safety analysis. Patients had undergone a median of 5 (range 3–15) prior lines of therapy. The proportion of patients who were refractory to lenalidomide, refractory to bortezomib, and double (lenalidomide +bortezomib) refractory were 73%, 70%, and 64% respectively. The median number of ClaPD cycles received was 4 (range 1–23). Response to ClaPD was progressive disease (PD): 9.3%, stable disease (SD): 32%, minimal response (MR): 5.2%, partial response (PR): 32%, very good partial response (VGPR): 17.5%, stringent complete remission (sCR): 4.1%, giving an overall response rate (ORR, ≥PR) of 53.6% and a ≥VGPR rate of 21.6%. Clinical benefit (≥SD) was achieved in 90.7%. Median time to PR and maximum response was 1 (range 1–7) and 2 (range 1–14) cycles, respectively. After a mean follow up time of 10.1 months, 41 patients (42%) remain on study free from disease progression, with a median progression free survival of 8.2 months (95% CI: 5.1, 10.3). Median overall survival has not been reached with 72 patients (74%) alive at last follow-up. The most common grade 3 and 4 toxicities included anemia (25%), neutropenia (40%), hyperglycemia (11%), and fatigue (6%). Febrile neutropenia was uncommon at 2%. There were 4 cases of lower extremity venous thrombosis (4.1%, 1 at grade 1, 3 at grade 2) and no instances of pulmonary embolism. There was no treatment related mortality. Conclusions: ClaPD is a highly effective regimen for heavily treated RRMM that has progressed after prior treatments. Response to ClaPD is rapid and sustained at > 8 months in the majority of subjects. The tolerability profile is comparable to lenalidomide and incidence of thromboembolic events was low with low-dose aspirin prophylaxis. These data support the use of pomalidomide therapy in RRMM that has progressed after lenalidomide. Disclosures: Mark: Celgene Corp: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium Inc.: Speakers Bureau. Off Label Use: Pomalidomide is not indicated to treat multiple myeloma. This drug is a next-generation immunomodulatory agent. We are investigating its activity and safety for use in relapsed or refractory myeloma. Zafar:Celgene Corp: Speakers Bureau. Pekle:Celgene Corp: Speakers Bureau. Coleman:Celgene Corp: Speakers Bureau. Niesvizky:Onyx, Millenium, Celgene. Speakers bureau: Millenium and Celgene: Consultancy, Research Funding.

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Isatuximab plus carfilzomib and dexamethasone in east Asian patients with relapsed multiple myeloma: IKEMA subgroup analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20015 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20015-e20015

Author(s):

Kihyun Kim ◽

Chang Ki Min ◽

Youngil Koh ◽

Kenichi Ishizawa ◽

Sung-Hyun Kim ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Residual Disease ◽

East Asian ◽

Progression Free Survival ◽

Complete Response ◽

Efficacy And Safety ◽

Asian Patients ◽

Number Of Patients ◽

East Asian Patients

e20015 Background: The Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) plus carfilzomib and dexamethasone (Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (hazard ratio [HR] 0.53; 99% confidence interval [CI] 0.32–0.89; P= 0.0007). We evaluated the efficacy and safety of Isa-Kd in the East Asian patients (19 Japanese, 27 Korean). Methods: RMM pts who received 1-3 prior lines of therapy were stratified to receive Isa-Kd or Kd. Isa-Kd arm received Isa (10 mg/kg intravenously) weekly for 4 weeks, then every 2 weeks. Both arms received K (20 mg/m2 days 1-2, 56 mg/m2 thereafter) twice-weekly for 3 of 4 weeks, and d (20 mg) twice-weekly. Treatment continued until disease progression or unacceptable adverse events (AE). The primary endpoint was prolongation of PFS. Key secondary endpoints included; very good partial response or better (≥VGPR), complete response (CR) rate and minimal residual disease negativity (MRD–) rate. Results: East Asian pts (25 Isa-Kd, 21 Kd) were randomized. Pt characteristics were similar in the East Asian subgroup compared with the intent to treat (ITT) population (N = 302). Median age (Isa-Kd 64.0 [range 45–83] years vs Kd 60.0 [range 33–73] years); median prior lines Isa-Kd 2.0 (range 1–3) vs Kd 1.0 (range 1–3); refractory to lenalidomide 16.0% Isa-Kd vs 47.6% Kd; refractory to PI 20.0% Isa-Kd vs 33.3% Kd; high-risk cytogenetics 48.0% Isa-Kd vs 42.9% Kd. After a median follow-up of 20.7 months, the addition of Isa to Kd improved ≥VGPR, CR and MRD– rates (Table). The HR 0.64 (95%CI: 0.231-1.764) for disease progression or death favored Isa-Kd. Grade ≥3 AEs were observed in 79.2% Isa-Kd vs 55.0% Kd pts, serious TEAEs in 45.8% Isa-Kd vs 50.0% Kd; TEAEs leading to treatment discontinuation were lower in the Isa-Kd group (4.2% Isa-Kd vs 10.0% Kd). Overall, 64.0% Isa-Kd vs 42.9% Kd pts were still receiving treatment. Conclusions: Efficacy and safety results of Isa-Kd in East Asian pts are consistent with the results of the overall IKEMA population, in which significantly better efficacy (PFS, CR, ≥VGPR and MRD– rate) was reported in favor of Isa-Kd without an increase in the number of patients with serious TEAEs or discontinuations. Isa-Kd is a potential treatment option for East Asian pts with RMM. Clinical trial information: NCT03275285. [Table: see text]

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A niche-dependent myeloid transcriptome signature defines dormant myeloma cells

Blood ◽

10.1182/blood.2018880930 ◽

2019 ◽

Vol 134 (1) ◽

pp. 30-43 ◽

Cited By ~ 22

Author(s):

Weng Hua Khoo ◽

Guy Ledergor ◽

Assaf Weiner ◽

Daniel L. Roden ◽

Rachael L. Terry ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Disease Progression ◽

Drug Targets ◽

Myeloid Cell ◽

Progression Free Survival ◽

Healthy Human ◽

Myeloma Cells ◽

Depth Of Response ◽

Transcriptome Signature

Abstract The era of targeted therapies has seen significant improvements in depth of response, progression-free survival, and overall survival for patients with multiple myeloma. Despite these improvements in clinical outcome, patients inevitably relapse and require further treatment. Drug-resistant dormant myeloma cells that reside in specific niches within the skeleton are considered a basis of disease relapse but remain elusive and difficult to study. Here, we developed a method to sequence the transcriptome of individual dormant myeloma cells from the bones of tumor-bearing mice. Our analyses show that dormant myeloma cells express a distinct transcriptome signature enriched for immune genes and, unexpectedly, genes associated with myeloid cell differentiation. These genes were switched on by coculture with osteoblastic cells. Targeting AXL, a gene highly expressed by dormant cells, using small-molecule inhibitors released cells from dormancy and promoted their proliferation. Analysis of the expression of AXL and coregulated genes in human cohorts showed that healthy human controls and patients with monoclonal gammopathy of uncertain significance expressed higher levels of the dormancy signature genes than patients with multiple myeloma. Furthermore, in patients with multiple myeloma, the expression of this myeloid transcriptome signature translated into a twofold increase in overall survival, indicating that this dormancy signature may be a marker of disease progression. Thus, engagement of myeloma cells with the osteoblastic niche induces expression of a suite of myeloid genes that predicts disease progression and that comprises potential drug targets to eradicate dormant myeloma cells.

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Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2016.69.2517 ◽

2017 ◽

Vol 35 (25) ◽

pp. 2900-2910 ◽

Cited By ~ 111

Author(s):

Juan-Jose Lahuerta ◽

Bruno Paiva ◽

Maria-Belen Vidriales ◽

Lourdes Cordón ◽

Maria-Teresa Cedena ◽

...

Keyword(s):

Multiple Myeloma ◽

Residual Disease ◽

Bone Marrow Involvement ◽

Progression Free Survival ◽

Response Assessment ◽

Pooled Analysis ◽

Disease Stage ◽

Cox Models ◽

Depth Of Response ◽

The Impact

Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of “operational cure” was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM.

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Outcomes Following Syngeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma: A Matched Comparison to Autologous Transplantation.

Blood ◽

10.1182/blood.v108.11.50.50 ◽

2006 ◽

Vol 108 (11) ◽

pp. 50-50 ◽

Cited By ~ 2

Author(s):

Asad Bashey ◽

Waleska S. Perez ◽

Mei-Jie Zhang ◽

David H. Vesole ◽

Donna E. Reece ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Treatment Failure ◽

Disease Progression ◽

Propensity Scores ◽

Progression Free Survival ◽

Free Graft ◽

Free Survival ◽

Autologous Hct

Abstract Relapse is the main cause of treatment failure following autologous hematopoietic cell transplantation (HCT) for multiple myeloma (MM). Syngeneic HCT offers the advantage of a myeloma-free-graft. However, a potential disadvantage is the lack of a graft versus myeloma effect (GVM). We compared the probabilities of treatment-related mortality (TRM), disease progression, progression-free survival (PFS) and overall survival (OS) after syngeneic versus autologous HCT for MM done between 1988 and 2003. Median follow up was >70 months in both groups. 43 syngeneic HCT recipients were matched to 170 autologous HCT recipients using a propensity score. A numerical propensity score for each syngeneic HCT recipient was calculated using the variables of age, Durie-Salmon stage at diagnosis, sensitivity to pretransplant therapy, time from diagnosis to HCT and year of HCT. Propensity scores ranged from 0.004–0.286. Syngeneic HCT recipients (cases) were matched in random order to autologous transplant (control) recipients with similar propensity scores. Patients who underwent tandem transplants were excluded. Median age (range) was 53 and 52 years in cases and controls. Most patients in both groups (60% of cases, 64% of controls) were transplanted within 12 months of diagnosis. Except for a higher proportion of patients with IgG myeloma (59% vs. 39%, p<0.01) and PBSC grafts (92% vs. 51%, p<0.01) in the control group there were no statistically significant differences in baseline characteristics of the two groups. 5-year outcomes are summarized in the table. 5-year outcome, probability (95% CI) Syngeneic Autologous Treatment-related mortatlity 14 (5–26) 10 (6–15) Disease progression 42 (26–58) 71 (64–78) Progression-free survival 44 (28–60) 19 (13–26) Overall survival 59 (43–74) 40 (32–48) Medican follow up survivors, months 71 (23–161) 85 (3–145) In multivariate analysis, risks of progression and treatment failure were significantly lower after syngeneic than autologous HCT [disease progression RR= 0.43 (95%CI, 0.23–0.78, p=0.004); treatment failure RR= 0.59 (95%CI 0.35–0.98, p=0.04)]. TRM at 1 year was 14% (5–26) in the syngeneic group and 9% (5–13%) in controls (p=0.33). The 5-year risk of mortality was lower in the syngeneic group but the difference was not statistically significant (RR= 0.61, 95%CI 0.36–1.05, p=0.07). Disease recurrence accounted for 79% of deaths in the autologous and 47% in the syngeneic cohort. We conclude that syngeneic HCT for MM results in superior PFS and lower progression rates compared to autologous HCT, confirming previous smaller analyses and emphasizing the importance of a disease-free graft. Interestingly, these data suggest that relapse rates similar to those observed after nonmyeloablative allogeneic transplantation – another source of tumor free grafts – can occur in the absence of clinical graft versus host disease.

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Use of Free Light Measurements in Clinical Trials of Novel Agents in Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3584.3584 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3584-3584

Author(s):

Amitabha Mazumder ◽

Sundar Jagannath

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Clinical Trials ◽

Warning System ◽

Complete Response ◽

Threshold Level ◽

Novel Agents ◽

Response Criteria ◽

Disease Response ◽

M Proteins

The free light assay has been reported to be valuable in monitoring patients with non-secretory multiple myeloma (MM). Furthermore, because of its short half-life, it may be useful even in patients who produce intact M-proteins. Recently, FLC has also been included in a revised response criteria for MM (BGM Durie et al International uniform response criteria for multiple myeloma. Leukemia, 7/20/06, online, 1–7,2006). We decided to study the applicability of the measurement of free light chains (FLC) in patients who were treated on clinical trials at our center with novel agents such as bortezomib and lenalidomide. We followed 21 patients with non- or hyposecretory MM with FLC measurements. These patients did not have measurable intact M-proteins and had only small amount of urine total protein (UTP) or Bence-Jones protein (BJP) present (< 0.3 mg/24hours). In 7 patients on bortezomib trials and 6 patients on lenalidomide trials, the involved FLC decreased by > 50% without the ability to detect any change in the UTP or BJP. The disease response seen was confirmed by bone marrow exams when available. Conversely, in 3 patients on each of the 2 agents, there was progression (> 25% increase) in the involved FLC without measurable increase in the small amount of UTP or BJP present, confirmed by either bone marrow or skeletal progression. Thus, in these patients, the FLC provided the only convenient means of monitoring. In 14 and 12 patients on bortezomib and lenalidomide respectively who had measurable UTP and BJP or serum M-proteins, there was a > 50% decrease in the FLC upto 8 weeks before any significant changes were seen in the urine protein measures or in serum M-proteins. Furthermore, the decrease continued after the UTP and BJP had reached a low possibly threshold level. In fact, 1 complete response on bortezomib was seen, confirmed by bone marrow studies, even with residual UTP (possibly due to bisphosphonate effect). Conversely, in 11 and 10 patients on bortezomib and lenalidomide respectively with measurable UTP and BJP or serum M, the increase in the involved FLC preceded progression in the parameters by upto 6 weeks. Thus, in these patients, the FLC provided an early warning system for their response or lack thereof. With respect to the criteria included in the reference cited above, the difference between the FLC was less meaningful in those patients with renal insufficiency, since both are significantly elevated in this state. The ratio however was the least meaningful since it was either 0 or infinite for a long time period depending upon which FLC was involved. Thus, FLC measurements are useful for monitoring patients who might not otherwise be eligible or benefit from clinical trials of novel agents. It can also serve as a early harbinger of response or progression. However, the limitations of the assay with respect to ratios and differences need to noted.

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

Blood ◽

10.1182/blood.v114.22.4878.4878 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4878-4878

Author(s):

Byeong Seok Sohn ◽

Eun Kyoung Kim ◽

Dok Hyun Yoon ◽

Myoung Joo Kang ◽

Dae Ro Choi ◽

...

Keyword(s):

Multiple Myeloma ◽

Progressive Disease ◽

Response Assessment ◽

M Protein ◽

Response Criteria ◽

Absolute Increase ◽

Serum Free Light Chain ◽

Measurable Disease ◽

Transplant Registry

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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