Levels of Uninvolved Immunoglobulin Predict Clinical Status and Progression-Free Survival for Multiple Myeloma Patients

Abstract Introduction: The levels of serum monoclonal immunoglobulins (M-Igs) are used to monitor multiple myeloma (MM) patients. However, these assessments do not discriminate between normal polyclonal immunoglobulins (uninvolved) and M-Igs since they cannot determine the type of light chain associated with each immunoglobulin class (i.e. IgGκ, IgGλ, IgAκ, IgAλ, IgMκ, and IgMλ). The HevyLite® +(HLC) assays are able to accomplish this but the usefulness of these results for MM patients needs to be further established. We evaluated the levels of involved and uninvolved HLC levels, their ratios and differences and their relationship to outcomes among MM patients. Materials and Methods: Serum samples (n=189) from MM patients were analyzed using the HLC assays. Manufacturer’s HLC normal reference ranges were used. HLC results were correlated with clinical status as determined at the time of sampling and divided into groups according to clinical status (complete response (CR), ≥ partial response (PR) , < partial response, and progressive disease (PD)). Normality was assessed using the D’Agostino-Pearson omnibus normality test. Statistical comparisons were made using t-student’s or Mann-Whitney tests as appropriate as well as Fisher’s test. Progression-free survival (PFS) was calculated using Kaplan--Meier analysis for specific regimens received during the time the samples were taken. All tests were double-tailed and p-values lower than 0.05 were considered to be statistically significant. Results: All MM serum samples analyzed had IgG (62%) or IgA (38%) isotypes. Results from the involved HLC/uninvolved HLC ratios and their differences demonstrated that samples from patients with PD had significantly both higher ratios and differences (P<0.0001) compared with patients with ≥ PR. Similar results were also observed for the involved HLC values (P<0.0001). The uninvolved HLC values were significantly lower (P<0.0001) for patients with PD compared with patients with ≥ PR. Similar results were obtained when we examined the percentage of patients who were in > PR compared with those with < PR so that patients in > PR were more likely to have normal uninvolved HLC levels than among patient with <PR (P<0.0001). In addition, we evaluated the proportion of patients in CR or PR based on their levels of uninvolved HLC being in the normal or below the normal range. The results showed that patients in CR were much more likely to have normal uninvolved HLC levels than among those with below normal uninvolved HLC levels (P < 0.0001). Similarly, patients in CR also were more likely to have normal uninvolved HLC levels than among those in PR (P=0.0040). Next, PFS was determined for patients with normal and below normal uninvolved HLC values. Patients with normal uninvolved HLC levels showed a much longer PFS (45 months) than among patients with less than normal uninvolved HLC levels (11 months; P=0.0019). Similarly, PFS was calculated for patients with normal and above normal involved HLC levels. Patients with normal involved HLC levels had a much longer PFS (33 months) than among patients with involved HLC levels that were above the normal range (11 months; P=0.0405). Conclusion: This study shows that involved HLC/uninvolved HLC ratios, differences between the involved and uninvolved HLCs, higher absolute levels of involved HLC, and lower levels of uninvolved HLC correlate with clinical status for MM patients. In addition, MM patients with normal uninvolved HLC levels have a longer PFS whereas those with involved HLC levels above the normal range show a shorter PFS. These results demonstrate the usefulness of the HLC assay for determining outcome for multiple myeloma patients. Disclosures No relevant conflicts of interest to declare.

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Prevalence of Oligoclonal Bands in Multiple Myeloma Patients Who Achieved Better Results Than Very Good Partial Response after Treatment with Standard or High Doses Chemotherapy-Final Analysis

Blood ◽

10.1182/blood.v126.23.4210.4210 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4210-4210

Author(s):

Luiza soares Vieira ◽

Edvan de queiroz Crusoe ◽

Manuella de S. Sampaio Almeida ◽

Lais Sousa ◽

ana Lucia Perez ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Conflicts Of Interest ◽

Progression Free Survival ◽

Final Analysis ◽

Complete Response ◽

High Dose Chemotherapy ◽

Oligoclonal Bands ◽

High Dose ◽

Good Partial Response

Abstract Introduction - Oligoclonal bands (OB) are monoclonal proteins distinct from those originally identified in the multiple myeloma (MM) diagnosis. Some authors consider that appearance of these bands confers a better prognosis and may be linked to immune reconstitution. There is no data of the exact prevalence of OB emergence in patients with very good partial response (VGPR) or better after different treatment schedules. Objectives - To determine the prevalence of OB in MM patients treated with or without high-dose chemotherapy that obtained at least VGPR and its prognostic value. Methods- This is a retrospective and prospective cohort study. Data were collected from records of patients that achieved at least VGPR to identify the OB emergence. Subsequently, new sample collections from the positive patients were made in order to monitor the progress and duration of the maintenance of these bands. Results-Median follow-up was 42m and 101 patients were included. Median age was 58y (29-87) and 55% were male. IgG was the most frequent component (60%). Durie-Salmon IIIA/B was identified in 92% of the population; ISS was 33% in stage I, 30% in stage II, and 31% in stage III. The prevalence of OB identified by SPE and IF was 50.5% (51 cases), with a higher prevalence in those who underwent transplantation and those who achieved complete response (p=0.00139 and p=0.0368, respectively). Progression free survival (PFS) was longer in the OB group (45.4m x 34.7m p = 0.0075). Conclusion - The OB prevalence in this population was 50.5% and oligoclonality resulted in a longer PFS. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Targeting Complete Response with Upfront Bortezomib Followed By Autologous Transplantation and Consolidation Therapy for Untreated Multiple Myeloma (TUBA study)

Blood ◽

10.1182/blood.v128.22.3463.3463 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3463-3463

Author(s):

Hideki Nakasone ◽

Kiriko Terasako-Saito ◽

Teiichi Hirano ◽

Atsushi Wake ◽

Seiichi Shimizu ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Progression Free Survival ◽

Complete Response ◽

Induction Treatment ◽

High Dose ◽

Induction Phase ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Free Survival

Abstract [Background] Multiple myeloma (MM) is generally considered incurable. Recently, novel drugs, including bortezomib, have demonstrated a survival benefit for newly diagnosed MM patients compared with classical treatments. Complete response (CR) after treatment is known to be associated with superior progression-free survival. Thus, we prospectively evaluated the efficacy and safety of boretezomib + dexamethasone (BD) for patients with newly diagnosed MM, followed by autologous hematopoietic stem cell transplantation (ASCT). We added BD consolidation therapy to aim CR if CR was not achieved after ASCT. [Patients and methods] This clinical study prospectively recruited newly diagnosed MM patients eligible for ASCT between 2010 and 2012. Due to health insurance issues in Japan, two courses of high-dose dexamethasone (HD-DX) had been administrated prior to BD induction treatment until Nov. 2011, while BD was administrated as an initial induction treatment since Dec. 2011. BD induction treatment included 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 with 20mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. This BD induction cycle was repeated every 3 weeks for 4 courses. Thereafter, filgrastim-based mobilization and ASCT following high-dose melphalan administration was performed. If patients did not achieve CR after ASCT, BD consolidation therapy (bortezomib: 1.3 mg/m2 on days 1, 8, and 15; dexamethasone 20 mg/day on days 1-2, 8-9, and 15-16) every 4 weeks was added to target CR (Figure 1) (UMIN-CTR: UMIN000002442). [Results] The median observational duration among survivors was 1536 days (range: 464-2023) at this analysis. Of the 47 enrolled MM patients, 46 (male 27; female 19) were eligible for BD induction treatment, while the remaining one achieved CR before BD induction. The median age of the patients was 59 (range: 35-67) years. Of the 44 patients whose karyotype analyses were available, normal karyotype was observed in 35. Abnormal karyotype included complex type in 4, diploid in 1, and other abnormalities in 4. FISH revealed deletion of p53 in 5 of 39 patients whose information was available; deletion of 13-chromosome in 16 of 42, IgH-MAF fusion in 1 of 40; IgH-FGFR3 fusion in 5 of 41; IgH-BCL1 fusion in 9 of 39. Of the 46 MM patients, 19 received HD-DX prior to BD induction, and 34 received ASCT after BD induction treatment (Figure 1). During the BD induction phase, 3 patients experienced disease progression, and BD treatment was discontinued in 9 patients because of their consent withdrawal (n=2) and adverse events (n=7) including interstitial pneumonia in 2, persistent neuropathy in 1, CMV enterocolitis in 1, heart failure in 1, diabetes mellitus in 1, and liver dysfunction in 1. After BD induction phase (n=46), their response was >= CR in 4 (8%), very good partial response (VGPR) in 10 (22%), partial response (PR) in 18 (39%), stable disease (SD) in 2 (4%), and progression or withdrawal in 12 (26%). After ASCT, their response was >=CR in 9 (20%), VGPR in 11 (24%), PR in 12 (26%), SD in 1 (2%), and additional progression or withdrawal in 1 (2%). Of the 24 patients who received ASCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses (range: 1- 8). BD consolidation was discontinued in 4 patients due to persistent neuropathy or cytopenia. Finally, maximum response after ASCT with or without BD consolidation was >= CR in 19 (41%), VGPR in 7 (15%), PR in 6 (13%), < SD in 2 (2%, Figure 2). Through BD consolidation, CR was achieved in 8 of 11 patients with post-ASCT VGPR and 2 of 12 patients with post-ASCT PR. In total, 4-year progression-free survival (PFS) and overall survival (OS) was 43% (95%CI: 28-57%) and 80 % (95%CI: 64-90%), respectively. Focusing on CR patients after ASCT and those who actually received BD consolidation, PFS adjusted for karyotype and age were not different between CR patients after ASCT and after BD consolidation, while patients with VGPR or less after consolidation had significantly lower PFS (Figure 3). [Conclusion] BD induction and ASCT provided CR rate of 27% among ASCT patients, although BD induction may expectedly cause adverse events including persistent neuropathy and viral infections. Patients who achieved CR after ASCT showed good PFS, and targeting CR through BD consolidation might improve CR rate. It is worthwhile to prospectively compare the efficacy of BD consolidation only for patients who failed to achieve CR or universal consolidation strategy. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding.

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Treatment sequencing patterns for relapsed refractory multiple myeloma (RRMM) in the era of new therapies in a single center institution.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e19513 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e19513-e19513

Author(s):

Alexandre Tungesvik ◽

Praneeth Reddy Sudalagunta ◽

Jessica Huang ◽

Elizabeth Dimaggio ◽

Gabe De Avila ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Progression Free Survival ◽

Complete Response ◽

Response To Therapy ◽

Cancer Center ◽

Free Survival ◽

New Therapies ◽

First Response ◽

Line Of Therapy

e19513 Background: Although there is much to be optimistic about in the multiple myeloma community as the approval of new therapies and regimen-combinations for relapsed refractory disease continues to grow, determining the best option for a patient can be complicated. Both carfilzomib- (C) and daratumumab- (D) based regimens have demonstrated superior efficacy in this setting, but there is a paucity of data supporting which should be selected first, and if regimen sequence influences outcomes. The aim of this study is to describe sequencing patterns in the era of these newer agents and to determine if there is a difference in outcomes for patients with RRMM who received one of the following treatment sequences: C-regimen with a D-regimen given immediately prior (DC); C-regimen without any prior D (C only); D-regimen with a C-regimen given immediately prior (CD); or D-regimen without any prior C (D only). Methods: This is a retrospective analysis of patients with RRMM consecutively treated at Moffitt Cancer Center between 1/1/2015 and 6/25/18. Response to therapy was assessed using the International Myeloma Working Group (IMWG) criteria. Progression-free survival (PFS) was measured in days from the start of therapy to progression. Time to response (TTR) was measured in days from the start of therapy to first response. Results: 132 patients with RRMM who received 1-3 prior lines of therapy with at least one line of therapy containing either C or D were identified. Overall, the majority of patients were treated with C only (n = 101), 10 received DC, 31 received D only, and 35 received CD. In patients that received C only, partial response (PR) was achieved in 38%, very good partial response (VGPR) was 20%, and stringent complete response (sCR) was 2%. In patients that received DC, PR was 20% and VGPR was 10%; no patient achieved a sCR. Of the patients that received D only, PR was 29%, VGPR was 10%, and sCR was 3%. In patients that received CD, PR was 31% and VGPR was 26%; no patient achieved sCR. Median PFS in patients who received C only, DC, D only, and CD was 117 days, 126 days, 104 days, and 190 days, respectively. TTR in patients who received C only, DC, D only, and CD was 82 days, 39 days, 98 days, and 88 days, respectively. Conclusions: The data suggests that RRMM patients who receive either CD or DC appear to have a PFS advantage over those patients who did not. Notably, an early TTR was found in patients that received DC. Further analysis is ongoing.

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Clinical Outcome of Bortezomib Retreatment in Patients with Relapsed or Refractory Multiple Myeloma

BioMed Research International ◽

10.1155/2014/145843 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Jae-Sook Ahn ◽

Sung-Hoon Jung ◽

Seung-Shin Lee ◽

Seo-Yeon Ahn ◽

Deok-Hwan Yang ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Sensory Neuropathy ◽

Progression Free Survival ◽

Complete Response ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Grade 3 ◽

Peripheral Sensory ◽

Good Partial Response

This retrospective study investigated the clinical efficacy and safety of bortezomib retreatment in patients with relapsed or refractory multiple myeloma (MM). A total of 30 patients who relapsed or progressed after≥6 months since the last dose of their previous bortezomib therapy were included in this study. During the median 6 cycles (range: 2–12) of bortezomib retreatment, 10 (33.3%), 2 (6.7%), and 6 (20.0%) patients achieved complete response, very good partial response, and partial response, respectively. Grade 3 or 4 neutropenia (47.0%), thrombocytopenia (43.0%), anemia (10.0%), and peripheral sensory neuropathy (3.0%) were observed. The median time to progression, progression-free survival, and overall survival were 5.8 months (95% CI: 2.6–9.0), 5.5 months (95% CI: 4.2–6.8), and 13.4 months (95% CI: 6.1–20.7), respectively. Patients who received bortezomib retreatment≥12 months from initial last therapy had a 1-year OS rate of 65.8% (95% CI: 43.5–88.1) while patients receiving retreatment after 6–12 months interval had a 1-year OS rate of 41.7% (95% CI: 13.9–69.5) (P=0.038). In conclusion, this study demonstrates that retreatment with bortezomib is an effective strategy for patients with MM who relapsed at a long interval after initial bortezomib therapy.

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Efficacy Of Bortezomib-Based Regimens With Or Without An Immunomodulatory Agent In Older Adults With Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood.v122.21.5580.5580 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5580-5580

Author(s):

Jordan Atkins ◽

Susan A Fowler ◽

Methodius Tuuli ◽

Aimee S James ◽

Tanya M Wildes

Keyword(s):

Systematic Review ◽

Multiple Myeloma ◽

Overall Survival ◽

Partial Response ◽

Meta Analysis ◽

Progression Free Survival ◽

Complete Response ◽

Inclusion Criteria ◽

Free Survival ◽

Good Partial Response

Abstract Introduction Multiple myeloma (MM) is an incurable disease within older adults, caused by the malignant proliferation of plasma cells and destruction of skeletal structure, with subsequent end-organ dysfunction. In the elderly and transplant ineligible population, chemotherapeutic regimens that include novel and conventional drugs are currently being employed to attain optimal response and survival outcomes. We performed a systematic review and meta-analysis to investigate the efficacy of the proteasome inhibitor bortezomib, in combination with an immunomodulatory drug (IMiD) versus bortezomib-containing regimens alone in improving overall survival, progression-free survival, and response in patients aged 65 and older ineligible for stem cell transplant. Methods We searched Pubmed/Medline, Embase, Scopus, CENTRAL, DARE, and clinicaltrials.gov databases for randomized controlled trials (RCTs) published from January 1946 until March 2013 using search terms such as: “bortezomib” “thalidomide/analogs and derivatives” and “lenalidomide.” Primary outcomes such as overall survival “OS” and progression-free survival “PFS” were harvested from standard indexes and on-topic articles. We abstracted data from relevant studies for analysis. Heterogeneity was assessed using Cochrane's Q and Higgin's I2 with p<0.1 considered significant. Pooled risk ratios (RR) and hazard ratios (HR) were estimated using DerSimonain and Laird random effect models. Results We identified 762 studies, 201 of which were duplicates that were excluded. Of these studies, 561 met initial inclusion criteria. After screening and systematic review, we found a majority of the articles originated from sub-analyses or reviews of 2 major studies which fully met inclusion criteria: 1) bortezomib-melphalan-prednisone-thalidomide (VMPT) versus bortezomib-melphalan-prednisone (VMP) [Palumbo JCO 2010] and 2) bortezomib-thalidomide-prednisone (VTP) versus VMP [Mateos Lancet Onc 2010). Of the two studies included, 384 patients received thalidomide and bortezomib-containing regimens (VMPT or VTP), and 387 patients received VMP. Thalidomide-containing combinations were associated with improvement in complete response (pooled RR 1.55 [95% Confidence intervals 1.23-1.95]) and very good partial response (pooled RR 1.19 [95% Confidence intervals 1.04-1.38]). There was no evidence of significant heterogeneity associated with either of these outcomes across the studies (I2=0; p=0.559 and I2=0; p=0.600). There were no significant differences in partial response (pooled RR 1.08; 95% CI 0.98-1.19), overall survival (pooled HR 1.04; 95% CI 0.65-1.44), or progression-free survival (pooled HR 0.91; 95% CI 0.29-1.42). There were also no significant differences in toxic side effects (Table). Conclusion Based on the limited data included in this meta-analysis, we found that the addition of thalidomide to a bortezomib-based regimen was associated with improved complete response and very good partial response, but no improvement in overall or progression-free survival. Larger studies of thalidomide and other immunomodulatory agents are required to further clarify the role of adding IMiDs to bortezomib-based regimens in the treatment of MM. Disclosures: No relevant conflicts of interest to declare.

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Combination of Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) for Relapsed Multiple Myeloma: Results of a Phase I/II Clinical Trial.

Blood ◽

10.1182/blood.v108.11.407.407 ◽

2006 ◽

Vol 108 (11) ◽

pp. 407-407 ◽

Cited By ~ 1

Author(s):

Antonio Palumbo ◽

Maria Teresa Ambrosini ◽

Giulia Benevolo ◽

Patrizia Pregno ◽

Norbert Pescosta ◽

...

Keyword(s):

Partial Response ◽

Phase I ◽

Response Rate ◽

Oral Prednisone ◽

Progression Free Survival ◽

Complete Response ◽

Second Line ◽

Open Label ◽

Free Survival ◽

Line Of Therapy

Abstract BACKGROUND: In newly diagnosed patients, the addition of thalidomide or bortezomib (Velcade™) to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter, open-label, non randomized, phase I/II trial, the safety/efficacy profile of the 4 drug combination, bortezomib (Velcade™), melphalan, prednisone, and thalidomide (VMPT) was evaluated in patients with relapsed/refractory myeloma. METHODS: Bortezomib was administered by IV bolus on days 1, 4, 15, 22 at three dose levels: in the first cohort (10 patients) at 1.0 mg/m2; in the second cohort (10 patients) at 1.3 mg/m2and in the third cohort (10 patients) at 1.6 mg/m2. Oral melphalan was administered at 6 mg/m2 on days 1–5, oral prednisone at 60 mg/m2 on days 1–5. Thalidomide was delivered at 50 mg on days 1–35. Each course was repeated every 35 days for a total of 6 courses. RESULTS: Thirty patients, median age 66 years (range 38–79), with relapsed or refractory myeloma were enrolled. Fourteen patients received VMPT as second line of therapy, 16 as third line. Twenty patients received prior autologous transplant, 10 conventional chemotherapy and 9 thalidomide-based regimens. After a median of 6 courses, 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good partial response (VGPR). Among patients who received VMPT as second line treatment, the PR rate was 79%, and the immunofixation negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 non-hematological adverse events included: infections (5 patients), fatigue (1), vasculitis (1) and peripheral neuropathy (2); no grade 4 toxicities were recorded. CONCLUSIONS: Initial results showed that VMPT is an effective salvage therapy with a high proportion of responses. Toxicities were manageable. The incidence of neurotoxicities was unexpectedly low.

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First Asia-Pacific Co-Operative Multicenter Multiple Myeloma Clinical Trial: Preliminary Results of the “dtZ”/“DAZZLE” Study.

Blood ◽

10.1182/blood.v114.22.4940.4940 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4940-4940

Author(s):

Gerrard Teoh ◽

Kihyun Kim ◽

Alok Srivastava ◽

Vasant Pai ◽

Sung-Soo Yoon ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Conflicts Of Interest ◽

Complete Response ◽

Osteonecrosis Of The Jaw ◽

High Rate ◽

Asia Pacific ◽

Hematopoietic Stem ◽

Asian Patients ◽

Tract Infections

Abstract Abstract 4940 Introduction Many physicians have anecdotally reported that Asian patients with multiple myeloma (MM) are frequently unable to tolerate full doses of dexamethasone (Dex) and/or thalidomide (Thal). Unfortunately, co-operative clinical studies from the Asia-Pacific countries are presently lacking and the effective dose of the Dex/Thal combination in Asians is unknown. Since higher doses of zoledronic acid (Zol) have been shown to exert an anti-MM effect in pre-clinical models of MM, we investigated whether higher frequency dosing of Zol combined with lower doses of Dex/Thal could be an effective and better tolerated regimen in Asian patients. Moreover, since attainment of very good partial response (VGPR), near complete response (nCR) or complete response (CR) prior to autologous hematopoietic stem cell transplantation (AHSCT) correlates with good outcome in MM, we wanted to determine if this lower-dose Dex/Thal with higher-frequency dosing Zol regimen could be a good preparative regimen in transplant-eligible patients. Patients and Methods In this international co-operative multicenter phase II non-randomized single arm study in previously untreated patients with MM (n=44), all patients received up to 6 cycles of three-weekly Dex/Thal/Zol (or “dtZ”). Doses of Dex ranged from 20 mg weekly to 20 mg four times a week; and doses of Thal ranged from 50 mg weekly to 100 mg every night. Zol 4 mg was given three-weekly. Response was graded using Blade's criteria. Results The study population included 67.3% Oriental (Korean and Chinese), 30.8% Indian and 1.9% Malay patients. 15.4% of patients were ISS stage I, 61.5% stage II and 23.1% stage III prior to treatment. 39 (88.6%) patients demonstrated at least a partial response (PR); and 23 (52.3%) of patients achieved VGPR (18.2%), near nCR (15.9%) or CR (18.2%). The fastest time to VGPR/nCR/CR was 1 cycle. Most patients tolerated treatment very well and were managed in the outpatient clinic. Sepsis was the most frequently reported grade 3 or 4 toxicity – 8 (18.2%) patients developed bronchopneumonia, and 3 (6.8%) gastrointestinal or urinary tract infections. 1 (2.3%) patient was suspected of having pulmonary embolism. There were 4 (9.1%) deaths – 3 from severe sepsis and 1 from an unknown cause. Importantly, there were no reports of peripheral neuropathy, osteonecrosis of the jaw (ONJ) or end stage renal failure. In fact, there was an overall 2.4% improvement in the median creatinine clearance time (CCT). Finally, the percentage of CD34 stem cells was not adversely affected by treatment with dtZ. Conclusions The dtZ regimen appears to be an effective and well-tolerated treatment regimen for Asian patients with newly-diagnosed MM. The high rate of VGPR/nCR/CR will greatly facilitate AHSCT in transplant-eligible patients. Judicious use of low-dose Thal has abrogated the numerous side-effects associated with Thal and greatly improved patient tolerance. Even though Zol is administered at a higher frequency, it is not associated with worsening of renal function or ONJ. Infections are the most frequent and worrisome complications of treatment. These are likely to be related to the dose of Dex. Accordingly, it is probably wise to further lower the dose of Dex in future studies. (This study is registered with NIH PRS # 00263484.) Disclosures No relevant conflicts of interest to declare.

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Final Results from the Phase IIa Study of the Anti-CXCL12 Spiegelmer® Olaptesed Pegol (NOX-A12) in Combination with Bortezomib and Dexamethasone in Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.2111.2111 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2111-2111 ◽

Cited By ~ 1

Author(s):

Heinz Ludwig ◽

Katja Weisel ◽

Maria Teresa Petrucci ◽

Xavier Leleu ◽

Anna Maria Cafro ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Dose ◽

High Risk ◽

Partial Response ◽

Plasma Cells ◽

Progression Free Survival ◽

M Protein ◽

Dose Titration ◽

Free Survival ◽

Protein Change

Abstract Background Olaptesed, an L-stereo-isomer RNA aptamer, binds and neutralizes the chemokine CXCL12. By interaction with the chemokine receptors CXCR4 and CXCR7, CXCL12 is responsible for trafficking and homing of normal and malignant blood cells to the bone marrow. Preclinical studies have shown synergistic activity of CXCL12-targeting and anti-myeloma agents, specifically bortezomib (BTZ). Thus, targeting the myeloma niche may increase treatment efficacy. Aims This open label single arm study was conducted to assess the activity and safety of olaptesed when added to the combination of BTZ and dexamethasone (DEX) in patients with relapsed / refractory multiple myeloma (MM). Patients and Methods Twenty-eight relapsed or refractory MM patients (males:females 14:14) were enrolled and treated according to a dose titration design. Olaptesed was administered intravenously at doses increasing from 1 mg/kg to 2 mg/kg and 4 mg/kg in cycles 1, 2 and 3, respectively, at 1 hour prior to bortezomib administration. During cycles 4 to 8, olaptesed was dosed at the highest individually titrated dose. BTZ (1.3 mg/m2) was given on days 1, 4, 8 and 11 as intravenous injection. Oral DEX (20 mg) was added on the day of and on the day after BTZ administration. Response was evaluated based on the uniform IMWG response criteria (Rajkumar SV et. al. Blood 2011; 117: 4691-5). Plasma cell mobilization was studied after a pilot dose of 1 to 4 mg/kg olaptesed administered to the initial 10 patients before start of the regular treatment regimen. Results From Aug 2012 to Feb 2014 we enrolled 28 patients who had received a median of 2 (range 1-6) lines of prior therapy. Pretreatments were lenalidomide (LEN) in 20, BTZ in 14 and carfilzomib in 1 patient. Ten patients had autologous stem cell transplantations prior to entering this study. The patient population enrolled presented predominantly with advanced disease and with adverse outcome predictors. Ten patients had ISS stage III. High-risk cytogenetics were identified in 9 of the 20 patients (45%) with FISH testing available for t(4;14), t(14;16) and/or del17p. Eleven patients were refractory to their last prior treatment, which contained BTZ in 8 cases. After two early withdrawals, 26 patients were available for outcome evaluations. The median number of completed cycles was 8. Progression led to treatment termination in 8 patients. The dose of olaptesed was titrated to 4 mg/kg in all 18 patients treated for 3 or more cycles. The single dose of olaptesed administered to 10 pilot-patients effectively mobilized plasma cells, which increased by approximately 200% for up to 3 days. Based on “best response” of the 26 evaluable patients, the overall response rate was 73%: Two patients (8%) achieved a complete response (CR), 6 patients (23%) a very good partial response (VGPR) and 11 patients (42%) a partial response (PR). Minimal response was recorded in 2 patients (8%), 4 patients (15%) had stable disease and 1 patient (4%) progressive disease. In the 9 evaluable patients with high-risk cytogenetics, the clinical responses were similar. The ORR was 67% with VGPR in 3 (33%) and PR in 3 (33%) patients. Of the 14 patients pre-treated with BTZ, 1 had a CR and 8 a PR (ORR 64%). M-protein decreased rapidly from treatment cycle 1 to cycle 4 with a decrease of ≥50% being observed in 15 of the 26 evaluable patients. Figure 1 shows a waterfall plot of the maximum observed decrease in M-protein. Figure 1: Waterfall Plot of Maximum M-Protein Change Figure 1:. Waterfall Plot of Maximum M-Protein Change Median progression-free survival (PFS) of the evaluable population was 6.5 months. It was also 6.5 months in the 9 patients with high-risk cytogenetics and 6.3 months in the 14 patients pre-treated with BTZ (Figure 2). The median follow-up was 6.3 months. Figure 2: Progression-Free Survival Figure 2:. Progression-Free Survival Treatment with olaptesed in combination with BTZ-DEX was safe and well tolerated without any appreciable increase in adverse events. Conclusions A single dose of olaptesed effectively mobilized plasma cells. Olaptesed in combination with BTZ and DEX resulted in an ORR rate of 73% and PFS of 6.5 months. Response rates and PFS were similar in patients with or without high risk cytogenetic features or with or without previous exposure to BTZ. The combination regimen was well tolerated. These findings merit further exploration of this strategy in randomized trials. Disclosures Weisel: NOXXON Pharma AG: Consultancy. Petrucci:Celgene: Honoraria; Jannsen-Cilag: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Leleu:Janssen, Celgene, leopharma, Takeda, Amgen, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Laurent:Bristol-Myers Squibb: Honoraria. Kruschinski:NOXXON Pharma AG: Employment. Dümmler:NOXXON Pharma AG: Employment. Riecke:NOXXON Pharma AG: Employment. Engelhardt:NOXXON Pharma AG: Consultancy.

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Efficacy and Safety of Bortezomib Based Regimens Retreatment in Relapsed Multiple Myeloma Patients: Results from a Retrospective Study.

Blood ◽

10.1182/blood.v126.23.5387.5387 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5387-5387

Author(s):

Wenjun Wu ◽

Gaofeng Zheng ◽

Xiaoyan Han ◽

Yi Zhao ◽

Donghua He ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Confidence Interval ◽

Incidence Rate ◽

Conflicts Of Interest ◽

Progression Free Survival ◽

Initial Therapy ◽

Efficacy And Safety ◽

Grade 3 ◽

Group 1

Abstract Objective: To evaluate the efficacy and safety of bortezomib retreatment in relapsed multiple myeloma (MM) patients, who previously responded to bortezomib. Methods: This retrospective observational study included data from 45 patients and evaluated the efficacy and safety of bortezomib based retreatment in these patients, who had achieved at least a partial response (PR) on initial bortezomib therapy in our hospital from May 2006 to May 2013. Results: The overall response rate (ORR) was 71.2%, among them 9% patients achieved CR, 11.1% patients achieved very good partial response (VGPR), 51.1% patients achieved PR. All patients were divided into 3 groups according to the response of initial bortezomib therapy, including CR group, VGPR group and PR group. After bortezomib retreatment, the ORR of the 3 groups was 76.9%, 75% and 62.5%, respectively. According to the response of bortezomib retreatment, the patients were divided into 2 groups: group 1 who at least achieved PR, group 2 who showed no response. The median progression-free survival (PFS) after bortezomib retreatment for group 1 and 2 was 9( 95% confidence interval 7.947~10.051) and 10 (95% confidence interval 8.381∼11.619) months, respectively (P>0.05), while the median overall survival (OS) after bortezomib retreatment was 71 (95% confidence interval 66.694∼75.306)) and 37 (95% confidence interval 1-28) months, respectively (P<0.05). In patients with bortezomib retreatment had different degrees of adverse events (AE) , the most AE for grade 1~2. The most common grade ≥3 AE was thrombocytopenia, neutropenia and anemia. The incidence rate of grade ≥3 AE peripheral neuropathy bortezomib was 15%. Conclusion: Bortezomib based regimens retreatment was effective and tolerable in relapsed MM patients, who had achieved at least a partial response (PR) on initial therapy. The incidence rate of AE was not significantly increased. Disclosures No relevant conflicts of interest to declare.

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Weekly Topotecan for Recurrent Ovarian, Fallopian Tube and Primary Peritoneal Carcinoma: Tolerability and Efficacy Study—The Israeli Experience

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e3182866944 ◽

2013 ◽

Vol 23 (3) ◽

pp. 475-480 ◽

Cited By ~ 5

Author(s):

Tamar Safra ◽

Tara Berman ◽

Adelya Yachnin ◽

Ilan Bruchim ◽

Mihai Meirovitz ◽

...

Keyword(s):

Overall Survival ◽

Partial Response ◽

Clinical Benefit ◽

Response Rate ◽

Progression Free Survival ◽

Complete Response ◽

Free Survival ◽

Platinum Sensitive ◽

Tubal Cancer ◽

Grade 3

ObjectivesThe purpose of this study was to assess the clinical activity and toxicity of weekly topotecan in a large cohort of epithelial ovarian (EOC), primary peritoneal (PPC), and tubal cancer patients.MethodsRecords of patients with recurrent EOC, PPC, and tubal cancer who were treated with weekly topotecan (4.0 mg/m2 on days 1, 8, and 15 on a 28-day cycle) after failure of more than 1 prior regimen were retrospectively reviewed in 8 centers in Israel.ResultsTwo hundred four patients were evaluated for efficacy and toxicity. Median age was 62 years (range, 27–89 years); 121 (59.3%) were platinum sensitive. Patients were exposed to a median of 2 previous lines (range, 1–9), and 48.5% received only 1 prior chemotherapy regimen. Median follow-up was 15.5 months (range, 2.5–112 months). Overall response rate was 26.5%, of which 11 patients (5.4%) had complete response, and 43 patients (21.1%) had partial response. Clinical benefit rate (complete response + partial response + stable disease) was 65.7%. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.5–4.5 months). There was no significant difference between platinum-sensitive and platinum-resistant patients regarding response rate or progression-free survival. Median overall survival from disease diagnosis was 45.0 months (95% CI, 40.04–49.6 months) and 16.0 months (95% CI, 12.3–19.7 months) from initiation of topotecan therapy. Overall survival was significantly different between patients with platinum-sensitive and platinum-resistant disease (19.9 vs 10.8 months, respectively, P = 0.003; 95% CI, 8.1–16.3 months). Multivariate analysis showed that only platinum sensitivity and topotecan line were associated with overall survival. Weekly topotecan was well tolerated—with only 16.7% of patients experiencing grade 3 to 4 hematologic toxicities. There were no other grade 4 toxicities, and only 6.9% grade 3 toxicities.ConclusionsIn this large cohort of recurrent EOC, PPC, and tubal cancer, weekly topotecan was well tolerated with good clinical benefit rate, comparable to previous studies.

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