Bortezomib-based Induction Therapy Research Articles

Assessment of prolonged proteasome inhibition through ixazomib-based oral regimen on newly diagnosed and first-relapsed multiple myeloma: A real-world Chinese cohort study.

To evaluate the effectiveness, safety, and convenience of in-class transition (iCT) from intravenous bortezomib-based induction to ixazomib-based oral regimens. This retrospective real-world study was conducted in 16 Chinese hospitals between October 2017 and April 2023 and analyzed newly diagnosed (NDMM) and first-line relapsed multiple myeloma (FRMM) patients who attained at least a partial response from bortezomib-based induction therapy, followed by an ixazomib-based oral regimen for 2 year or until disease progression or intolerable toxicity. The study enrolled 199 patients, median age: 63 years old, male 55.4%, 53% as high risk (HR), and 47% as standard risk. Cytogenetic risk stratification by metaphase fluorescence insitu hybridization (M-FISH), based on the Mayo Clinic risk stratification system. The median duration of total PI therapy was 11 months, with ixazomib-based treatment spanning 6 months. At the 20-month median follow-up, 53% of patients remained on therapy. The 24-month PFS rate was 84.3% from the initiation of bortezomib-based induction and 83.4% from the start of ixazomib-based treatment. Overall response rate (ORR) was 100% post-bortezomib induction and 90% following 6 cycles of the ixazomib-based regimen. Based on the Sankey diagrams, 89.51% of patients maintained or improved their disease response after 2 cycles of iCT, 6 cycles (90.14%), and 12 cycles (80%). The HR level of Mayo was found to be a significant independent factor in a worse remission (hazard ratio (HR) 2.55; p = 0.033). Ixazomib's safety profile aligned with previous clinical trial data, with 49% of patients experiencing at least one AE of any grade. The most common AEs included peripheral neuropathy, nausea and vomiting, diarrhea, thrombocytopenia, and granulocytopenia. In the real-world Chinese MM population, NDMM and FRMM patients responded favorably to PI-based continuous therapy, demonstrating substantial response rates. The ixazomib-based iCT allows for sustained PI-based treatment, offering promising efficacy and tolerable AEs.

Efficacy Analysis of Bortezomib Combined with Lenalidomide in Newly Diagnosed Multiple Myeloma with 1q21 Gain/Amp.

1q21 gain/Amp is one of the most common cytogenetic abnormalities. There are controversies about its effects on prognosis and may be associated with inferior outcomes in patients with newly diagnosed multiple myeloma (NDMM). To explore the optimal induction treatment, we analyzed and compared the efficacy of combinations of bortezomib-lenalidomide-dexamethasone (VRD) and only bortezomib-based triplet regimens without lenalidomide (only bortezomib-based) as induction therapy in patients with NDMM with 1q21 gain/Amp. Seventy-six NDMM patients with 1q21 gain/Amp who were admitted to our center from 2016 to 2022 were retrospectively analyzed in this study. The progression and efficacy of the patients were observed. Within our study group, the overall survival rate stood at 75.0%, and the progression-free survival (PFS) rate reached 40.8% in NDMM patients with 1q21 gain/Amp. The best outcome assessment was that 17.1% achieved complete response (CR) and 44.7% achieved very good partial response (VGPR). Patients in the VRD group had a deeper response (VGPR: 63.6% vs 37.0%, P = 0.034), lower disease progression rate (31.8% vs 70.3%, P = 0.002), longer sustained remission (median 49.7 months vs 18.3 months, P = 0.030), and longer PFS (median 61.9 months vs 22.9 months, P = 0.032) than those treated with only bortezomib-based induction therapy. No significant differences were found among patients with partial response or better (86.4% vs 77.8%, P = 0.532) or CR (27.3% vs 13.0%, P = 0.180). Multivariate analysis showed that only bortezomib-based induction therapy (P = 0.003, HR 0.246, 95% CI 0.097-0.620), International Staging System stage III (P = 0.003, HR 3.844, 95% CI 1.588-9.308) and LMR <3.6 (P = 0.032, HR 0.491, 95% CI 0.257-0.940) were significantly associated with adverse PFS. When compared with the sequential administration of bortezomib and lenalidomide or only bortezomib-based protocols, NDMM patients with 1q21 gain/Amp may benefit more from VRD as initial treatments.

Evaluation of Easym, a Clonotypic Mass Spectrometry Assay, and Euroflow Minimal Residual Disease Assessment in Multiple Myeloma

Introduction: Minimal residual disease (MRD) negativity is increasingly recognised as the optimal measure of therapeutic response for multiple myeloma (MM) patients and is associated with improved survival. Bone marrow (BM) assessment of MRD with next-generation sequencing (NGS) or next-generation flow cytometry (NGF) can achieve a minimum sensitivity of 10 -5 however an invasive procedure is required. Additionally, this single-site BM biopsy may be limited by specimen quality and failure to capture the spatial heterogeneity of MM. Peripheral blood-based mass spectrometry (PB-based MS) offers the potential for highly sensitive, non-invasive sequential MRD assessment. EasyM is a PB clonotypic MS assay involving de novo amino acid sequencing of the full-length M-protein and quantification of unique peptides with parallel reaction monitoring. EasyM has been compared to 8-colour multiparameter flow cytometry with a sensitivity of 10 -4 (Liyasova et al, Clin Cancer Res, 2021) and clonoSEQ (Slade et al, Blood, 2022), but not to NGF to our knowledge. In this context, we have evaluated EasyM in MM patients undergoing sequential NGF (EuroFlow platform) MRD assessment. Methods: We retrospectively identified MM patients enrolled in the Australasian Leukaemia and Lymphoma Group MM19 (ACTRN12616000772448) and MM21 (ACTRN12618001490268) trials with measurable M-protein ≥2g/L by serum protein electrophoresis and/or free light chains ≥100mg/L at baseline. Briefly, the MM19 trial evaluated the addition of ixazomib to thalidomide and dexamethasone consolidation therapy for 12 months in transplant eligible newly diagnosed MM (TE NDMM) patients undergoing front-line autologous stem cell transplantation (ASCT), whilst the MM21 trial evaluated an intensive salvage approach using daratumumab-lenalidomide-dexamethasone (DRd) as re-induction (DRd x 4 cycles) and post-ASCT consolidation (DRd x 12 cycles followed by R maintenance until disease progression) in TE NDMM patients failing (&amp;lt;partial response as best response) front-line bortezomib-based induction therapy. NGF MRD status was determined using the standardised 8-colour EuroFlow platform at pre-ASCT, post-ASCT, and end of consolidation timepoints in MM19 and MM21 patients and additionally post-cycle 2 of consolidation in MM21 patients. Matched serum samples were evaluated with the EasyM assay. Concordance between NGF and MS was assessed by the Chi-squared and McNemar's tests. Results: A total of 43 patients were identified for analysis, with 9 MM19 and 34 MM 21 patients. 1 patient was not sequenced due to low baseline values and 2 patients had no clonotypic target tryptic peptides to monitor MRD. EasyM was undetectable (MS-) in 3 (8%) patients. 2 patients achieved MS- pre-ASCT and the third achieved MS- post-cycle 2 of consolidation. All 3 patients remain in complete response (CR) at 44-48 months post-ASCT. Sequential MS (Figure 1) revealed rising EasyM levels in 2 patients, preceding relapse by 15 and 25 months; of note, 1 patient had matched BM and was NGF MRD negative. Serum samples for MS with matched BM for NGF (Table 1) were available for 25 patients pre-ASCT, 32 post-ASCT, 26 post-cycle 2 of consolidation, and 28 end of consolidation with NGF MRD negativity (NGF-) of 8%, 31%, 38%, and 75% at these timepoints, respectively. Of the 111 matched samples in total, 43 (39%) were NGF- but only 7 (6%) were MS-, and 73 (66%) were concordant. The Chi-squared test for association between MS and NGF was not significant at all 4 timepoints. The McNemar's test p-values were &amp;gt;0.999, 0.004, 0.008, and &amp;lt;0.001 for the 4 timepoints, indicating that MS+/NGF- were more likely than MS-/NGF+ discordances at all timepoints except for pre-ASCT. Of the 30 matched samples with confirmed CR status, 5 (17%) were MS+/NGF+, 19 (63%) were MS+/NGF-, and 6 (20%) were MS-/NGF- (Chi-squared and McNemar's p-values of 0.549 and &amp;lt;0.001). Conclusion: This preliminary data highlights the potential of EasyM for sequential PB-based clonotypic MS MRD monitoring in MM. Concordance with standard BM NGF was poor, with 63% of samples with confirmed CR showing detectable M-protein by EasyM but NGF MRD negativity, consistent with the higher sensitivity of EasyM. Comparison of larger sample sets and validation through prospective clinical trials is warranted to better assess the clinical utility of EasyM and rationalise BM-based assessment for MM patients.

The quantification of circular RNA 0007841 during induction therapy helps estimate the response and survival benefits to bortezomib-based regimen in multiple myeloma.

Circular RNA_0007841 (Circ_0007841) facilitates multiple myeloma (MM) progression and resistance of the bortezomib by experimental studies, while its clinical implication in MM patients is still unclear. This study intended to evaluate the longitudinal change and prognostic role of circ_0007841 expression in MM patients receiving bortezomib-based induction therapy. In this prospective study, bone marrow plasma cell (BMPC) samples were gained from 97 MM patients at diagnosis and after bortezomib-based induction therapy, and from 30 healthy controls (HCs) proposing BM donation. Then, circ_0007841 expression in BMPC samples was measured by reverse transcription-quantitative polymerase chain reaction. Additionally, MM patients were followed up for a median of 29.4months. Circ_0007841 expression was increased in MM patients compared to HCs (P < 0.001), but it was decreased after bortezomib-based induction therapy in MM patients (P < 0.001). Moreover, circ_0007841 expression at diagnosis was associated with the presence of t (4; 14) (P = 0.034), while its expression after bortezomib-based induction therapy was linked with higher revised international staging system stage (P = 0.025) in MM patients. Interestingly, circ_0007841 expression after bortezomib-based induction therapy was lower in MM patients who achieved complete remissions (P = 0.001) and overall responses (P = 0.002) compared to those who did not. Prognostically, circ_0007841 expression after bortezomib-based induction therapy (over the median vs. below the median) independently predicted shorter progression-free survival (hazard ratio (HR): 2.497, P = 0.002) and overall survival (HR: 3.107, P = 0.008) in MM patients. Circ_0007841 quantification during induction therapy may reflect the response and survival benefits to bortezomib-based regimen in MM patients.

Bortezomib-based induction therapy followed by autologous hematopoietic cell transplantation in newly diagnosed multiple myeloma patients: A single-center experience and review of Indian literature.

High-dose chemotherapy with melphalan, followed by autologous hematopoietic stem cell transplantation (AHCT) remains the standard of care for consolidation therapy of fit patients with newly diagnosed multiple myeloma (NDMM), for more than 20 years now. This is a retrospective study of NDMM patients who underwent AHCT at our center from 2011 to 2018. Data was undertaken using the hospital electronic medical records (EMR). Among transplant eligible patients (which were 764), 78 patients (10.2%) underwent AHCT. The predominant stage in the study cohort was International Scoring System (ISS)-III (55%), and IgG-kappa (44%) was the commonest subtype of multiple myeloma (MM). Light chain myeloma was found in 23.5% of patients. Pretransplant, 42%, 48%, and 10% patients were in more than very good partial response (>VGPR), very good partial response (VGPR), and partial response (PR), respectively. The median duration of follow-up was 57.2 months (range: 12.1-120.2 months). The entire cohort's 5-year overall survival (OS) and progression-free survival (PFS) were 89.1% and 41.8%, respectively. Bortezomib based triplet induction regimens were effective and well tolerated in this retrospective analysis of Indian patients. We observed that AHCT effectively achieves deep and durable remission in MM.

MCQs on Bortezomib-based induction therapy followed by autologous hematopoietic cell transplantation in newly diagnosed multiple myeloma patients: A single-center experience and review of Indian literature.

MCQs on Bortezomib-based induction therapy followed by autologous hematopoietic cell transplantation in newly diagnosed multiple myeloma patients: A single-center experience and review of Indian literature.

Daratumumab Carfilzomib Lenalidomide Dexamethasone Provides Effective Salvage for Functionally and Cytogenetically High-Risk Myeloma Patients, Except Those Expressing Module-1 Transcriptional Signature: Extended Follow-up from Kydar Multicenter Clinical/Translational Trial.

Background Myeloma patients (Pts) with resistance to a bortezomib-based induction therapy, either primary refractory or those relapsing early after completing induction, define a population of functional high-risk myeloma, shown to be associated with dismal prognosis. We designed a phase 2 clinical-translational trial to evaluate the safety and efficacy of a quadruple salvage regimen of carfilzomib (CFZ)/ lenalidomide (LEN)/dexamethasone (DEX) / daratumumab (DARA) (KRD-D) in myeloma Pts with functional high-risk (KyDaR, NCT04065789), and to identify molecular pathways of refractoriness based on transcriptional signatures associated with clinical resistance. Here we report final clinical data following 18-months (mo) study treatment and extended survival follow-up. Methods Forty-one newly diagnosed myeloma Pts treated with a bortezomib-containing induction regimen, who either: i) failed to achieve a minimal response after 2 cycles or a partial response (PR) after 4 cycles (cohort A), ii) had early relapse within 18 months from starting of therapy (cohort B) were enrolled to receive second line KRD-D treatment in eighteen 28-day (d) cycles (C) or until disease progression/unacceptable toxicity. CFZ: 56 mg/m2 IV days 1,8,15 (C 1-9), d 1,15 (C 10-18). LEN: 25 mg (Frail: 15mg) d1-21; Dex 40mg (Frail: 20mg) weekly; DARA: IV 16mg/Kg weekly (C 1-2), q14d (C 3-6), q28d. After 18 cycles, Pts continued to receive DARA/LEN. We applied longitudinally our calibrated protocol for single cell RNA sequencing (scRNA-seq) of myeloma plasma cells (Ledergor et al, Nat Med 2018) to identify transcriptional signatures associate with response or resistance, defined as PR or better (IMWG criteria) after 3 cycles. Primary endpoints were safety and tolerability. Secondary endpoints included overall response rate (ORR); progression free survival (PFS), and overall survival (OS). Results Forty-one Pts enrolled across 14 medical centers in Israel between June 2018-August 2019, patients had highly aggressive MM characteristics: 67% had intermediate/high risk and 30.5% had double hit FISH abnormalities, 39% had extramedullary disease, and 38% were frail. High expression of module-1 scRNAseq transcriptional signature associated with therapy resistance as previously described (Cohen YC et al, Nat Med 2021) was detected in 36%. At end-of study data cut-off (12NOV2021) the median follow-up was 30.7 mo (95% CI 26-35.3), and the median number of CFZ cycles administered was 10 (range 1-18). Nineteen Pts completed 18-months of KRD-D therapy. Reasons for early therapy discontinuation (n=22) included: disease progression (12), adverse event (AE, 6), consent withdrawal (3) and physician decision (1). All Pts had at least 1 treatment emergent AE (TEAEs), most were grade 1-2; There were 35 patients with TEAE grade ≥3, 4 (9.8%) patients discontinued study therapy due to AEs. Grade ≥3 TEAEs occurring in ≥10% of Pts included neutropenia (34%), thrombocytopenia (24%), sepsis (22%), pneumonia (19%) and musculoskeletal pain (12%); 4 patients died due to TEAEs (1 myocardial infarction, 3 sepsis). Durable and deep responses were achieved. ORR was 90% (37/41): near CR-stringent CR 22% / very good partial response 42% / PR 27%. Median duration of response was 25.6 mo (95% CI 11.5-39.7). Median PFS and OS were 15.4 and 28.2 months, respectively; 18-month PFS and OS were 49% and 57%, respectively. In univariable analysis, cohort (A vs B), age (≤70 vs >70) and high-risk cytogenetics (yes vs no) yielded similar OS. Over-expression of module-1 was highly predictive of poor PFS (3.8 mo vs not reached [NR], p=0.000006 and OS (13.8 mo vs NR, p=0.0003) [Fig1A]. A factorial analysis of module-1 X double-hit FISH showed the dominance of the former in prediction of OS [Fig 1B]. Frail Pts (IMWG criteria) had a median OS of 25 mo [95% CI 8.0-41.4] vs NR in intermediate/Fit Pts (p=0.07). Conclusions A cohort of functionally high-risk MM Pts, based on their resistance to an upfront bortezomib-based induction, were effectively salvaged by second line KRD-D quadruple regimen, achieving an ORR of 90% and durable responses. High expression of module-1 transcriptional signature, as discovered by scRNA-seq analysis was present in 36% of these Pts, and identified an ultra-high-risk population in which KRD-D provided inferior survival. Such patients may be considered for early experimental interventions such as novel immune-therapeutics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Low Non Relapse Mortality and Good Hematological Response after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients with Renal Insufficiency at Transplant: A Prospective Société Francaise De Greffe De Moelle-Thérapie Cellulaire Observational Study

Background: High dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (ASCT) is widely used in newly diagnosed multiple myeloma (NDMM) patients as upfront therapy. However, the safety and efficacy of ASCT in patients with renal insufficiency (RI) is controversial, which have led to an inconsistent arbitrary cut-off for creatinine clearance (CrCl) for performing ASCT. Here, we analyzed prospectively the outcomes of NDMM patients with severe RI who underwent ASCT. Methods: We enrolled prospectively, from April 2018 to Sept 2020 in 17 SFGM-TC centers, 50 NDMM patients who had a serum CrCl of <40 mL/min (CKD-EPI) at the time of ASCT. They all received bortezomib-based induction therapy and had achieved at least a partial response before proceeding to ASCT. The recommended dose of melphalan was 140 mg/m2 and it was infused at least 3 x106/kg autologous CD34+ cells. Consolidation/maintenance post-ASCT was according to the physician's choice. The primary endpoint was non-relapse mortality (NRM). Overall survival (OS) and progression free survival (PFS) were estimated with Kaplan-Meier method, and cumulative incidence of relapse (CIR) and NRM were estimated using cumulative incidence function to account for competing events of death without relapse or death unrelated to myeloma. Results: At diagnosis, a renal biopsy was done in 9 (no amyloidosis, 6 cast nephropathy and 3 others). 82% were male. The median medullary plasmocytosis was 42% (11-80), light chain MM was frequent in 28 patients (56%), IgG in 13 (26%), IgA in 8 (16%) and 1 IgD. Seven (16%) had extra medullary disease. The ISS score was I (1), II (7) and III (34) (8 missing). At enrollment at the time of ASCT: median age was 56 years (33-68). Induction chemotherapies had included bortezomib plus IMiDs in 28 (56%) patients, CyBorDex in 17 (34%), bortezomib dex in 4 (8%) and 1 other (2%). Thirty nine patients (80%) had received 4 or less cycles of chemotherapy and 13 (26%) had ≥2 lines of chemotherapy. The pre-transplant disease status was sCR in =3 (6%), CR in =7 (14%), VGPR in =22 (45%), and PR in =17 (35%) of patients (1 not evaluable ( NE)). The number of days of cytapheresis was 2 or less in 93% of cases and the median number of CD34+ cells collected was 5.4 x 106 (1.1-15.1) (3 missing).The HCT-CI score was 0 (4), 1 (8), 2 (11), 3 (11), missing (16) and 97% had a Karnofsky score ≥70%. HDM was 100 mg/m2 in 1, 140 mg/m2 in 44/50 patients and 200 mg/m2 in 5/50 with 6 patients receiving a tandem ASCT. Seventy three percent received consolidation post ASCT (1 missing) and 69% had maintenance therapy (lenalidomide: 53%, thalidomide: 26%, bortezomib: 21%). Toxicity: We observed one death during the first 100 days post-ASCT, secondary to a septic shock on day 42. The median time to neutrophil engraftment (>500/mm3) was 13 days (10-136) and to platelet engraftment (>20 000/mm3) 16 days (8-136). Among patients receiving RBC transfusions (43%) and platelet transfusions (49%), the median number of RBC transfusions was 3 (2-14) and that of platelet transfusions was 2 (1-44). Response: Nine patients (60%) achieved dialysis independence from the time of diagnosis: 15 patients were on dialysis at diagnosis, 6 at the time of ASCT and 4 three months post-ASCT. At 100 days post-ASCT, the hematological response had improved in 62 % of patients, from PR to VGPR (15%), from PR to CR/sCR (15%), from VGPR to CR/sCR (30%) and from CR to sCR (2%). The best response obtained was 4 (9%) PR, 18 (39%) VGPR, 19 (41%) CR and 5 (11%) sCR with one patient relapsing and 3 NE. At 2 years, the NRM was 4% (95% CI: 0%-12%), the OS was 84% (95% CI:74%-95%), the PFS was 70% (95% CI:58%-84%) and the CIR was 30 % (95% CI:17%-43%) (Figure). Conclusions: HDM with ASCT proved to be safe and effective in NDMM patients with RI at transplant. NRM was 4% at 2 years and 62% improved their hematological response. Renal response will be reported. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Secondary Analysis of the MM21 Trial: Response Adaptive Salvage Treatment with Daratumumab-Lenalidomide-Dexamethasone (DRd) for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients Failing Front-Line Bortezomib-Based Induction Therapy

Secondary Analysis of the MM21 Trial: Response Adaptive Salvage Treatment with Daratumumab-Lenalidomide-Dexamethasone (DRd) for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients Failing Front-Line Bortezomib-Based Induction Therapy

Poster: MM-253 Efficacy, Safety, and Quality of Life (QoL) in Patients With Newly Diagnosed Multiple Myeloma (NDMM) After In-Class Transition (iCT) From Parenteral Bortezomib-Based Induction Therapy to ALL-Oral Ixazomib-Lenalidomide-Dexamethasone (IRd): Data From the Phase 4, Community-Based US Poster: MM-6 Study (Fully Accrued Cohort)

Poster: MM-253 Efficacy, Safety, and Quality of Life (QoL) in Patients With Newly Diagnosed Multiple Myeloma (NDMM) After In-Class Transition (iCT) From Parenteral Bortezomib-Based Induction Therapy to ALL-Oral Ixazomib-Lenalidomide-Dexamethasone (IRd): Data From the Phase 4, Community-Based US Poster: MM-6 Study (Fully Accrued Cohort)

MM-149 Impact of Early Relapse on Survival of Patients With Multiple Myeloma After Autologous Stem Cell Transplantation

The survival of patients with multiple myeloma (MM) has improved in recent years due to the combination of new treatments together with autologous stem cell transplantation (ASCT) and maintenance therapy. Early relapse (ER) has been identified as an independent risk factor for shorter overall survival (OS) having even a greater impact than high-risk cytogenetic alterations. Evaluate OS of patients with ER and review the factors associated. Retrospective, observational and single-center study that included patients with MM who received bortezomib-based induction therapy and ASCT from 2010 to 2020. ER was considered as relapse or progression within 12 months after ASCT. We included a total of 200 patients comparing the group with ER vs the non-ER patients (NER). The most common induction treatment used was CyBorD in the ER group 23 (74%) vs. 124 (74%) in NER patients; followed by VTD and RVD. From the entire cohort 104 (52%) patients received maintenance, the 71% with lenalidomide. Complete response post-transplantation was achieved in 103 (51%) patients. After a median follow-up of 37.5 months (IQR; 15-67), the median PFS was 48 months (95% CI; 40-60). A total of 31 patients (16%) presented ER, with a median relapse time of 7 months (95% CI; 4-9). These patients had more frequently ISS III (48% vs 32%, p<0.05) and partial response to treatment (29% vs 15%, p 0.06) with less frequent maintenance therapy (32% vs 56%, p<0.01). The OS at 5 years for patients with ER was 22% with a median of 21 months; vs 86% at the same time in the NER group with a median not reached. ER was one of the most important prognostic factors for decreased survival after ASCT (hazard ratio, 9.26, p<0.001), even adjusting for cytogenetic risk. ER represents a poor prognosis even with new treatment options and beyond cytogenetic risk. Identifying prognostic factors associated with ER could be useful for performing a risk-adapted treatment. In addition, these groups of patients should be incorporated into clinical trials with the purpose of identifying useful and novel rescue treatments in the future.

MM-253 Efficacy, Safety, and Quality of Life (QoL) in Patients With Newly Diagnosed Multiple Myeloma (NDMM) After In-Class Transition (iCT) From Parenteral Bortezomib-Based Induction Therapy to All-Oral Ixazomib-Lenalidomide-Dexamethasone (IRd): Data From the Phase 4, Community-Based US MM-6 Study (Fully Accrued Cohort)

Achieving prolonged therapy with parenteral proteasome inhibitors (PIs) in clinical practice can be challenging. To increase the duration of PI-based therapy, improve outcomes, and maintain QoL. Prospective study (NCT03173092) evaluating iCT from parenteral bortezomib-based induction to all-oral IRd. IRd was received for up to 39 cycles or until progression/toxicity (Manda CLML 2020). Interim data (N=101) were previously reported (Rifkin ASH 2021). We report results from the fully accrued study cohort (enrollment completed, May 2021; N=141). US community sites. Transplant-ineligible/delayed-transplant (≥24 months) NDMM patients with ≥stable disease after 3 cycles of bortezomib-based induction. Primary endpoint: 2-year progression-free survival (PFS) rate. Other endpoints included: key secondary, overall response rate (ORR; partial response [PR]+very good PR [VPGR]+complete response [CR]) and duration of treatment (DOT); secondary, overall survival (OS), safety, and QoL. At Feb-28-2022, 140 patients (median age, 72.5 years [range, 48-90]; 79% ≥65 years; 42% ≥75 years) had received IRd; 94% had ≥1 comorbidity at IRd initiation. Median follow-up was 20.0 months. 2-year PFS was 69% (95% confidence interval [CI]: 59-77%). ORR was 62% (CR, 8%; VGPR, 24%; PR, 30%) after bortezomib-based induction, increasing to 78% (CR, 33%; VGPR, 27%; PR, 18%) after iCT. At data cut-off, 28 patients (20%) were ongoing on IRd, median DOT with IRd was 10.0 months, and median duration of all PI-based treatment was 12.7 months. 2-year OS was 85% (95% CI: 76-90%). 66% of patients had grade ≥3 treatment-emergent adverse events (TEAEs) (treatment-related, 36%), 44% had serious TEAEs (treatment-related, 14%), and 6 on-study deaths had occurred. Most common TEAEs (any-grade/grade ≥3) were diarrhea (48%/9%), peripheral neuropathies not elsewhere classified (39%/4%), and fatigue (34%/4%). Modification/discontinuation of ixazomib, lenalidomide, or dexamethasone due to TEAEs occurred in 59%/15% of patients. Patient-reported QoL (EORTC QLQ-C30 Global Health Status/QoL score) and treatment satisfaction (TSQM-9 Global Satisfaction, Effectiveness, and Convenience scores) were maintained on IRd. Improved responses and promising PFS and OS were seen following iCT to IRd in these mostly elderly, community-treated patients with NDMM and comorbidities, with no adverse impact on QoL/treatment satisfaction. Safety results were consistent with previous reports.

Clinical characteristics and prognosis of patients with newly-diagnosed multiple myeloma with t(11;14)

Objective: To explore the clinical characteristics and prognosis of multiple myeloma (MM) patients with t(11;14). Methods: The clinical data of patients newly diagnosed with MM with t(11;14), which confirmed by fluorescence in situ hybridization (FISH), from January 1, 2016 to May 31, 2021 in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine was retrospectively collected. A total of 45 patients were included. Bortezomib based induction therapy were given to 88.9% (40/45) patients, while 11.1% (5/45) received Imids-based therapy. Fourteen patients underwent the autologous hematopoietic stem cell transplantation (AHSCT). The clinical characteristics, overall response rate (ORR), progression free survival (PFS), overall survival (OS) and risk factors affecting survival were analyzed. Results: The average age of patients were (58.8±9.6) years, and 62.2%(28/45)were male. A relatively high incidence of bone lesion 82.2%(37/45)was observed. After 4 cycles induction therapy, the ORR was 66.7% (30/45), and ≥very good partial response (VGPR) was 31.3% (14/45). The rate of ≥VGPR increased to 92.9% (13/14) after AHSCT. The follow-up time [M(Q1,Q3)] was 27(20,42)months. The PFS was 34 (95%CI: 23-45) months, the median OS was 44 (95%CI:33-51) months. Median PFS were 48 (only 3 cases of progressive disease, CI not available) months and 24 (95%CI:13-35) months in the transplantation group and non-transplant group respectively (P=0.115). Median OS were 60 (only 1 case of death, CI not available) months and 48 (95%CI:22-74) months in the transplantation group and non-transplantation group, respectively (P=0.238). Cox regression analysis indicated that the number of plasma cell ≥50% in bone marrow and CD20 expression on myeloma cells were the risk factors for PFS[OR=3.272,95%CI:1.167-9.170,P=0.024;OR=3.480,95%CI:1.082-11.234,P=0.036]. No significant effective factor on OS was found. Conclusions: For multiple myeloma patient with t(11;14), the response rate with novel agents induction therapy is not high, but autologous stem cell transplantation can deepen remission. The high burden of bone marrow plasma cells and the expression of CD20 may be associated with the poor prognosis.

S174: HIGH LEVEL OF CIRCULATING TUMOUR DNA AT DIAGNOSIS CORRELATES WITH DISEASE SPREADING AND DEFINES MULTIPLE MYELOMA PATIENTS WITH POOR PROGNOSIS

Background: Multiple Myeloma (MM) is a plasma cell (PC) disorder characterized by the presence of skeletal involvement at the time of diagnosis, as detected by MRI and/or FDG PET/CT, in most of the patients. The patchy nature of the disease is probably related to the ability of fitter clones to spread into peripheral blood reaching distant sites, where favourable microenvironment conditions might promote clones’ seeding. Recently, cell-free DNA (cfDNA) has been proven to resume the heterogeneity of spatially distributed clones. However, it has to be determined to which extent cfDNA correlates with disease distribution and its possible implications with patients’ outcome. Moreover, the potential of cfDNA to track the evolutionary dynamics and the heterogeneity of MM, possibly anticipating the emergence of therapy resistant residual cells, remains to be confirmed. Aims: Aim of this study is to quantitatively and qualitatively evaluate cfDNA at diagnosis and during follow-up in correlation with imaging data to possibly define the integration of this approach with molecular bone marrow (BM) and whole-body residual disease assessment. Methods: A total of 88 newly diagnosed MM patients were screened at baseline with 18F-FDG PET/CT, and molecularly assessed by Ultra Low Pass-Whole Genome Sequencing (ULP-WGS). In a subgroup of 22 patients, cfDNA was monitored monthly, whereas PET/CT was reassessed after induction therapy to evaluate metabolic tumor response. For each pts, ULP-WGS was used to characterize both the neoplastic PC clone(s) in the BM (gDNA) and the cfDNA from peripheral blood. Data were analysed by ichorCNA and Clonality R packages. Results: At diagnosis, the cfDNA tumor fraction (TF) was significantly lower as compared to gDNA TF [median (M) TF: 4.4 vs. 59.7%, respectively]. Nevertheless, high cfDNA TF levels (> 4.4% cfDNA TF values; range: 4.4-84.3%) correlated with high gDNA TF levels (>65.7% gDNA TF values; range: 65.7-96.7%). This observation was further confirmed by a significant correlation between cfDNA TF and the percentage of BM CD138/CD38 positive plasma cells (r=0.47; p<.0001). Interestingly, patients with high cfDNA TF at baseline were more likely to present with extramedullary disease (EMD) and a higher number of focal lesions, and also featured a more active tumour metabolism, as compared to pts with low TF (EMD 4/44=9% vs. 1/44=2.3%, p=ns; M n. PET lesions: 1.7 vs. 2.5, p= 0.003; SUVmax: 5.2 vs. 9.6, p = 0.01). Despite an overall concordance between cfDNA and BM genomic profiles (80/88=90.9%), those patients with high cfDNA TF showed more frequently evidence of spatial heterogeneity, as highlighted by a substantial divergence of copy number alterations profiles between cfDNA and gDNA (7/8=87.5% of pts with divergent profiles). Finally, high cfDNA TF at diagnosis predicted for poorer prognosis as compared with low cfDNA TF (PFS at 20 months: 67% vs. 86%, p=0.05; OS at 20 months: 90% vs. 100%, p=0.04). Interestingly, after bortezomib-based induction therapy, imaging data and cfDNA TF levels were concordant; notably, in 4/10 (40%) patients with median SUVmax 5.8 and >2 PET lesions, cfDNA TF was still detectable (>1% TF), thus corroborating a possible role for cfDNA in monitoring response to therapy. Summary/Conclusion: In conclusion, patients with high cfDNA TF displayed imaging data that overall suggested a higher propensity to a metastatic spread of the disease, which finally correlated with poorer prognosis. Future studies will be addressed to exploit the use of cfDNA in disease monitoring. Acknowledgements: AIRC IG2019, AIL BOLOGNA ODV

P879: EXENT AND FLC MASS SPECTROMETRY FOR SEROLOGICAL IDENTIFICATION AND QUANTIFICATION OF MONOCLONAL IMMUNOGLOBULINS IN MULTIPLE MYELOMA

Background: Mass spectrometry has broad potential for screening and monitoring monoclonal gammopathies. The technology overcomes some of the limitations inherent to standard electrophoretic methods for identifying monoclonal immunoglobulins and is amenable to automation. Aims: Here we assess the performance of the EXENT assays for the quantification of M-proteins and whether free light chain evaluation by mass spectrometry (FLC-MS) offers added sensitivity during multiple myeloma monitoring. Methods: The MM5 trial compared two regimens of bortezomib-based induction therapy and of lenalidomide consolidation followed by lenalidomide maintenance in newly diagnosed multiple myeloma patients. We used mass spectrometry for identifying serum M-proteins in samples at baseline (n=434), post-induction (n=340), and post-consolidation (n=294). Briefly, polyclonal antibodies (anti-IgG,-IgA,-IgM,-total κ and -total λ [EXENT, The Binding Site, UK] and anti-free κ and -free λ [FLC-MS]) covalently attached to paramagnetic microparticles were separately incubated with serum, washed, treated to elute and reduce patient immunoglobulins, and spotted onto MALDI plates with HCCA matrix. Spectra were generated using the MALDI-TOF-MS system. Light chain mass spectra were obtained using EXENT software to yield immunoglobulin isotype, mass-to-charge ratio (m/z) and quantity (g/L). Results were compared to serum protein electrophoresis, immunofixation, and FLC ratios (Freelite®, The Binding Site, UK). Results: EXENT demonstrated improved sensitivity over immunofixation for identifying the M-protein at each time-point of the MM5 trial: 99% vs. 95% at baseline; 91% vs 80% post-induction; and 63% vs. 46% post-consolidation. Agreement between methods was 87%. The addition of FLC-MS to EXENT further improved sensitivity to 100%, 95.0%, and 72% at each respective time-point, whereas the combination of immunofixation and FLC ratios resulted in sensitivities of 100%, 90%, and 54%. Overall concordance between EXENT+FLC-MS and the combination of immunofixation and FLC ratios was 100% at baseline, 93% post-induction, and 73% post-consolidation. In all, 158 (11%) samples had an M-protein by EXENT+FLC-MS only, and 28 (2%) by the combination of immunofixation and FLC ratios. 18 and 92 patients achieved an IMWG complete response after induction and consolidation, respectively. EXENT identified an M-protein in 5 (28%), and 23 (25%) of these patients, whereas EXENT+FLC-MS was more sensitive and detected monoclonal proteins in 11 (61%), and 38 (41%) patients, respectively. There was acceptable quantitative agreement for M-protein measurements between EXENT and serum protein electrophoresis (n=631: Passing-Bablok fit: y=0.85x-0.58; coefficient of determination R2= 0.89; Bland-Altman relative bias (95%CI): -32.62% (-123.79-58.55%)). However, there was a substantial discordance in 285 samples <10g/L by serum protein electrophoresis (y=0.58x+0.54; R2=0.28; -44.84% (-179.29 – 84.60%)) compared to 346 samples >10g/L (y=0.85x-0.25; R2=0.82; -19.91% (95%CI: -97.32 – 23.56%)); suggesting overestimation by serum protein electrophoresis at lower levels. Summary/Conclusion: EXENT provides superior performance for the identification of M-proteins throughout monitoring. Sensitivity can be improved by incorporating FLC-MS assessments, thus providing a means for determining serological residual disease in patients at complete response by IMWG criteria. Quantification of the M-protein by mass spectrometry compares well to standard methods and offers accurate results at levels below the analytical threshold of confidence for electrophoretic approaches.

Abstract 3373: Circulating tumour DNA mutations correlate with relapse in a phase II trial of bortezomib-primary refractory multiple myeloma patients receiving salvage therapy

Abstract Background: Multiple myeloma (MM), an incurable plasma cell malignancy, has a relative 5-year overall survival (OS) of 48.5% for newly diagnosed patients. Prospective real-world data reveals that 23% of transplant eligible MM patients relapse within 12 months of starting first-line bortezomib based therapy with a median OS of only 16.8 months (high-risk - HR). Genomic studies for these HR patients could inform rational secondary therapeutic options and prolong survival. Bone marrow (BM) genomic analysis in MM has methodological and conceptual shortcomings owing to the spatially and genomically heterogeneous nature of MM that can be largely overcome with circulating tumour DNA (ctDNA) analysis. Objective: To determine whether ctDNA analysis can define the mutational spectrum of patients with HR MM. Design: Phase II, multicentre single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in 50 transplant-eligible newly diagnosed MM patients from September 2016 to April 2018 (Australasian Leukaemia and Lymphoma Group (ALLG) - MM17 trial) who were refractory (REF) to or demonstrated a suboptimal response (SOR) to bortezomib-based induction therapy. A total of 186 peripheral blood plasma and BM samples were obtained at baseline, at Cycle 3 day 1 (C3D1), end of the study (EOS) and/or at relapse. Somatic variants were identified with an ultra-sensitive targeted amplicon sequencing (TAS) assay incorporating 22-genes known to be mutated in MM. The mutational spectrum was correlated with progression-free survival (PFS) and OS. Results: TAS of 31 BM samples and 48 ctDNA samples revealed that in BM, KRAS mutations were detected in 42% of patients followed by ATR in 29% while in ctDNA, ATR mutations were prominent (36%), followed by FGFR3 and ATM (27% and 26.8%). We compared the ctDNA mutational spectrum at baseline between non-relapse and relapse patients on KTd and identified a significant difference in the proportion of patients with specific mutations - RAS/RAF: 3% vs 25%; ATM/ATR/TP53: 17% vs 41%, respectively (p&amp;lt;0.0001). Patients with RAS/RAF and/or ATM/ATR/TP53 ctDNA mutations at baseline had significantly shorter PFS and OS (p=0.003 and p=0.02, respectively). Comparative ctDNA TAS for baseline, C3D1, EOS/relapse, demonstrated that in 87.5% of patients, one or more dominant mutations driving relapse in KTd were already present prior to starting salvage therapy. We also performed ctDNA analysis to compare patients who were REF or SOR to front-line therapy and identified 62% of REF patients had RAS/RAF or ATM/ATR/TP53 mutation compared to 35% of SOR patients (p=0.0002, Fisher’s exact test). Conclusions: Our results demonstrate that RAS/RAF and ATM/ATR/TP53 mutations in ctDNA are prognostic biomarkers of outcome to secondary salvage therapy in HR patients thus enabling design of targeted therapeutic approaches to improve survival. Citation Format: Sridurga Mithraprabhu, John Reynolds, Anna Kalff, Krystal Bergin, Rose Turner, Hang Quach, Noemia Horvath, Ian Kerridge, Flora Yuen, Kawa Choi, Malarmathy Ramachandran, Ashley George, Tiffany Khong, Brian Durie, Andrew Spencer. Circulating tumour DNA mutations correlate with relapse in a phase II trial of bortezomib-primary refractory multiple myeloma patients receiving salvage therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3373.

MO135: Efficacy and Safety of Bortezomib Combined with Autologous Stem Cell Transplantation in the Treatment of MGRS

Abstract BACKGROUND AND AIMS To evaluate the efficacy and safety of bortezomib combined with autologous stem cell transplantation (ASCT) in the treatment of monoclonal gammopathy of renal significance (MGRS). METHOD The clinicopathologic data of 16 patients with non-AL MGRS who received bortezomib combined with ASCT in Jinling Hospital of Nanjing University School of Medicine from February 2012 to June 2021 were retrospectively analysed. RESULTS Twelve patients were male and four were female, with a median age of 49 years, a median serum creatinine was 1.71 mg/ dL (1.45, 2.09) and a median eGFR wad 42.1 mL/min/1.73 m2 (29.0, 51.6). Renal pathological types included seven patients were light chain deposition disease, two patients were heavy chain deposition disease, one patient was light and heavy chain deposition disease, five patients were light chain proximal tubulopathy and one patient was proliferative glomerulonephritis with monoclonal immunoglobulin deposition. Sixteen patients received bortezomib-based induction therapy with a median three courses before transplantation. Stem cells were successfully collected from all patients and CD34 + cell counts were 4.4–13.55 × 106/kg (8.77 ± 3.29 × 106/kg). All patients had successful haematopoietic reconstitution, and a median time of achieving granulocyte count of 500/L was 10 (9, 10) days, and a median time of achieving platelet count of 20 000/L was 12 (11, 13) days. The major treatment complications during transplantation were mucositis (87.5%), diarrhoea (62.5%), fever (56.3%), and nausea and vomiting (18.8%); the other rare complications were acute kidney injury, skin rashes and liver function damage. Haematologic responses were achieved in 15 patients (93.8%), with 10 patients (62.5%) achieved complete responses, 3 patients (18.8%) achieved very good partial responses, 2 patients (12.5%) achieved partial responses, and 1 patient had no haematologic responses. Before treatment with ASCT, seven patients (43.8%) achieved partial response, of which four achieved complete response after ASCT, and one patient did not achieve hematologic response but achieved complete response after ASCT. A total of 12 patients (75%) achieved renal response before ASCT and 14 patients (87.5%) achieved renal response after ASCT. The median follow-up time was 43.5 months. One patient died during the follow-up due to infection, and one patient developed end-stage renal disease during the follow-up. Three patients relapsed, with a median time of 49 months. CONCLUSION Our data demonstrated that ASCT is a safe and effective treatment for rigorously selected non-AL MGRS patients, with few serious treatment complications and high haematological and organ response rates.

Lack of Renal Recovery Predicts Poor Survival in Patients of Multiple Myeloma With Renal Impairment

BackgroundRenal impairment (RI) confers a poor prognosis in multiple myeloma. Reversibility of renal function is associated with improved survival in such patients. Patients in developing countries often present at an advanced stage and renal impairment is present in up to 40% of patients at diagnosis. We studied the renal outcome and survival of these patients with bortezomib-based induction therapy. Materials and MethodsIt was a single-center prospective study in a tertiary care multi-specialty institute in patients of newly diagnosed multiple myeloma (NDMM) who presented with RI from July 2018 to December 2019. The diagnosis of multiple myeloma was made based on IMWG14 criteria. All patients received bortezomib and or immunomodulatory drug-based triplet or quadruplet induction therapy. Hematological and renal outcomes were assessed as per IMWG 2016 criteria. ResultsAmong 216 consecutive patients of NDMM, RI was seen in 91 (42.2%) patients. The median age of 91 patients was 60 years. (range- 32-80 years). Light chain myeloma was seen in 26% (n = 24) of patients. The median estimated glomerular filtration rate (eGFR) was 15.36 mL/min (3.1-38 mL/min) and a majority of patients were in the advanced ISS stage. (ISS III = 85.7%). Thirty-six (39.5%) patients received hemodialysis at presentation. Renal response was seen in 67 (73%) patients and 20 (out of 36; 55%) became dialysis independent over a median time of 38 days (Range 15-160 days). At a median follow-up of 14.7 months, 30 (33%) patients had died, of which, 14 (15.4%) patients had early mortality (within 2 months of diagnosis). Presence of light chain myeloma and cast nephropathy (definite or probable) were identified as independent predictors of poor renal recovery on multivariate analysis. (HR = 2.841; 95% CI [1.471-5.486], P = .002 for light chain myeloma; HR = 1.859; 95% CI (1.087-3.180); P = .024 for cast nephropathy) Patients with low eGFR at presentation (<12.5 mL/min) were more likely to have persistent renal insufficiency. (HR-3.521; 95% CI (1.856-6.679), P = .000). Patients who attained sustained renal recovery had improved survival as compared to patients in whom renal function failed to improve. (median OS- not reached vs. 8.3 months, P = .000) Achievement of hematological response and independence from hemodialysis was associated with improved survival on multivariate analysis. ConclusionRenal impairment was reversible in almost three-fourths of NDMM patients. achievement of hematological response and hemodialysis independence were independent predictors of improved overall survival in NDMM patients with RI.

Evaluation of serum glucose-regulated protein 78 (GRP78) as a biomarker of treatment response to bortezomib-based induction regimen in multiple myeloma: A cross-sectional pilot study.

GRP78 overexpression in myeloma cells has been associated with bortezomib resistance in multiple myeloma (MM). However, serum GRP78 as a maker of bortezomib-based treatment response remains unexplored. The objective of the study was to evaluate serum GRP78 levels in MM patients who underwent a bortezomib-based induction regimen. This cross-sectional study included adult MM patients (n=30) who completed at least four cycles of bortezomib-based induction therapy. Healthy volunteers (n=30) and newly diagnosed MM patients (n=19) were also recruited to identify the disease-associated change in GRP78 levels. Serum GRP78 was estimated by ELISA. Surface and intracellular expression of GRP78 in bone marrow plasma cells was evaluated in ten MM patients by flow cytometry. Among 30 MM patients [median (range): 52 (38-68) years; 20 males] who completed at least four cycles of bortezomib-based induction therapy, 20 were responders and 10 were non-responders. Serum GRP78 levels were not significantly different between responders [median (IQR): 5.2 (3.1, 8.0) μg/ml] and non-responders [median (IQR): 4.3 (0.1, 7.1) μg/ml] (p=0.4). Although non-significant (p=0.3), median serum GRP78 was higher in newly diagnosed patients when compared to healthy volunteers. Bone marrow plasma cells ranged from 0.2 to 57.8% in the analyzed samples. Intracellular GRP78 expression in bone marrow plasma cells was higher (1.6 to 5 times) when compared to surface expression. To conclude, serum GRP78 levels vary widely in different MM patient groups but did not correlate with response to a bortezomib-based induction regimen.

Response Adaptive Salvage Treatment with Carfilzomib-Thalidomide-Dexamethasone for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients Failing Front-Line Bortezomib-Based Induction Therapy - Final Analysis from the Australasian Leukemia and Lymphoma Group (ALLG) MM17 Trial

Response Adaptive Salvage Treatment with Carfilzomib-Thalidomide-Dexamethasone for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients Failing Front-Line Bortezomib-Based Induction Therapy - Final Analysis from the Australasian Leukemia and Lymphoma Group (ALLG) MM17 Trial