Double Autologous Stem Cell Transplantation Research Articles

Iberdomide Maintenance after Autologous Stem-Cell Transplantation in Newly Diagnosed MM: First Results of the Phase 2 EMN26 Study

Background. Iberdomide is a novel oral cereblon E3 ligase modulator (CELMoD TM) with enhanced direct antitumor effects and immune stimulatory effects, compared to lenalidomide or pomalidomide. In the ongoing phase 1/2 CC-220-MM-001 study, iberdomide plus dexamethasone had a favorable safety profile and demonstrated clinically meaningful activity in triple-class refractory multiple myeloma (MM) patients, including those refractory to lenalidomide and pomalidomide (IMiDs ®). Based on these data, we aimed to evaluate the safety and clinical activity of 3 different doses of iberdomide as a novel maintenance treatment post-transplant in newly diagnosed MM patients. Here we report results from the first interim analysis for patients who have been treated with at least 6 treatment cycles, or discontinued treatment earlier. Methods. The EMN26 study is a multicohort, phase 2 study conducted in 4 European countries. Patients aged 18 years or older with MM, who had achieved at least a partial response (PR) after induction therapy containing a proteasome inhibitor (PI) plus IMiD followed by single or double autologous stem-cell transplantation (ASCT) +/- consolidation, were enrolled into one of 3 different cohorts (iberdomide 0.75, 1.0, or 1.3 mg on days 1-21 of each 28-day cycle; treatment continued until progression or unacceptable toxicity; 40 patients in each cohort). The primary outcome is improvement in response, and secondary outcomes include safety and progression-free survival (PFS). Response was evaluated at screening and after every cycle (bone marrow analysis was done at screening, at 6 and 12 months after treatment initiation, and to confirm (s)CR). This trial is ongoing and is registered with ClinicalTrials.gov (NCT04564703). Results. At data cut-off (May 31, 2023) 31 patients were enrolled in the 0.75 mg cohort, and 40 patients each in the 1.0 and 1.3 mg cohorts (total of 111). A total of 69 patients had received ≥6 cycles of iberdomide treatment or discontinued earlier (n=34 in 1.0 mg cohort; n=35 in 1.3 mg cohort; n=0 in 0.75 mg cohort [this cohort was added later]). Median age of these 69 patients was 59 years, and 57% were male. At diagnosis, 37% of patients presented with International Staging System (ISS) stage 1 disease, 35% with ISS stage 2, and 28% with stage 3. High-risk disease (del(17p), t(4;14), and/or t(14;16)) was present in 14% of patients. All patients received a PI/IMiD-containing induction regimen which also included daratumumab in 41% of patients. Double ASCT was administered to 19% and post-ASCT consolidation to 7%. Best response at the time of enrollment in the study was PR in 15%, very good (VG)PR in 59%, complete response (CR) in 12%, stringent (s)CR in 15% [≥CR: 26%] in the 1.0 mg cohort, and PR in 3%, VGPR in 69%, CR in 11%, sCR in 17% [≥CR: 29%] in the 1.3 mg cohort. After 6 treatment cycles, there was comparable deepening of response in both cohorts (1.0 mg cohort: PR 6%, VGPR 44%, CR 3%, sCR 47% [≥CR: 50%]; 1.3 mg cohort: PR 3%, VGPR 37%, CR 9%, sCR 51% [≥CR: 60%]). Improvement of response was reported in 48% (90% CI 32-65%) of patients treated with 1.0 mg iberdomide and 45% (90% CI 29-62%) in the 1.3 mg iberdomide cohort ( Figure), which are significantly higher than the null hypothesis of ≤20% response improvement within 6 months. The most common grade 3 or worse adverse events (AEs) during cycles 1-6 were neutropenia (21% in 1.0 mg cohort and 46% in 1.3 mg cohort), infections (3% and 14%), fatigue/asthenia (12% and 14%). There were no events of ≥grade 3 thrombocytopenia, anemia, diarrhea, VTE, or neuropathy. Dose reductions were used to manage AEs in 18% of patients in the 1.0 mg cohort and 31% in the 1.3 mg cohort. Treatment discontinuation occurred in 3 patients in 1.0 mg cohort (1 due to AE, 2 PD), and 4 patients in 1.3 mg cohort (2 due to AE, 1 PD, and 1 death [unknown cause]). PFS at 6 months was 97% and 94% in the 1.0 and 1.3 mg cohorts. With longer follow-up, results from the 0.75 mg cohort and MRD conversion data will be presented at the meeting. Conclusions. Iberdomide represents a novel effective post-ASCT maintenance strategy with a favorable safety profile and superior response improvement at 6 months than what has been observed with lenalidomide maintenance (26% at 6 months in the EMN02 study). Additional follow-up is needed to define the recommended maintenance dose that will be used in the randomized phase 3 EXCALIBER maintenance study, which will evaluate iberdomide vs. lenalidomide maintenance post-ASCT.

Sequential Imaging with Diffusion-Weighted Whole-Body MRI (DW-MRI) and PET-CT Identifies Patients at High Risk of Relapse in Multiple Myeloma

Introduction: Although the vast majority of patients with newly diagnosed multiple myeloma (NDMM) achieve deep responses during first-line therapy, most of them face relapse over time. Focal lesions, which are seen in up to 80% of NDMM, play a crucial role in MM evolution and can act as reservoirs for relapse disease. As a consequence, the combination of imaging- and minimal residual disease (MRD) negativity has been defined as a new response category. However, the dynamics and location of focal lesions during the treatment course remains poorly characterized and the answer to what imaging modality should be used to visualize focal residual disease remains elusive. In this study, we employed two techniques, PET-CT and DW-MRI, at multiple pre-defined time points to longitudinally track resistant lesions and investigate the combined prognostic value of these imaging modalities with other prognostic markers. Methods: We included 170 NDMM patients who were diagnosed between the years of 2010-2015 to ensure sufficient median follow-up time, which was 10 years. Median age of the study cohort was 60 years (range: 34-76), 104 were male (61%), and 31 patients (18%) had high-risk according to gene-expression profiles. All patients underwent PET-CT and DW-MRI evaluation at three pre-defined timepoints: baseline, post autologous stem-cell transplantation (ASCT) and at relapse. Minimal residual disease testing (MRD) by 8 color flow cytometry at a sensitivity level of 10 -5 post ASCT was available for 70 patients. Results: At baseline, 144/170 patients (85%) presented with focal lesions. Both imaging modalities, PET-CT and DW-MRI, showed positive results in 116 patients (68%). However, 21 patients (12%) had focal lesions detectable only by DW-MRI, while 7 patients (4%) showed focal lesions solely in PET-CT. After ASCT, only 12 patients had PET-CT positive lesions, whereas DW-MRI detected focal lesions in 53 patients, indicating a much higher detection rate with DW-MRI. Overall, 55 out of 170 patients (32%) showed residual lesions at this time point. The 26 patients w/o focal lesions in both PET-CT and DW-MRI at baseline remained negative post ASCT. Except for one patient, focal lesions after ASCT were persistent from initial diagnosis. Of note, two-thirds of the patients had residual focal lesions in the humeri and/or femora, which is surprising given that myeloma is considered a disease of the axial skeleton. Next, we correlated the presence of residual lesions with baseline patient characteristics, including age, gender, stage, and cytogenetic risk factors. Compared to patients w/o residual lesions, PET-positive patients showed an enrichment of rISS stage III (7 vs 50%, p<0.001) and deletion 17p (10 vs 33%, p=0.04). In contrast, patients who were DW-MRI positive only showed no significant association with any of the investigated variables. Both PET- and DW-MRI positive lesions post ASCT were associated with poor PFS (median 1.5 and 2.4 years, respectively vs. 9.4 years in imaging-negative patients, p<0.001) and OS (median 3.7 and 5.7 years, respectively vs. 11.3 years, p<0.001). Importantly, in a multivariate model the adverse prognostic effect of residual lesions was independent of baseline risk factors. To increase the power of the following combined imaging/MRD analysis, we defined an “Imaging+” group, which included the patients with PET+ and/or DW-MRI+ focal lesions. Among the 20 patients who achieved MRD-negative and imaging-negative status, an excellent PFS was observed, with only three events occurring in an 8-year follow-up. Residual lesions despite MRD negativity were only seen in two patients, and one of them progressed after 1.5 years. Dismal PFS was seen for double-positive patients (median 1.4 years), significantly worse compared to patients with MRD positivity only (8.9 years). Conclusion: Taken together, DW-MRI captures more patients with prognostically relevant residual focal lesions compared to PET-CT and should therefore be considered as a preferable imaging modality post ASCT. The high number of residual lesions in the extremities suggests a role of humeri and femora as reservoirs for treatment-resistant cells, deserving further investigation. For patients with MRD and imaging double positivity post ASCT, prognosis is dismal and alternate therapeutic approaches should be considered.

Treatment of primary plasma cell leukaemia with carfilzomib and lenalidomide-based therapy (EMN12/HOVON-129): final analysis of a non-randomised, multicentre, phase 2 study

Primary plasma cell leukaemia is a rare and aggressive plasma cell disorder with a poor prognosis. The aim of the EMN12/HOVON-129 study was to improve the outcomes of patients with primary plasma cell leukaemia by incorporating carfilzomib and lenalidomide in induction, consolidation, and maintenance therapy. The EMN12/HOVON-129 study is a non-randomised, phase 2, multicentre study conducted at 19 academic centres and hospitals in seven European countries (Belgium, Czech Republic, Denmark, Italy, Norway, The Netherlands, and the UK) for previously untreated patients with primary plasma cell leukaemia aged 18 years or older. Inclusion criteria were newly diagnosed primary plasma cell leukaemia (defined as >2 ×109 cells per L circulating monoclonal plasma cells or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Patients aged 18-65 years (younger patients) and 66 years or older (older patients) were treated in age-specific cohorts and were analysed separately. Younger patients were treated with four 28-day cycles of carfilzomib (36 mg/m2 intravenously on days 1, 2, 8, 9, 15, and 16), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 8, 9, 15, 16, 22, and 23). Carfilzomib-lenalidomide-dexamethasone (KRd) induction was followed by double autologous haematopoietic stem-cell transplantation (HSCT), four cycles of KRd consolidation, and then maintenance with carfilzomib (27 mg/m2 intravenously on days 1, 2, 15, and 16 for the first 12 28-day cycles, and then 56 mg/m2 on days 1 and 15 in all subsequent cycles) and lenalidomide (10 mg orally on days 1-21) until progression. Patients who were eligible for allogeneic HSCT, could also receive a single autologous HSCT followed by reduced-intensity conditioning allogeneic HSCT and then carfilzomib-lenalidomide maintenance. Older patients received eight cycles of KRd induction followed by maintenance therapy with carfilzomib and lenalidomide until progression. The primary endpoint was progression-free survival. The primary analysis population was the intention-to-treat population, irrespective of the actual treatment received. Data from all participants who received any study drug were included in the safety analyses. The trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR5350; recruitment is complete and this is the final analysis. Between Oct 23, 2015, and Aug 5, 2021, 61 patients were enrolled and received KRd induction treatment (36 patients aged 18-65 years [20 (56%) were male and 16 (44%) female], and 25 aged ≥66 years [12 (48%) were male and 13 (52%) female]). With a median follow-up of 43·5 months (IQR 27·7-67·8), the median progression-free survival was 15·5 months (95% CI 9·4-38·4) for younger patients. For older patients, median follow-up was 32·0 months (IQR 24·7-34·6), and median progression-free survival was 13·8 months (95% CI 9·2-35·5). Adverse events were most frequently observed directly after treatment initiation, with infections (two of 36 (6%) younger patients and eight of 25 (32%) older patients) and respiratory events (two of 36 [6%] younger patients and four of 25 [16%] older patients) being the most common grade 3 or greater events during the first four KRd cycles. Treatment-related serious adverse events were reported in 26 (72%) of 36 younger patients and in 19 (76%) of 25 older patients, with infections being the most common. Treatment-related deaths were reported in none of the younger patients and three (12%) of the older patients (two infections and one unknown cause of death). Carfilzomib and lenalidomide-based therapy provides improved progression-free survival compared with previously published data. However, results remain inferior in primary plasma cell leukaemia compared with multiple myeloma, highlighting the need for new studies incorporating novel immunotherapies. Dutch Cancer Society, Celgene (a BMS company), and AMGEN.

Higher efficacy of Etoposide + Cytarabine Plus Pegfilgrastim in poorly mobilizing Multiple Myeloma and lymphoma Patients

Background aimsAn optimal strategy for mobilizing hematopoietic stem cells in poorly mobilizing patients with multiple myeloma (MM) and lymphoma has not yet been determined. MethodsWe retrospectively analyzed the efficacy and safety of etoposide combined with cytarabine (etoposide 75 mg/m2, daily d1∼2; Ara-C 300 mg/m2, every 12 h d1∼2), plus pegfilgrastim (6 mg d6) in 32 patients with MM or lymphoma, among whom 53.1% were defined as “proven poor mobilizers.” ResultsThis approach resulted in adequate mobilization (≥2.0 × 106 CD34+ cells/kg) in 93.8% of patients and optimal mobilization (≥5.0 × 106 CD34+ cells/kg) in 71.9% of patients. A total of 100% of patients with MM reached at least 5 × 106 CD34+ cells/kg collected, the amount required for double autologous stem cell transplant. In total, 88.2% of patients with lymphoma reached at least 2 × 106 CD34+ cells/kg collected, the amount required for a single autologous stem cell transplant. This was achieved with a single leukapheresis in 78.1% of cases. A median peak number of 42.0/μL circulating CD34+ cells and a median number of blood CD34+ cells counts in 6.7 × 106/L were collected among 30 successful mobilizers. Approximately 6.3% of patients required plerixafor rescue, which was successful. Nine (28.1%) of the 32 patients suffered grade 2∼3 infections, and 50% required platelet transfusions. ConclusionsWe conclude that chemo-mobilization with etoposide, Ara-C and pegfilgrastim in poorly mobilizing patients with MM or lymphoma is very effective and has acceptable toxicity.

ВОЛЧАНОЧНЫЙ НЕФРИТ: КЛИНИЧЕСКИЙ СЛУЧАЙ С ДВОЙНОЙ ТРАНСПЛАНТАЦИЕЙ. ВКЛАД Ар.А. ДЕМИНА В ИЗУЧЕНИЕ ЗАБОЛЕВАНИЯ

Introduction. Lupus nephritis (LN) is common in systemic lupus erythematosus (SLE), a severe autoimmune disease with a poor prognosis. Restoring the immune system and self-tolerance using high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (AHSCT) is a new approach in the treatment of refractory SLE. The effectiveness of SLE with LN treatment in the long-term follow-up should be the subject for study. Methods. Patient I., 25 years old, with refractory SLE and LN is described. Standard therapy was ineffective, the SLEDAI score remained 22 points, so the patient underwent high-dose immunosuppressive therapy (HIT) with ASCT, and she was included in the registry of the European Group for Blood and Marrow Transplantation of the European League Against Rheumatism (EBMT/EULAR). Results. As a result of ASCT, complete clinical and serological remission was achieved (score on the SLEDAI scale – 0 points) for 3 years. Then there was a relapse with nephrotic syndrome and anti-DNA positivity which led to the end-stage renal failure. Despite therapy, the disease activity persisted, and the patient was on regular hemodialysis for 1 year, then underwent allogeneic kidney transplantation. Currently, 18 years have passed since HIT and AHSCT and 11 years since renal transplantation. The patient receives standard post-transplant immunosuppression, and her condition remains stable, the renal allograft is functioning, the SLEDAI score is 2 points (low titer anti-DNA positivity). Discussion. Modern standards of chemotherapy (hydroxychloroquine, mycophenolate mofetil, cyclophosphamide, corticosteroids), bioactive immunotherapy (rituximab, belimumab, obinituzumab, anifrolumab), “multi-target therapy” (standard + tacrolimus, voclosporin, mycophenolate mofetil), and new approaches (immuno- and nephrotransplantation) for lupus nephritis. Conclusion. The successful long-term results of the first case of immunoablation with high-dose immunosuppressive therapy and double autologous stem cell and allogeneic kidney transplantation for SLE with refractory lupus nephritis and an analysis of the effectiveness of modern treatment approaches are presented.

Autologous Stem Cell Transplantation in Multiple Myeloma: Where Are We and Where Do We Want to Go?

The introduction of high-dose therapy in the 1990s as well as the development of drugs such as thalidomide, lenalidomide, and bortezomib in the 2000s led to an impressive improvement in outcome of patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). Clinical trials conducted in the first ten years of the twenty-first century established as standard therapy for these patients a therapeutic approach including induction, single or double ASCT, consolidation, and maintenance therapy. More recently, incorporating second-generation proteasome inhibitors carfilzomib and monoclonal antibody daratumumab into each phase of treatment significantly improved the efficacy of ASCT in terms of measurable residual disease (MRD) negativity, Progression Free Survival (PFS), and Overall Survival (OS). The availability of techniques such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment allowed the design of MRD-based response-adjusted trials that will define, in particular, the role of consolidation and maintenance therapies. In this review, we will provide an overview of the most recent evidence and the future prospects of ASCT in MM patients.

OAB-058: Predictive relevance of sustained MRD negativity and of early loss of MRD negativity during maintenance therapy after transplant in newly diagnosed Multiple Myeloma patients

<h3>Background</h3> sustained MRD negativity is emerging as a surrogate biomarker of patients (pts)' outcome in clinical trials. We implemented this tool in our clinical practice and we analyzed outcome according to sustained MRD negativity in MM pts treated with autologous stem cell transplantation (ASCT) at our Institution. <h3>Methods</h3> We retrospectively analyzed the outcome of 77 newly diagnosed MM pts (median age 61 years) diagnosed between January 2015 to December 2019 in ≥ VGPR after ASCT. Bone marrow samples were collected for MRD by 8-color FCM (Sn 10-5) at day +100 after ASCT, before maintenance. Sustained 1 year MRD negativity was also evaluated and the prognostic impact of MRD status on PFS and OS was analyzed. <h3>Results</h3> out of 77 pts, 28 (36%) were ISS stage 3 and 18 (23%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 51, VRD 5, Dara-VRD 5, KRD 14, KCD 2. Single ASCT with MEL200 conditioning was performed in 49 pts (64%), whereas 28 pts (36%) received double ASCT. Subsequent maintenance was performed with lenalidomide (70), daratumumab-lenalidomide (5), carfilzomib-lenalidomide (2). Response rates were VGPR 26%, CR 61% and sCR 13%. MRD before maintenance was positive in 20 pts (26%) and negative in 57 (74%). Sustained MRD negativity lasting ≥ 1 year was documented in 49 pts (64%), whereas early loss of MRD negative status was observed in 8 (10%) of cases. After a median follow up of 40.2 months, PFS was significantly longer in pts with sustained MRD negativity (≥1 year) compared to MRD positive patients before maintenance: median NR vs 41.4 months, p 0.0002, HR 0.17 (0.044-0.65). The worst PFS (24.7 months) was observed in pts with early loss of MRD negativity (<1 year) and was significantly inferior if compared both to pts with sustained MRD negativity (p<0.0001, HR 0.06; 0.01-0.54) and to MRD positive pts before maintenance (p 0.03, HR 0.35; 0.11-0.16), with significantly different outcome of the three subgroups (p<0.0001). Different OS trend was also observed among the three subgroups: NR in sustained MRD negative pts, 58.5 months in MRD positive pts and 35.3 months in pts with early loss of MRD negativity (p<0.0001), although OS difference between sustained MRD negativity (≥ 1 year) and MRD positive pts was not statistically significant on a direct comparison (p 0.054). The worst OS observed in pts with early loss of MRD negativity (<1 year) was significantly inferior if compared both to pts with sustained MRD negativity (p<0.0001, HR 0.05; 0.003-0.80) and to MRD positive pts before maintenance (p 0.020, HR 0.21; 0.035-1.26). <h3>Conclusion</h3> we confirm the predictive value of MRD assessment after ASCT and therefore the importance of achieving sustained MRD negativity regardless of different treatment strategies. Moreover, the detection of early loss of MRD negativity can help the physician to identify pts with particularly poor prognosis

Full or intensity-reduced high-dose melphalan and single or double autologous stem cell transplant with or without bortezomib consolidation in patients with newly diagnosed multiple myeloma.

A post hoc subgroup analysis of two phase III trials (NCT00416273, NCT00416208) was carried out to investigate the influence of 100/140 and 200mg/m² melphalan as well as single/double autologous stem cell transplantation (ASCT) on progression-free survival (PFS). Additionally, the effect of bortezomib consolidation on PFS was analyzed. Following induction therapy and high-dose melphalan with subsequent ASCT, patients with newly diagnosed multiple myeloma (NDMM) were randomized 1:1 to either four 35-day cycles of bortezomib consolidation (1.6mg/m² IV on days 1, 8, 15, 22) or observation. Of the 340 patients included in this analysis, 13.5% received 1×MEL100/140, 22.9% 2×MEL100/140, 31.2% 1×MEL200, and 32.4% 2×MEL200. With higher cumulative melphalan dose, PFS improved (P=.0085). PFS curves of patients treated with 2×MEL100/140 and 1×MEL200 were very similar. The superior dose effect of MEL200 over MEL100/140 was non-existent in the bortezomib consolidation arm but pronounced in the observation arm (P=.0015). Similarly, double ASCT was only beneficial in patients without bortezomib consolidation (P=.0569). Full dose melphalan and double transplantation seem advantageous only as long as patients are not receiving bortezomib consolidation afterwards.

Double Autologous Stem Cell Transplantation Significantly Prolongs Progression-Free Survival and Overall Survival in Comparison with Single Autotransplantation in Newly Diagnosed Multiple Myeloma: An Analysis of Phase 3 EMN02/HO95 Study

Background The role of single vs double autologous stem cell transplantation (ASCT) for newly diagnosed (ND) multiple myeloma (MM) continues to be debated in the novel agent era. Methods The phase III EMN02/HO95 study was designed to administer 3-4 cycles of bortezomib-cyclophosphamide-dexamethasone as induction therapy for NDMM and afterwards to randomize eligible patients to receive (randomization 1, R1) standard-dose intensification treatment with bortezomib-melphalan-prednisone (VMP) for four 42-day cycles or high-dose intensification treatment with melphalan at 200 mg/m2 (HDM) plus ASCT. A second randomization to receive or not receive consolidation therapy was planned after the intensification phase, followed by lenalidomide maintenance in both arms. In centers committed to a double ASCT policy, patients were randomized (1:1:1) to receive VMP or single ASCT (ASCT-1) or two sequential courses of HDM (administered 2 to 3 months apart) plus double ASCT (ASCT-2) in order to prospectively compare ASCT-1 vs ASCT-2, which was an additional study objective. For this purpose, and for consistency with the primary study end point, progression-free survival (PFS) from R1 was evaluated. Results A total of 1503 patients aged ≤65 years were registered and 1192 were eligible for R1. By study design, 618 patients who received the diagnosis of MM in centers with a double ASCT policy were randomly assigned to VMP (n=203) or ASCT-1 (n=208) or ASCT-2 (n=207). 415 of these patients who were randomized to receive ASCT-1 or ASCT-2 were included in the current pre-specified analysis. Median age was 58 years for patients in the ASCT-1 group and 57 years for those in the ASCT-2 group. The frequency of ISS stage III was 19% in both groups. According to IMWG criteria, a high-risk (HiR) cytogenetic profile defined by t(4;14) ± t(14;16) ± del(17p) positivity (HiR-cyto-3) was detected in 26% and 21% of patients who were evaluable in ASCT-1 (80%) and ASCT-2 (86%) groups. The presence of amp(1q) ± del(1p) ± 1 or more of t(4;14), t(14;16) and del(17p) identified a HiR cytogenetic profile (HiR-cyto-5) which was detected in 55% of patients in ASCT-1 arm and 50% of those in ASCT-2 arm. Median follow-up from R1 was 38 (IQR: 29-47) months for the overall patient population (36 and 39 months for patients randomized to ASCT-1 and ASCT-2, respectively). On an intention-to-treat basis, 3-year estimate of PFS was 73% (95% CI=66-79) for ASCT-2 group vs 64% (CI=57-71) for ASCT-1 group (HR=0.70; CI=0.50-0.98; P=0.040), which represented a 30% reduced risk of progression or death in the ASCT-2 group compared with the ASCT-1 group (Fig. 1a). PFS benefit associated with ASCT-2 was confirmed in subgroups of patients with HiR-cyto-3 (HR=0.42; CI=0.21-0.84; P=0.014), revised ISS (R-ISS) stage II+III (HR=0.64; CI=0.43-0.97; P=0.034), age >55 years (HR=0.64; CI=0.43-0.96; P=0.033); HiR-cyto-5 (HR=0.65; CI=0.42-1.01; P=0.059) and best ≥VGPR (HR=0.64; CI=0.44-0.94; P=0.023). Importantly, ASCT-2 overcame the adverse prognosis conferred by HiR-cyto-3 (3-year PFS: 76% vs 69% for patients with standard-risk cytogenetic profile; P=0.482) (Fig. 1b). In particular, 3-year PFS estimate for patients randomized to ASCT-2 and carrying or lacking del(17p) was 72% vs 73%, respectively (P=0.534). The corresponding PFS values in the ASCT-1 group were 43% vs 67%, respectively (P=0.014). In a multivariate Cox regression analysis, randomization to ASCT-2 (HR=0.65; CI=0.44-0.95; P=0.029), R-ISS I (HR=0.60; CI=037-0.98; P=0.042), absence of HiR-cyto-5 (HR=0.35; CI=0.22-0.55; P Conclusions Randomization to ASCT-2 was superior over ASCT-1 in terms of prolonged PFS and OS for the overall patient population and for poor prognosis subgroups of patients with advanced R-ISS disease stage and HiR cytogenetic profile. Incorporation of bortezomib into ASCT-2 abrogated the increased risk of progression or death imparted by t(4;14) ± t(14;16) ± del(17p), and in particular by del(17p) positivity. Disclosures Gay: Amgen: Honoraria; Mundipharma: Membership on an entity9s Board of Directors or advisory committees; Roche: Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria; Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria. Bringhen: Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Amgen: Membership on an entity9s Board of Directors or advisory committees; Mundipharma: Membership on an entity9s Board of Directors or advisory committees; Karyipharm: Membership on an entity9s Board of Directors or advisory committees. Musto: janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria. Palumbo: Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Sonneveld: Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy.

Melphalan Dose in Myeloma Patients over 65 Years of Age Undergoing High-Dose Therapy and Autologous Stem Cell Transplantation

IntroductionConsolidating high-dose chemotherapy with melphalan followed by autologous stem cell transplantation (ASCT) is believed to be superior to conventional chemotherapy alone in fit multiple myeloma patients ≥65 years. However, contemporary high quality data on the overall efficacy and safety of ASCT in this elderly age group are missing, and the conditioning regimen including the optimal melphalan dose is a matter of debate. Our present study aims at addressing the issue of the melphalan dosing prior to ASCT in patients ≥ 65 years of age.MethodsThis is an observational, multi-center, non-interventional research project based on data of the prospective Swiss Blood Stem Cell Transplantation Registry. Included are all Swiss patients ≥65 years with multiple myeloma who received high-dose chemotherapy followed by ASCT. Patients receiving melphalan at a dose of 200mg/sqm, and patients receiving melphalan at a dose of < 200mg/sqm were analyzed separately. For the 53 patients receiving double ASCT, only the first ASCT was considered, and survival was censored at the time of second ASCT. The main outcomes analyzed in the study were treatment-related mortality prior to day 100 (TRM), progression free survival (PFS), and overall survival (OS) estimates at two and five years.ResultsBetween 2000 and 2016, 414 patients with multiple myeloma aged 65 years and older received high-dose chemotherapy with melphalan and ASCT. Of those, 165 patients (40%) were female. The median age at ASCT was 67 years (range 65-77 years), and the median observation time of the surviving patients was 19 (range 0-215) months. Monoclonal component subtype was IgG (n=247, 60%), IgA (n=90, 22%), light chain (n=65, 16%), and others (n=12, 2%), respectively. Risk stratification according to the International Staging System (ISS) defined stage I in 136 (38.1%) patients, stage II in 144 (40.3%) patients, and stage III in 77 (21.6%) patients. Cytogenetic information was available for 212 (51.2%) patients, with 44 (20.8%) patients presenting high-risk features defined by the presence of del(17p), t(4;14), t(14;16), or combinations of these. Remission status prior to transplant was complete response (n=50, 12%), very good partial response (n=105, 25%), and partial response (n=229, 55%), respectively. Most patients had a Karnofsky Performance Status (KPS) of 90-100% prior to ASCT (n=318, 80.3%), while a KPS ≤ 80% was observed in 78 (19.7%) patients. Two hundred ninety-one patients (70%) received a melphalan dose of 200mg/sqm, and 123 patients (30%) received less than 200mg/sqm (median 140mg/msq, range 70 to 180mg/sqm). Patients who received melphalan doses <200mg/sqm were slightly older (67.8 years vs. 67.3 years, p=0.004), and had higher serum creatinine levels (80 µmol/l vs. 74 µmol/l, p<0.001), but did not differ with regards to ISS stage, cytogenetic risk group, remission status, and KPS prior to ASCT. At day 100, seven patients (1.7%) had died due to transplant-related complications, without differences between the two melphalan dose groups (p=0.429). Median PFS in the melphalan 200mg/sqm group was 25.9 months (21.1-30.7 months), and in patients receiving lower melphalan doses 25.2 months (17.9-32.5 months), respectively (p=0.656) (Figure1A). Estimated overall survival at 2 years and 5 years were 84.1% (79.0-89.2%), and 60.2% (51.4-69.0%) in the melphalan 200mg/sqm group, as compared to 85.1% (77.6-92.5%) and 56.0% (40.5-71.5%) in patients receiving lower melphalan doses (p=0.701) (Figure 1B). In a multivariate analysis adjusted for renal function, ISS stage, age at ASCT, and KPS, the melphalan dose was not associated with differences in the PFS or the OS.ConclusionsThe present study shows that high-dose melphalan and ASCT is feasible and safe in an elderly patient population with multiple myeloma. No significant differences in TRM, PFS and OS were observed between patients treated with melphalan 200mg/sqm, and patients treated with lower melphalan doses. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Subcutaneous bortezomib-containing regimens as up-front treatment of newly diagnosed transplant-eligible multiple myeloma patients: a retrospective, non-interventional observational study

Subcutaneous (SC) bortezomib-based regimens represent the standard induction therapy prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma patients. Published data are based principally on intravenous (IV) administration: this retrospective observational study aimed to define patients’ outcomes upon SC bortezomib administration, before and after ASCT. Of 131 enrolled patients, 86% received bortezomib-dexamethasone plus thalidomide (VTD), 5% plus cyclophosphamide (VCD), and 9% alone (VD), for a median of 4 cycles induction therapy, followed by single (52%) or double (48%) ASCT. 48 patients received consolidation with the same induction regimen. 35% had at least one adverse event, mainly gastrointestinal disorders and peripheral neuropathy (PN). ORR was 93.1%, 97.7% and 100%, after induction, ASCT(s) and consolidation, respectively. Median PFS and PFS2 were 55.8 months and 72 months, respectively, (median follow-up 45.3 months), while median OS was unreached. Concluding, SC bortezomib has similar efficacy with reduced PN than IV administration.

Comparison of single and double autologous stem cell transplantation in multiple myeloma patients.

BackgroundAutologous stem cell transplantation (ASCT) is one of the standard treatments of choice for eligible multiple myeloma (MM) patients. Herein, we aimed to analyze MM patients at our center and compare the clinical outcomes of single and double ASCT patients.Materials and methodsPatients who were diagnosed as having MM and had undergone single or double ASCT in our clinic between the years 2003 and 2020 were retrospectively examined.ResultsIn this study, the median time of second ASCT is approximately 3.6 years from the first ASCT. Overall survival (OS) duration of the single and double transplanted groups was 4,011 ± 266 vs 3,526 ± 326 days, respectively (p: 0.33). Progression-free survival (PFS) duration of the single and double transplanted groups was 2,344 ± 228 vs 685 ± 120 days, respectively (p: 0.22). Disease assessment after ASCT stable or progressive disease, partial remission, and very good partial or complete remission (CR) in single and double ASCT groups was 62/44/105 and 8/4/5, respectively (p: 0.22).ConclusionThe present study points out that the second ASCT treatment option for MM patients may not be effective as suggested, especially in the era of novel MM drugs, since our results come from the past data that novel drugs were not exist. In conclusion, we found no benefit with second ASCT in MM patients in terms of PFS and OS or CR rates, and the novel anti-myeloma drugs might decrease the need for a second transplant.

Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study

The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. In this randomised, open-label, phase 3 study, patients aged 18-65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1-2, 4-5, 8-9, and 11-12 in the VTD regimen, and 40 mg on days 1-4 and 9-12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2-131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28-41) compared with 17% (13-23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50-0·77]; p<0·0001). 60% (95% CI 54-67) of patients in the VTD group were alive at 10 years versus 46% (40-54) of patients in the TD group (HR 0·68 [95% CI 0·51-0·90]; p=0·0068). VTD was an independent predictor of improved progression-free survival (HR 0·60 [95% CI 0·48-0·76]; p<0·0001) and overall survival (HR 0·68 [0·50-0·91]; p=0·010). The incidence of second primary malignancies per 100 person-years was 0·87 (95% CI 0·49-1·44) in the VTD group compared with 1·41 (0·88-2·13) in the TD group. Incorporation of VTD into double autologous HSCT resulted in clinically meaningful improvements in long-term progression-free survival and overall survival, confirming that a regimen including bortezomib and an immunomodulatory drug is the gold standard treatment for patients with newly diagnosed myeloma who are fit for high-dose chemotherapy. Seràgnoli Institute of Haematology, University of Bologna, and BolognAIL.

Minimal Residual Disease (MRD) at 10-6 Measured By Next Generation Flow (NGF) during Daratumumab Consolidation Therapy: Analysis at 18 Months Follow up of DART4MM Study (Daratumumab Treatment For Multiple Myeloma Eradication)

Minimal Residual Disease (MRD) at 10-6 Measured By Next Generation Flow (NGF) during Daratumumab Consolidation Therapy: Analysis at 18 Months Follow up of DART4MM Study (Daratumumab Treatment For Multiple Myeloma Eradication)

Consolidation Treatment with VRD Followed By Maintenance Therapy Versus Maintenance Alone in Newly Diagnosed, Transplant-Eligible Patients with Multiple Myeloma (MM): A Randomized Phase 3 Trial of the European Myeloma Network (EMN02/HO95)

Consolidation Treatment with VRD Followed By Maintenance Therapy Versus Maintenance Alone in Newly Diagnosed, Transplant-Eligible Patients with Multiple Myeloma (MM): A Randomized Phase 3 Trial of the European Myeloma Network (EMN02/HO95)

Comparison of single and double autologous stem cell transplantation in multiple myeloma patients

Background Autologous stem cell transplantation (ASCT) is one of the standard treatments of choice for eligible multiple myeloma (MM) patients. Herein, we aimed to analyze MM patients at our center and compare the clinical outcomes of single and double ASCT patients. Materials and methods Patients who were diagnosed as having MM and had undergone single or double ASCT in our clinic between the years 2003 and 2020 were retrospectively examined. Results In this study, the median time of second ASCT is approximately 3.6 years from the first ASCT. Overall survival (OS) duration of the single and double transplanted groups was 4,011 ± 266 vs 3,526 ± 326 days, respectively (p: 0.33). Progression-free survival (PFS) duration of the single and double transplanted groups was 2,344 ± 228 vs 685 ± 120 days, respectively (p: 0.22). Disease assessment after ASCT stable or progressive disease, partial remission, and very good partial or complete remission (CR) in single and double ASCT groups was 62/44/105 and 8/4/5, respectively (p: 0.22). Conclusion The present study points out that the second ASCT treatment option for MM patients may not be effective as suggested, especially in the era of novel MM drugs, since our results come from the past data that novel drugs were not exist. In conclusion, we found no benefit with second ASCT in MM patients in terms of PFS and OS or CR rates, and the novel anti-myeloma drugs might decrease the need for a second transplant.

Different MAF translocations confer similar prognosis in newly diagnosed multiple myeloma patients

The MAF translocations, t(14;16) and t(14;20), are considered as adverse prognostic factors based on few studies with small sample sizes. We report on their prognostic impact in a large group of 254 patients – 223 (87.8%) with t(14;16) and 31 (12.2%) with t(14;20). There were no intergroup differences in survival estimates. Median progression-free survival was 16.6 months for t(14;16) and 24.9 months for t(14;20) (p = 0.28). Median overall survival (OS) was 54.0 months and 49.0 months, respectively (p = 0.62). Median OS in patients who underwent double autologous stem cell transplantation (ASCT) was 107.0 months versus 60.0 months in patients who received single ASCT (p < 0.001). ISS 3 was associated with shorter OS (HR = 1.89; 95% CI 1.24–3.19; p = 0.005) in Cox analysis. Our study suggests that t(14;20) should be considered as an adverse factor of equal prognostic implication to t(14;16).

TEM-MM-101: A Phase I/IIa Dose Escalation Study Evaluating the Safety and Activity of Autologous CD34+ Enriched Hematopoietic Progenitor Cells Genetically Modified for Human Interferon-α2 in Multiple Myeloma Patients with Early Relapse after Intensive Front Line Therapy

BACKGROUND Multiple Myeloma (MM) is an incurable malignancy heralded by an immunosuppressive tumor microenvironment (TME). Therapeutic efforts to reprogram the TME and release innate and adaptive immunity may synergize with current anti-MM drugs, deepen responses and ultimately prolong long-term survival. We have developed an ex vivo gene therapy approach that locally delivers interferon-alpha (IFNa) into the TME through the Tie2+ myeloid progeny of transplanted gene-modified hematopoietic stem and progenitor cells (HSPCs). Preclinical studies in the immunocompetent Vk*Myc murine model as well as in the hematochimeric xenotransplantation setting demonstrate that IFNa gene therapy has anti-MM effect and may subvert the immunosuppressive MM TME, acting both on myeloma cells as well as on the immune infiltrate. Additional toxicology data, demonstrates that a mixture of genetically modified and unmodified CD34+ cells can be transplanted safely. We have therefore progressed into the clinic at Ospedale San Raffaele in Milan, Italy, with our gene therapy approach (Temferon). METHODS The TEM-MM-101 study recruits patients with MM in early relapse (within 18 months) after intensive front line therapy defined as triplet induction (at least 3 cycles including a proteasome inhibitor and/or immunomodulatory drug [IMID]) followed by single or double autologous stem cell transplantation, or, triplet or quadruplet induction including at least a proteasome inhibitor and an IMID, followed by consolidation/maintenance treatment. Three cohorts of 3 patients will be included in the study. Patients will be dosed sequentially in each cohort with data review by an independent data monitoring committee before dose escalation to the next cohort. Key eligibility criteria include achieving at least a VGPR after second line salvage therapy, age 18-70 years, ECOG &lt;2 and Karnofsky &gt;70%, adequate cardiac, renal, hepatic and pulmonary function, and willingness to use appropriate contraception if relevant. Important exclusion criteria include the presence of active autoimmune disease or ineligibility for autologous bone marrow transplant. After confirmation of eligibility, patients undergo autologous peripheral blood HSPC mobilization with lenograstim and plerixafor, before undergoing apheresis. After purification, CD34+ cells undergo transduction with a third-generation, vesicular stomatitis virus-G pseudo-typed lentiviral vector driving myeloid-specific IFNa2 expression. Patients will be offered maintenance treatment from successful HSPC collection until Temferon release. A reduced intensity conditioning regimen is administered at Day -2 followed by ASCT and administration of Temferon at Day 0. Following hematological recovery, patients will be discharged from the Transplant Unit with regular outpatient follow up. After Day +100 from Temferon infusion, patients will resume anti-myeloma consolidation/maintenance treatment according to best clinical practice, unless there is Temferon engraftment and absence of disease on Day +100 evaluations, documented by stringent complete response (sCR) according to the IMWG response criteria, imaging (PET, MRI) negativity, and bone marrow minimal residual disease &lt; 10-4 by multi-parameter flow cytometry, to be confirmed by next generation sequencing. If these response criteria are met on Day +100, patients may stay off maintenance treatment, as long as MRD≤10-5 documented on bone marrow aspirates performed every 3 months, starting from the Day +180 visit. The primary endpoints for this study are: Engraftment of Temferon between Day +30 and Day +100The proportion of patients achieving hematologic recovery by Day +30 from ASCTSafety of Temferon (short-term tolerability of Temferon; stable blood counts and absence of cytopenias &gt; grade 2, unless related to myeloma progression or concomitant medications; absence of systemic IFNa toxicity; absence of Replication Competent Lentivirus; absence of hematologic malignancy that is distinct from progression of the primary neoplasm) The study is actively recruiting patients in Italy. In parallel, a study using Temferon in patients with glioblastoma multiforme with a similar study design and approach (TEM-GBM-001) is also in progress with the first cohort fully recruited. Disclosures Gentner: Genenta Science: Consultancy, Equity Ownership, Research Funding. Mazzoleni:Genenta Science: Employment, Equity Ownership. Russo:Genenta Science: Consultancy, Equity Ownership. Naldini:Genenta Science: Consultancy, Equity Ownership; Magenta Therapeutics: Equity Ownership; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), a joint venture between Fondazione Telethon and Ospedale San Raffaele (OSR): Other: Wiskott-Aldrich Syndrome (WAS) gene therapy was licensed to GlaxoSmithKline (GSK) in 2014. It was then licensed to Orchard Therapeutics (OTL) in April 2018. OTL is the current sponsor of the clinical trial..

ASH 2018—Highlights in Multiple Myeloma

More than 900 abstracts on multiple myeloma were presented at this year’s ASH in San Diego. Several trials explored the addition of the monoclonal antibody daratumumab to established treatment regimens in both newly diagnosed as well as relapsed and refractory multiple myeloma. A long-awaited study tried to evaluate the role of double autologous stem cell transplant in multiple myeloma in newly diagnosed transplant eligible multiple myeloma. In relapsed and refractory multiple myeloma updates from several large trials like CASTOR and POLLUX were presented. Another spotlight were lenalidomide-refractory patients, an important patient group that is emerging as an increasingly challenging collective. Finally, abstracts on several novel agents like selinexor, venetoclax, isatuximab, melflufen and AMG420 were presented. Although still very preliminary, these data are already quite promising and illustrate the ever-changing treatment landscape in multiple myeloma.

Is there still a role for stem cell transplantation in multiple myeloma?

High-dose chemotherapy and autologous stem cell transplantation (ASCT) are a standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (MM). The introduction of novel agents, which range from immunomodulatory drugs and proteasome inhibitors to monoclonal antibodies and have now been integrated into both induction and salvage regimens, has dramatically revolutionized the treatment landscape of MM and challenged the role of high-dose chemotherapy and ASCT in treating MM. These advances have led to a number of provocative questions. First, what is the current role of stem cell transplantation (SCT) in comparison with standard-dose therapy incorporating novel agents? Second, should ASCT be performed upfront ("early") or later ("delayed") in the course of the disease? Third, should single or double ASCT be performed? Fourth, is allogeneic SCT still an option for patients with MM? This article provides an overview of available data and evidence-based responses regarding the role of SCT in MM.