A comparison of peripheral blood stem cell collection outcomes for multiple myeloma, mobilization matters in the era of IMiD induction

Collection of peripheral blood stem cells (PBSCs) for autologous stem cell transplant (ASCT) requires mobilization from the bone marrow. There is variation in mobilization choice;during the COVID-19 pandemic BSBMT&CT guidelines recommended using granulocyte-colony stimulating factor (G-CSF) alone to minimize the use of chemotherapy. We report on the impact of mobilization regimen on stem cell collection, and whether IMiD-containing induction therapy impacts on mobilization and consequently transplant engraftment times for 83 patients undergoing ASCT at Leeds Teaching Hospitals. Cyclophosphamide plus G-CSF (cyclo-G) mobilization yielded more CD34+ cells (8.94 vs. 4.88 x106/kg, p = < 0.0001) over fewer days (1.6 vs. 2.4 days, p = 0.007), and required fewer doses of salvage Plerixafor than G-CSF only (13.6% vs. 35%, p = 0.0407). IMiD-containing induction impaired all of these factors. CD34+ doses > 8x106/kg were more frequent with Cyclo-G (62% vs. 11%, p = 0.0001), including for those receiving IMiD 1st line induction (50% vs. 13.3%, p = 0.0381). Note that 92.6% of those receiving IMiD-free inductions were mobilized with Cyclo-G. The novel agents used in modern induction regimens (e.g Daratumumab) have been shown to impair yields, increasing the importance of optimizing mobilization regimens in the first instance. Furthermore, as cellular therapies become established in the management of multiple myeloma emerging data highlights the potential benefits of stem cell top up in the management of the haematological toxicities of these therapies. Our findings support re-adoption of Cyclo-G as the gold standard for mobilization to optimize PBSC harvesting and ensure sufficient cells for subsequent ASCTs.Copyright © 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.

FEASIBILITY OF HAEMATOPOIETIC STEM CELL MOBILIZATION AFTER CONSOLIDATION WITH GEMTUZUMAB OZOGAMICIN AND INTERMEDIATE-DOSES ARA-C AND DAUNORUBICIN IN AML

Background: Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate Antibody is currently approved in combination with 7 + 3 in low- and intermediate risk acute myeloid leukaemia (AML). These patients are candidate for consolidation with autologous stem cell transplantation (ASCT) particularly when MRD- is obtained. GO can improve the rate of MRD negativity. There are limited data on the effect of its addition on the mobilization of Hemopoietic Stem Cells (HSC). Aims: To assess the feasibility of mobilization of HSC after re-introduction into market of GO at 3mg/m2 in 2019. Methods: We retrospectively studied AML patients undergoing 3+7 + GO induction and Ara-C + Daunorubicine + GO, consolidation (doses are derived from label instructions and ALFA0701 study) and mobilization on day +20 using GCSF 10μg/kg. CD34+ were monitored, and patients were harvested when a threshold of 20 cells/μL was reached in peripheral blood. Results: In 2020 and 2021, also considering constrains caused by COVID-19 pandemics, we attempted mobilization in our 3 Italian centres of 14 patients with a diagnosis of CD33+ de novo-AML. The median age was 52 years (range 29-65 yrs.), 4 were males and 10 females;11 patients carried a mutation of NPM1 and all had a normal karyotype except one with t(10p12;11q14) (Table 1). All received 3+7+GO induction and achieved a CR. Therefore, we started consolidation (total ARA-C 8g/m2) + GO as inpatient. Ten patients (71%) reached the established threshold of 20 CD34+ /μL and were successfully harvested, while 4 patients (29%) failed mobilization. The median day of apheresis was D+26 from the start to chemotherapy (range 22- 39). The median number of circulating CD34+ cells on the day of collection was 35.9 cells/μL (range 20-2153 cells/μL). The median CD34+ harvested was 4.65 x 106/kg (range 1.8- 44.6 x 106/kg). In our cohort, 4 patients (28% of the entire cohort and 40% of the harvested patients) underwent ASCT, 3 achieved favourable engraftment, while in the last patient ASCT is ongoing. Several reasons prevented ASCT in the remaining 6 patients: 3 patients underwent allogeneic SCT (2 had positive MRD on harvested apheresis;1 was reclassified as high-risk ELN2017 due to RUNX1 mutation resulting from NGS panel), 2 refused ASCT and one suffered early relapse. Summary/Conclusion: In our patients, the addition of GO did not impair HSC mobilization and harvesting that was reached in about 71% of cases, similarly to the AML-10 trial of the EORTC and GIMEMA Leukemia Groups where 70% of patients were successfully harvested. Our data are particularly interesting because in the pivotal ALFA0701 study, only one patient underwent Autologous- SCT, but in the control arm. An important limit of our case-series is that only 4 patients were auto-transplanted, so we have scant data on engraftment. In particular, evaluating day to engraftment of platelets would be interesting, given the known increase of thrombocytopaenia in patients treated with GO. In conclusion, mobilization with GO is feasible and further studies are warranted to evaluate the effects of fractioned doses of GO on HSC mobilization and ASCT outcome;the ongoing trial GIMEMA AML1819 - EudraCT number 2019-003871-20 - will prospectively assess the effect of GO, but with lower doses of ARA-C (total ARA-C 6 g/m2). (Table Presented).

IMPACT OF DARATUMUMAB (DARA) ADMINISTRATION DURING TRANSPLANT- ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA (TE NDMM) INDUCTION ON STEM CELL (SC) MOBILIZATION COUNT AND POST-TRANSPLANT ENGRAFTMENT

Background: The combination of an anti-CD38 monoclonal antibody, Dara, to the main induction protocols (VRd, VTd,VCd) significantly improved the response rate of TE NDMM before transplantation. However, there is a concern regardingthe possible interference in the SC collection and bone marrow engraftment, since SC, to some degree, express CD38on their surface. In the MAX Dara study, Dara-CTd protocol was used sequentially close to the pre- and post-autologousstem cell transplantation-(ASCT) (D-30 and D + 30), in order to take advantage of the molecule's action as an in vivopurge. Aims: In this analysis, we examine the impact of the number of Dara doses administered pre-mobilization on CD34 cellcount, SC apheresis yield, and post-ASCT engraftment. Methods: This is a phase II, open-label single-center clinical trial. The original protocol was Dara-CTd for up to four 28-day induction cycles and Dara-Td for up to four 28 days consolidation cycles. C-1500 mg oral (PO) per cycle, duringcycles 1 to 4, T at 100-200 mg PO on days 1 to 28, during cycles 1-8, (d) at 160 mg PO per cycle, during cycles 1 - 8 andDara at 16 mg/kg/dose intravenous (IV) on days 1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 – 8. Because of the Covid pandemic we had to adapted the protocol and moving 5-6 consolidation cycles to be used asinduction, increasing the total dose of Dara from 12 to 16 and the number of cycles from 4 to 6 before ASCT. Granulocytecolony-stimulating factor (G-CSF) was administered alone for SC mobilization and plerixafor added based on day 4 preharvestperipheral blood CD34 counts. The target of SC collection was to enable the performance of one ASCT (>2,5 x 106/kg). PMN and platelet engraftment post-ASCT was defined as the first day with sustained PMN count >1000 x 106/L andindependence from platelet transfusion in the preceding 7 days with a count >20 x 109/L, respectively Results: From a total of 21 pts that were included, 19 pts completed mobilization. 12 pts received 12and 7 pts received 16 induction Dara doses, respectively. The median number (range) of daysbetween the last dose of Dara infusion and SC harvest was 23 (16-63) days. A total of five (26%) ptsreceived plerixafor during mobilization. More pts from Dara 16 doses needed plerixafor comparingwith Dara 12 doses (42% vs 16%), but without difference between the groups. Pts underwent amedian (range) of 1 (1-2) days of apheresis. The median number of CD34+ cells collected in the totalgroup was 3.94×106/kg, and no difference was found between Dara 12 vs 16 doses (3.61×106/kg vs4.01x106/kg), p = 0.27. There was no difference in the number of SC collected considering theresponse rate after induction > or < VGPR, and the last day of Dara use > or < 30 days, before SCharvesting. Hematopoietic reconstitution rates were similar for Dara 12 vs 16 doses, a median(range) of 11.0 (9-13) vs 11.0 (11-14) days was required to achieve sustained ANC > 1000 cells/mm3, and a median (range) of 12.0 (9-14) vs 11.0 (8-16) days was required to achieve sustained platelets> 20,000 cells/mm3 without transfusion, respectively. Summary/Conclusion: SC mobilization was feasible with Dara-CTd induction. Despite the more doses of Dara usebefore mobilization increases the need of plerixafor use, the SC number difference was not significant comparing Dara 12vs 16 doses (p = 0.3). The infusion of Dara close to harvest did not interfere with SC collection. Adding DARA to CTdallowed successful transplantation in pts with TE NDMM.

Mobilization and collection of hematopoietic stem cells in poorly mobilizable patients with multiple myeloma and lymphoma across Germany: Interim analysis of the OPTIMOB study

Autologous stem cell transplantation (ASCT) is an effective procedure for the treatment of multiple myeloma (MM) and lymphoma patients, but an adequate hematopoietic stem cell (HSC) yield is essential. In some patients (poor mobilizers, PM), stem cell mobilization is difficult leading to repeated apheresis sessions and increased patients' burden. Plerixafor (PLX), in combination with granulocyte colony stimulating factor (G-CSF) has been shown to effectively mobilize HSCs in PM patients. The OPTIMOB study is a prospective, multi-center, non-interventional, observational study to evaluate the current approach of HSC mobilization and collection regimen as well as ASCT procedures in German MM and lymphoma patients with special focus on PM patients. It is expected to enroll at least 210 poor mobilizers in this study. This prespecified interim analysis was performed after the complete documentation of the first 100 poor mobilizers. Until data cut-off in November 2020, 461 patients from 28 sites were enrolled. 66% of the patients suffered from MM, 63% were male and mean age was 59 years (SD: ±9.55). In total, 38% of the patients were classified as PM. PLX was used in 83% of the PM patients during mobilization, mainly due to low CD34+ cell content in peripheral blood (72% of the patients). Collection target was reached in 72% of patients receiving PLX versus 50% of PM who did not receive PLX. In total, 87% of PM patients underwent apheresis. Mean collection result of the first day of apheresis was 7.2 cells x106/kg bw (SD: ± 28.13) in PM patients with PLX versus 3.7 cells x106/ kg bw [SD: ±3.44]) in PM patients without PLX. ASCT was performed in 67% of the PM patients at the data cut-off. Adverse events occurred in 39% of the study population but were not related to PLX use. Mean number of induction cycles and apheresis days as well as the elapsed time between start of mobilization and transplantation did not seem to change in the study population during the SARS-CoV-2 pandemic. However, there was a tendency towards more frequently use of G-SCF for mobilization instead of chemotherapeutic based mobilization regimes. In Germany, a high number of MM and lymphoma patients appear to be PMs. This interim analysis of the OPTIMOB study shows that adding PLX to standardized mobilization strategies is associated with an adequate mobilization of CD34+ cells in 3 out of 4 PMs, allowing them to undergo ASCT.

Impact of Induction Treatment on Stem Cell Collection: A COVID Related Study

Introduction: Standard induction therapy for multiple myeloma consists of 3-6 cycles of bortezomib, lenalidomide, and dexamethasone (VRd) or carfilzomib, lenalidomide and dexamethasone (KRd). Receiving greater than 6 cycles of a lenalidomide containing regimen is thought to negatively impact the ability to collect sufficient CD34+ stem cells for autologous stem cell transplant (Kumar, Dispenzieri et al. 2007, Bhutani, Zonder et al. 2013). Due to the COVID-19 pandemic, at least 20 patients at University of Maryland Greenebaum Comprehensive Cancer Center (UMGCC) had transplant postponed, potentially resulting in prolonged exposure to lenalidomide containing induction regimens. Here, in the context of modern stem cell mobilization methods, we describe a retrospective study that suggests prolonged induction does not inhibit adequate stem cell collection for transplant. Methods: By chart review, we identified 56 patients with multiple myeloma who received induction with VRd or KRd and underwent apheresis or stem cell transplant at UMGCC between 10/1/19 and 10/1/20. Patients were excluded if they received more than 2 cycles of a different induction regimen, had a past medical history of an inborn hematological disorder, or participated in a clinical trial of novel stem cell mobilization therapy. We defined 1 cycle of VRd or KRd as 1 cycle of “lenalidomide containing regimen”. In accordance with routine clinical practice, we defined standard induction as having received 3-6 cycles of lenalidomide containing regimen and prolonged induction as having received 7 or more cycles. Results: 29 patients received standard induction (Standard induction cohort) and 27 received prolonged induction (Prolonged induction cohort) with lenalidomide containing regimens. The median number of cycles received by the Standard cohort was 6 (range 4-6), and the median number of cycles received by the Prolonged cohort was 8 (range 7-13). The frequency of KRd use was similar between patients who received standard induction and prolonged induction (27.58% vs. 25.93%, respectively). Standard induction and Prolonged induction cohorts were similar with respect to clinical characteristics (Fig 1), as well as the mobilization regimen used for stem cell collection (p = 0.6829). 55/56 patients collected sufficient stem cells for 1 transplant (≥ 4 x 10 6 CD34 cells/kg), and 40/56 patients collected sufficient cells for 2 transplants (≥ 8 x 10 6 CD34 cells/kg). There was no significant difference in the total CD34+ stem cells collected at completion of apheresis between standard and prolonged induction (10.41 and 10.45 x 10 6 CD34 cells/kg, respectively, p = 0.968, Fig 2). Furthermore, there was no significant correlation between the number of cycles of lenalidomide containing regimen a patient received and total CD34+ cells collected (R 2 = 0.0073, p = 0.5324). Although prolonged induction did not affect final stem yield, prolonged induction could increase the apheresis time required for adequate collection or result in more frequent need for plerixafor rescue. There was no significant difference in the total number of stem cells collected after day 1 of apheresis between patients who received standard or prolonged induction (8.72 vs. 7.96 x 10 6 cells/kg, respectively, p = 0.557). However, patients who received prolonged induction were more likely to require 2 days of apheresis (44% vs. 25%, p = 0.1625) and there was a trend toward significance in which patients who received prolonged induction underwent apheresis longer than patients who received standard induction (468 vs 382 minutes, respectively, p = 0.0928, Fig 3). In addition, longer apheresis time was associated with more cycles of lenalidomide containing regimen, which neared statistical significance (R 2 = 0.0624, p = 0.0658, Fig 4). There was no significant difference between standard and prolonged induction with respect to the frequency of plerixafor rescue. Conclusions: Prolonged induction with lenalidomide containing regimens does not impair adequate stem cell collection for autologou transplant. Prolonged induction may increase the apheresis time required to collect sufficient stem cells for transplant, but ultimately clinicians should be re-assured that extending induction when necessary is not likely to increase the risk of collection failure. [Formula presented] Disclosures: Badros: Janssen: Research Funding;J&J: Research Funding;BMS: Research Funding;GlaxoSmithKline: Research Funding.

Progression Free Survival (PFS) Analysis of Daratumumab (Dara), Cyclophosphamide, Thalidomide and Dexamethasone: A Quadruplet Intensified Treatment for Transplant Eligible Newly Diagnosed Multiple Myeloma (TE NDMM) Patients

Background: Newly drugs access for MM treatment still a challenge in some countries. One of the most available inductions for TE NDMM patients (pts) worldwide is cyclophosphamide (C), thalidomide (T) and dexamethasone (d)-(CTd). Dara the first anti- CD38, had been combined with VCd, VTd and VRd and markedly increased the depth and duration of the response. We hypothesized that Dara and CTd combination could be safe and allow deeper activity as an alternative protocol. Aims: The aims of this analysis were to evaluate Progression Free Survival (PFS) of Dara-CTd treatment and minimal residual disease (MRD) after one year of Dara maintenance. Primary endpoint of the study was to evaluate the VGPR after two consolidation cycles post-autologous stem cell transplantation (ASCT). Methods: This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, creatinine clearance > 30 ml/min, normal cardiac, renal and liver function and the Easter Cooperative Oncology Group (ECOG) performance status = 0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg oral (PO) on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose intravenous (IV) on days 1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 - 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16mg/Kg and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara at 16mg/Kg was used monthly as maintenance until progression or limiting toxicity. G-CSF was used for stem cell (SC) mobilization and plerixafor had been allowed whenever the pts need. The MRD was evaluated by next-generation flow (NGF) based and PET-CT was performed when the patient obtained NGF negativity or finished consolidation. PFS outcome was estimated using Kaplan-Meier method. All pts received antiviral, anti-pneumocystis and anti-thrombotic prophylaxis. Data cut-off was June 15, 2021. Results: The first pts was enrolled in November 2018. A total of 24 pts were included, the median age being 60 (range 37- 67 years), 23 (92%) were non-white, 5 (21%) had an R-ISS = 1, 12 (54%) had an R-ISS = 2 and 4 (16%), an R-ISS = 3. Six (25%) pts had high-risk chromosomal abnormalities [del17p, t(4;14) or t(14;16)]. To date, all pts have completed induction, 20 have received transplant and 17 have completed D+90 post-transplant assessment. No SC mobilization failure was observed, and six (30%) pts needed plerixafor use. By ITT analysis after a median follow up of 20 months the PFS at 12 and 18 months was 86%. No PFS difference was observed between different subgroups. Regarding response rates, after the end of induction (cycle 4), 19 (90%) of the pts obtained > PR and 8 (38%) obtained >VGPR, including three MRD negativity by NGF. 17 pts have completed two consolidation cycles after transplant and 94% obtained > VGPR as best response, 13 (76%) obtained MRD negativity by NGF and 10 (58%) had negative PET-CT. Seven (41%) pts had both flow and PET-CT negativity. Six pts completed one year of maintenance and five of them (83%) still MRD negativity by NGF. Four pts died from infection, two of them related with covid infection (one before transplant and one during maintenance). Another case post-transplant, considered not related to the investigational agent and one after consolidation, related to the investigational agent. Two pts have discontinued treatment due to progression - 1 before ASCT e 1 during maintenance. The most common adverse events (AEs) grades 3 and 4 were neutropenia (n = 12), infusion reaction (n = 7), neuropathy (n = 6), lymphopenia (n = 4), infection (n = 3), hypertension (n = 1) and rash (n = 1). Summary/Conclusion: The Daratumumab - CTd protocol is an active regimen capable of producing deep and sustainable responses and improve the PFS of NDMM TE pts with a favorable safety profile. Clinical trial information: NCT03792620. Disclosures: De Queiroz Crusoe: Janssen: Research Fund ng. Hungria: Sanofi: Honoraria, Other: Support for attending meetings/travel;Takeda: Honoraria;Abbvie: Honoraria;Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel.