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Background: The four-drug combo has becoming one of the main induction treatment for TE NDMM patients (pts). We conducted a phase 2 study to assess the safety and preliminary efficacy of Cyclophosphamide (C), thalidomide (T), dexamethasone (d)-(CTd) and Dara combination. MAXDARA study has shown in the primary analysis with 21 included patients (pts), 4 and 8 pts MRD negativity after four induction cycles and two consolidation cycles post transplant, respectively. (Crusoe E et al ASH 2020, 2416 poster presentation). In the present analysis we evaluate the effect of deep response rate on PFS. Method(s): 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 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. The MRD was evaluated by next-generation flow (NGF) 10-6 and PET-CT was performed when the patient obtained NGF negativity or finished consolidation. PFS outcome was estimated using Kaplan-Meier method and PFS analysis were performed based on the different response rates. (Data cut-off was April 2022) Results: A total of 24 pts were included. The median age being 58 (range 37- 67 years), 15 (62.5%) pts were female, 22 (92%) were non-white, 6 (25%) had an R-ISS = 1, 12 (50%) had an R-ISS = 2 and 4 (16%), an R-ISS = 3. Sixteen (66.7%) pts were IgG isotype and Six (25%) had high-risk chromosomal abnormalities [1q+, del17p, t(4;14) or t(14;16)]. To date, 23 pts have completed induction, 21 performed transplant and 14 are still in treatment after one year of dara maintenance. By ITT analysis, 22 pts (91.6%) achieved (> PR) after 4 induction cycles. One pts achieved SD, one MR and one sCR. Eleven (39%) pts achieved PR, and 10 (35.7%) VGPR. After two consolidation cycles, ORR was 68%, 8 (28.6%) and 11 (39.3%) pts obtained sCR and VGPR, respectively. The best response during any time of the treatment were PR in 3 (12.5%) pts, VGPR in 12 pts (50%) and sCR in 8 (33.3%) pts. In a ITT analysis, NGF MRD 10-6 negativity were observed in 4(16.6%) after four induction cycles, and in 17 (70.8%) pts after two consolidation cycles post-ASCT. In a ITT analysis, after a median follow up (FU) of 26 months, the PFS was 37months for the entire group. The median PFS comparing sCR vs < VGPR were 37m vs 27m (p = 0.021), respectively, and comparing MRD negative by NGF vs no, had impacted even more on PFS with a median of 37m vs 16m (p = 0.004), respectively. The OS was not yet achieved and 83% of the patients still alive after a median FU of 27m. 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. Summary/Conclusion: The Daratumumab - CTd protocol is an active and safe regimen capable of producing deep and sustainable responses. The deeper response rate impacted on PFS, confirm that MRD negativity is critical to patient outcome. Copyright © 2022
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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.
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Background: Newly drugs access for MM treatment still a challenge in some countries. One of the most availableinductions 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 andduration of the response. We hypothesized that the combination of Dara and CTd could be safe and allow deeper activityas an alternative protocol. Aims: The primary endpoint was to evaluate the VGPR after two consolidation cycles post-autologousstem cell transplantation (ASCT). Secondary endpoints were the overall response rate during alltreatment phases and minimal residual disease (MRD), based on the International Myeloma WorkingGroup (IMWG) criteria that includes the next-generation flow (NGF) by the EuroFlow®and PET-CTand the safety profile. Methods: This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TENDMM, creatinine clearance > 30 mL/min, normal cardiac, renal and liver function and the EasterCooperative Oncology Group (ECOG) performance status = 0 - 2. The protocol was Dara-CTd for upto four 28-day induction cycles: C-500 mg oral (PO) on days 1,8 and 15, T at 100-200 mg PO on days1 to 28, (d) at 40 mg PO on days 1,8,15 and 22 and Dara at 16 mg/kg/dose intravenous (IV) on days1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 – 4, followed by ASCT. All ptsreceived up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16 mg/kg and (d) at 40 mg every other week, associated with T at 100 mg PO on days 1 - 28. Dara at 16 mg/kg was used monthly as maintenance until progression or limiting toxicity. G-CSF was used forstem cell (SC) mobilization and plerixafor had been allowed whenever the pts need. All pts receivedantiviral, anti-pneumocystis and anti-thrombotic prophylaxis. Results: The first pts was enrolled in November 2018. A total of 21 pts were included, the median age being 56 (range 37– 67 years), 19 (90%) were non-white, 3 (14%) had an R-ISS = 1, 12 (57%) had an R-ISS = 2 and 3 (14%), an R-ISS = 3. Five (24%) pts had high-risk chromosomal abnormalities [del17p, t(4;14) or t(14;16)]. To date, all pts have completedinduction, 19 have received transplant and 17 have completed D+90 post-transplant assessment. No SC mobilizationfailure was observed, and five (26%) pts needed plerixafor use. In an intention to treatment analysis, after the end ofinduction (cycle 4), 19 (90%) of the pts obtained > PR and 8 (38%) obtained >VGPR, including three MRD negativity byNGF. 17 pts have completed two consolidation cycles after transplant and 94% obtained > VGPR as best response, 12(70%) obtained MRD negativity by NGF and nine (53%) had negative PET-CT. Seven (41%) pts had both flow and PETCTnegativity. Three pts died from infection, one before transplant because of Covid infection, on post-transplant, considered not related to the investigational agent, and another after consolidation, related to the investigational agent. The most common nonhematological adverse events (AEs) grades 3 and 4 before ASCT were neuropathy (n = 6), infusion reaction (n = 7), infection (n = 2), hypertension (n = 1) and rash (n = 1). Summary/Conclusion: This is the first study that combined Dara with CTd as induction for TE NDMM pts. This presentdata has shown that the association of Dara-CTd achieved the primary end point once > 90% of the pts achieved VGPRafter two consolidations cycles, and safety profile was acceptable. Clinical trial information: NCT03792620.