Randomized comparison between KTd and KRd induction followed by second randomization to carfilzomib in transplant‐ineligable patients with newly diagnosed multiple myeloma.
Background
The incorporation of anti‐CD38 monoclonal antibodies (mAb) in induction regimens of newly diagnosed transplant‐eligible multiple myeloma (MM) patients has been established as a new ...standard. However, the optimal strategy of stem cell mobilization in this context is not yet clear.
Study Design and Methods
From May 2020 till September 2022, we retrospectively reviewed patients receiving anti‐CD38 mAb‐based induction therapy followed by stem cell mobilization either in a steady‐state protocol (SSM) using 10 μg/kg granulocyte colony‐stimulating factor (G‐CSF) for 5 days or in a chemotherapy‐based protocol (CM) using 1–4 g/m2 cyclophosphamide and G‐CSF.
Results
Overall, 85 patients (median age 61 years) were included in the analysis. In total, 90 mobilization attempts were performed, 42 with SSM and 48 with CM. There was no significant difference in the median concentration of CD34+ cells in peripheral blood (PB) prior to apheresis between SSM and CM (61/μL vs. 55.4/μL; p = .60). Cumulative CD34+ yields did not differ between the groups with median of 6.68 and 6.75 × 106/kg body weight, respectively (p = .35). The target yield (≥4 × 106 CD34+ cells/kg body weight) was reached in 88% (CM) and 86% (SSM), with a high proportion even after a single apheresis session (76% vs. 75%).
Plerixafor was found to be more frequently used in SSM (52%) than in CM (23%; p < .01). A total of 83 patients underwent autologous transplantation and all were engrafted.
Conclusions
Stem cell collection in patients undergoing anti‐CD38‐based induction therapy is feasible with either CM or SSM, although SSM more frequently requires plerixafor.
Sequential genotyping for phenotype‐driver mutations in JAK2 (exon 14), CALR (exon 9), and MPL (exon 10) is recommended in patients with myeloproliferative neoplasms. Yet, atypical JAK2‐ and ...MPL‐mutations were described in some triple‐negative patients. Whether noncanonical and/or concomitant JAK2‐ and MPL‐mutations exist in myelofibrosis (MF) regardless of phenotype‐driver mutations is not yet elucidated. For this, next‐generation sequencing (NGS) was performed using blood genomic DNA from 128 MF patients (primary MF, n = 93; post‐ET–MF, n = 18; post‐PV–MF, n = 17). While no atypical JAK2‐ or MPL‐mutations were seen in 24 CALR‐positive samples, two JAK2‐mutations c.3323A > G, p.N1108S; c.3188G > A, p.R1063H were detected in two of the 21 (9.5%) triple‐negative patients. Twelve of the 82 (14.6%) JAK2V617F‐positive cases had coexisting germline JAK2‐mutations JAK2R1063H, n = 6; JAK2R893T, n = 1; JAK2T525A, n = 1 or at least one somatic MPL‐mutation MPLY591D, n = 3; MPLW515 L, n = 2; MPLE335K, n = 1. Overall, MPL‐mutations always coexisted with JAK2V617F and/or other MPL‐mutations. None of the JAK2V617F plus a second JAK2‐mutation carried a TET2‐mutation but all patients with JAK2V617F plus an MPL‐mutation harbored a somatic TET2‐mutation. Four genomic clusters could be identified in the JAK2V617F‐positive cohort. Cluster‐I (10%) (noncanonical JAK2mutated (mut) + TET2wildtype (wt)) were younger and had less proliferative disease compared with cluster‐IV (5%) (TET2mut + MPLmut). In conclusion, recurrent concomitant classical and/or noncanonical JAK2‐ and MPL‐mutations could be detected by NGS in 15.7% of JAK2V617F‐ and MPLW515‐positive MF patients with genotype‐phenotype associations. Many of the germline and/or somatic mutations might act as “Significantly Mutated Genes” contributing to the pathogenesis and phenotypic heterogeneity. A cost‐effective NGS‐based approach might be an important step towards patient‐tailored medicine.
Introduction
Light chain involvement is observed in almost every patient (pt) with newly diagnosed multiple myeloma (MM). Owing to a relatively short half-life, rapid reduction in the involved free ...light chain (iFLC) is of potential prognostic value.
Methods
This retrospective analysis included 92 pts with newly diagnosed MM treated with bendamustine, prednisone, and bortezomib (BPV).
Results
After a median number of two (range 1–5) BPV cycles, the majority of pts (
n
= 86; 93%) responded with either sCR (
n
= 21), CR (
n
= 1), nCR (
n
= 25), VGPR (
n
= 20), or PR (
n
= 19). PFS and OS at 48 months were 39% and 67%, respectively. At baseline, 79 out of 92 pts (86%) had iFLC levels above the upper standard level and an abnormal ratio of involved to uninvolved free light chain ≥ 8. In a subgroup analysis of these pts, we evaluated the prognostic importance of an early reduction of the iFLC during the first two BPV cycles. A reduction ≥ 50% of the iFLC on day 8 of the first cycle was observed in 31 of 69 pts. These pts had a significantly better median PFS of 49 months as compared to 20 months in 38 pts with a lower iFLC reduction (
p
= 0.002). In contrast, OS did not differ significantly with a 48 months survival of 77% vs 69% (
p
> 0.05).
Conclusion
These results indicate that a rapid decrease in the iFLC on day 8 is an early prognostic marker for newly diagnosed MM pts undergoing BPV treatment.
Understanding the impact of induction and maintenance therapy on patients’ quality of life (QoL) is important for treatment selection. This study aims to compare patient‐reported QoL between patients ...treated with KTd or KRd induction therapy and K maintenance therapy or observation. QoL was assessed using the EORTC QOL‐C 30 and QOL‐MY20 questionnaires in the AGMT‐02 study, in which 123 patients with newly diagnosed transplant ineligible multiple myeloma were randomized to nine cycles of either KTd or KRd induction therapy, followed by 12 cycles of K maintenance therapy, or observation. Longitudinal assessments showed statistically significant improvements in global health‐related QoL, various disease symptoms and pain for both treatment regimens. KTd improved insomnia and fatigue, and KRd improved physical functioning. Cross‐sectional comparisons indicated a “slight” superiority of KTd over KRd in several scales, with the exception of higher neuropathy scores with KTd. During maintenance, longitudinal comparisons showed no statistically significant changes. Cross‐sectional comparisons revealed a “slight” improvement in cognitive functioning during carfilzomib therapy, but a worsening in most other QoL scales. Induction therapy led to improvements in most QoL items, while maintenance therapy with K maintenance was associated with “slight” or “moderate” impairments in several QoL scales compared with the observation group.
Patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT) have lower survival rates and may benefit from frontline regimens that include novel ...agents. This Phase 1b study (NCT02513186) evaluated preliminary efficacy, safety, and pharmacokinetics (PK) of isatuximab, an anti-CD38 monoclonal antibody, combined with bortezomib-lenalidomide-dexamethasone (Isa-VRd) in patients with NDMM ineligible for/with no intent for immediate ASCT. Overall, 73 patients received four 6-week induction cycles of Isa-VRd, then maintenance with Isa-Rd in 4-week cycles. In the efficacy population (n = 71), the overall response rate was 98.6%, with 56.3% achieving a complete response or better (sCR/CR), and 36/71 (50.7%) patients reaching minimal residual disease negativity (10
sensitivity). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 79.5% (58/73) of patients but TEAEs leading to permanent study treatment discontinuation were reported in 14 (19.2%) patients. Isatuximab PK parameters were within the previously reported range, suggesting that VRd does not alter the PK of isatuximab. These data support additional studies of isatuximab in NDMM, such as the Phase 3 IMROZ study (Isa-VRd vs VRd).
Introduction
Autologous stem cell transplantation (ASCT) is the standard treatment for younger patients with newly diagnosed multiple myeloma (MM). However, due to restrictive exclusion criteria, ...more than half of eligible patients are usually excluded from transplant studies.
Methods
This retrospective monocentric analysis included 540 patients with MM who received an ASCT between 1996 and 2019.
Results
Up to 2005, induction therapy consisted mainly of conventional chemotherapies, e.g. vincristine/doxorubicin/dexamethasone (VAD). In the following years, the triple-combinations based on bortezomib coupled with doxorubicin/dexamethasone (PAD), melphalan/prednisolone (VMP), cyclophposphamide/dexamethasone (VCD) or bendamustine/prednisolone (BPV) became the most popular treatment options. A progressive improvement in PFS was observed in patients treated with the two current induction therapies BPV (47 months) or VCD (54 months) compared to VAD (35 months,
p
< 0.03), PAD (39 months,
p
< 0.01 and VMP (36 months,
p
< 0.01). However, there was no significant difference in median OS (VAD 78, PAD 74, VMP 72, BPV 80 months and VCD not reached). In our analysis, we also included 139 patients who do fulfill at least one of the exclusion criteria for most phase 3 transplant studies (POEMS/amyloidosis/plasma cell leukemia, eGFR < 40 mL/min, severe cardiac dysfunction or poor general condition). Outcome for these patients was not significantly inferior compared to patients who met the inclusion criteria for most of the transplant studies with PFS of 36 vs 41 months (
p
= 0.78) and OS of 78 vs 79 months (
p
= 0.34).
Conclusions
Our real-world data in unselected pts also stress the substantial value of ASCT during the first-line treatment of younger MM pts.
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