Adverse outcome associated with daratumumab-based treatments in relapsed/refractory multiple myeloma patients with amplification of chromosome arm 1q21: a single-center retrospective experience

Barbieri, Emiliano; Maccaferri, Monica; Leonardi, Giovanna; Giacobbi, Francesca; Corradini, Giorgia; Lagreca, Ivana; Barozzi, Patrizia; Potenza, Leonardo; Marasca, Roberto; Luppi, Mario

doi:10.1007/s00277-022-04978-6

Cited by 7 publications

(7 citation statements)

References 10 publications

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“…2.3-39.4 months) in patients without amp(1q21), underscoring the difficulty of treating patients with this chromosomal abnormality. 28 Our findings on the effects of treatment with Kd in 1q21þ patients on the control arm of IKEMA are in line with prior results at short-term follow-up. 18 In that analysis, although with the limitations of cross-trial evaluations and different patient populations, treatment with Kd in IKEMA appeared to provide better disease control for 1q21þ patients than Pd in the ICARIA-MM study, compared to patients without 1q21þ.…”

Section: With 1q21þsupporting

confidence: 91%

Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long‐term outcomes in the Phase 3 IKEMA study

Facon,

Moreau,

Špicka

et al. 2024

Hematological Oncology

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Gain/amplification of 1q21 (≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma, can negatively affect prognosis, due to its involvement in resistance to anti‐myeloma therapy and disease progression. In this updated subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285) in relapsed/refractory multiple myeloma (RRMM), we evaluated progression‐free survival (PFS) and depth of response with the anti‐CD38 antibody isatuximab plus carfilzomib‐dexamethasone (Isa‐Kd) versus Kd, in 1q21+ patients and related subgroups, at long‐term follow‐up (44.2 months). Our analysis included patients with 1q21+ (≥3 copies, with/without high‐risk chromosomal abnormality [HRCA]), isolated 1q21+ (≥3 copies, without HRCA), gain(1q21) (3 copies, with/without HRCA), and amp(1q21) (≥4 copies, with/without HRCA). PFS benefit was achieved with Isa‐Kd versus Kd in patients with 1q21+ (HR 0.58, 95% CI: 0.37–0.92), with isolated 1q21+ (HR 0.49, 95% CI: 0.27–0.92), with gain(1q21), or amp(1q21), consistent with the overall population and prior interim 1q21+ subgroup analyses. Median PFS with Isa‐Kd versus Kd was 25.8 versus 16.2 months in 1q21+ patients and 38.2 versus 16.2 months in patients with isolated 1q21+. Clinically meaningful, higher rates of very good partial response or better, complete response or better (≥CR), minimal residual disease (MRD) negativity, and MRD negativity and ≥CR were reached with Isa‐Kd versus Kd in patients with 1q21+, isolated 1q21+, gain(1q21), or amp(1q21). In Isa‐Kd and Kd, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in 1q21+ patients, 36.2% versus 12.9% in patients with isolated 1q21+, 27.9% versus 13.5% in patients with gain(1q21), and 31.3% versus 20.0% in patients with amp(1q21), respectively. In conclusion, addition of Isa to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd, in 1q21+ patients at higher risk of progression, including patients with isolated 1q21+, gain(1q21), and amp(1q21), thus supporting Isa‐Kd an effective treatment option for patients with RRMM.

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Section: With 1q21þsupporting

confidence: 91%

Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long‐term outcomes in the Phase 3 IKEMA study

Facon,

Moreau,

Špicka

et al. 2024

Hematological Oncology

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“…134 In the same period, in RRMM patients without amp1q21 (n = 40), mPFS was not reached after a median follow-up of 18.4 months. 134 A real-world analysis of the Czech Registry of Monoclonal Gammopathies of Dara-Rd found no statistically significant benefit to Dara-Rd in patients with gain(1q21) versus patients who received Rd, with a hazard ratio of 1.33 for PFS by univariable Cox model. 135 Another study analyzed the prognostic impact of 1q21+ and gene expression profiling of 70 genes (GEP70) risk score in 81 RRMM patients treated with daratumumab-based regimens.…”

Section: Newly Diagnosed MMmentioning

confidence: 90%

“…No mPFS difference was observed for patients with 1q21+ versus patients without 1q21+ (24.5 months vs. 23.5 months, respectively) 129 . In contrast, a small real‐world retrospective study noted a suboptimal outcome in 8 consecutive daratumumab‐treated RRMM patients who had amp1q21, with an mPFS of 3.0 months after a median follow‐up of 10.01 months 134 . Only 1 patient achieved very good partial response, and 7 patients discontinued treatment, all due to disease progression 134 .…”

Section: Therapeutic Applications Of Anti‐cd38 Targeting Antibodiesmentioning

confidence: 91%

“…129 In contrast, a small real-world retrospective study noted a suboptimal outcome in 8 consecutive daratumumab-treated RRMM patients who had amp1q21, with an mPFS of 3.0 months after a median follow-up of 10.01 months. 134 Only 1 patient achieved very good partial response, and 7 patients discontinued treatment, all due to disease progression. 134 In the same period, in RRMM patients without amp1q21 (n = 40), mPFS was not reached after a median follow-up of 18.4 months.…”

Section: Newly Diagnosed MMmentioning

confidence: 99%

“…Only 1 patient achieved very good partial response, and 7 patients discontinued treatment, all due to disease progression 134 . In the same period, in RRMM patients without amp1q21 ( n = 40), mPFS was not reached after a median follow‐up of 18.4 months 134 . A real‐world analysis of the Czech Registry of Monoclonal Gammopathies of Dara‐Rd found no statistically significant benefit to Dara‐Rd in patients with gain(1q21) versus patients who received Rd, with a hazard ratio of 1.33 for PFS by univariable Cox model 135 .…”

Section: Therapeutic Applications Of Anti‐cd38 Targeting Antibodiesmentioning

confidence: 99%

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Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma

Bisht,

Fukao,

Chiron

et al. 2023

Cancer Medicine

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BackgroundCD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved—daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites.AimAmong the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38‐mediated T‐cell activation. Patients who respond to anti‐CD38 targeting treatment experience more marked changes in T‐cell expansion, activity, and clonality than nonresponders.ImplicationsResistance mechanisms that undermine the immunomodulatory effects of CD38‐targeting therapies can be tumor intrinsic, such as the downregulation of CD38 surface expression and expression of complement inhibitor proteins, and immune microenvironment‐related, such as changes to the natural killer (NK) cell numbers and function in the bone marrow niche. There are numerous strategies to overcome this resistance, which include identifying and targeting other therapeutic targets involved in, for example, adenosine production, the activation of NK cells or monocytes through immunomodulatory drugs and their combination with elotuzumab, or with bispecific T‐cell engagers.

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A predictive risk‐scoring model for survival prognosis of multiple myeloma based on gain/amplification of 1q21: Experience in a tertiary hospital in South‐Western China

Xiong,

Liang,

Tang

et al. 2024

Cancer Medicine

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BackgroundChromosomal 1q gains and amplifications (+1q21) are frequently observed in patients with newly diagnosed multiple myeloma (NDMM). However, the interpretation of the high‐risk (HR) prognostic implications stemming from 1q21 abnormalities remain challenging to implement effectively.MethodsIn a comprehensive analysis of 367 consecutive patients with symptomatic MM, we assessed the prognostic significance of +1q21 using FISH with a threshold of 7.4%. The patient cohort was randomly divided into a training set (66.5%, n = 244) and a validation set (33.5%, n = 133). A multivariate Cox regression analysis was conducted to identify significant prognostic factors associated with PFS. Weight scores were assigned to each risk factor based on the β‐value of the corresponding regression coefficient. A predictive risk‐scoring model involving +1q21 was then developed, utilizing the total score derived from these weight scores. The model's discriminative ability was evaluated using the AUC in both the training and validation sets. Finally, we compared the performance of the +1q21‐involved risk with the established R‐ISS and R2‐ISS models.ResultsUpon initial diagnosis, 159 patients (43.32%) exhibited +1q21, with 94 (59.11%) having three copies, referred to as Gain(1q21), and 65 (40.89%) possessing four or more copies, referred to as Amp (1q21). Both were significantly linked to a reduced PFS in myeloma (p < 0.05), which could be effectively mitigated by ASCT. The +1q21‐involved risk model, with an AUC of 0.697 in the training set and 0.725 in the validation set, was constructed including Gain(1q21), Amp(1q21), no‐ASCT, and TP53 deletion. This model, termed the ultra‐high‐risk (UHR) model, demonstrated superior performance in predicting shorter PFS compared to the R‐ISS stage 3 and R2‐ISS stage 4.ConclusionThe UHR model, which integrates the presence of +1q21 with no‐ASCT and TP53 deletion, is designed to identify the early relapse subgroup among patients with +1q21 in NDMM.

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Adverse outcome associated with daratumumab-based treatments in relapsed/refractory multiple myeloma patients with amplification of chromosome arm 1q21: a single-center retrospective experience

Cited by 7 publications

References 10 publications

Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long‐term outcomes in the Phase 3 IKEMA study

Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long‐term outcomes in the Phase 3 IKEMA study

Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma

A predictive risk‐scoring model for survival prognosis of multiple myeloma based on gain/amplification of 1q21: Experience in a tertiary hospital in South‐Western China

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