Subcutaneous Daratumumab Plus Pomalidomide and Dexamethasone (D-Pd) Versus Pomalidomide and Dexamethasone (Pd) Alone in Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Overall Survival Results from the Phase 3 Apollo Study

Dimopoulos, Meletios A.; Terpos, Evangelos; Boccadoro, Mario; Delimpasi, Sosana; Beksaç, Meral; Katodritou, Eirini; Baldini, Luca; Symeonidis, Argiris; Bila, Jelena; Oriol, Albert; Mateos, María‐Victoria; Einsele, Hermann; Orfanidis, Ioannis; Kampfenkel, Tobias; Liu, Weiping; Kosh, Michele; Tran, Namphuong; Carson, Robin; Sonneveld, Pieter

doi:10.1182/blood-2022-163483

Cited by 16 publications

(19 citation statements)

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“…The addition of anti-CD38 monoclonal antibodies like daratumumab and isatuximab to PI and IMIDs has significantly improved overall response rates, depth of response and MRD negativity in patients with multiple myeloma both in NDMM 4,5,7 as well as in relapsed/refractory settings. [9][10][11][12][13][14] Patients with disease refractory to anti-CD38 moAb have a very poor response to subsequent lines of therapy as well as short survival, 18-21 yet such information is based on patients with RRMM. In the NDMM setting, F I G U R E 1 Progression-free survival (A) and overall survival (B) for patients with newly diagnosed multiple myeloma experiencing disease progression after first-line quadruplet therapy with intent to pursue autologous stem cell transplantation, according to the timing of treatment failure.…”

Section: Discussionmentioning

confidence: 99%

“…Because patients initially treated with QUADs are exposed to all three main classes of anti‐MM agents and treatment failure are uncommon, little is known about outcomes once there is disease progression. Additionally, all regimens developed in the context of large phase 3 trials for the treatment of patients with RRMM were tested in populations without prior exposure to anti‐CD38 MoAbs 9–14 . Therefore, there is no high‐level evidence to guide the management of transplant‐eligible patients with NDMM who experience disease relapse after up‐front quadruplet induction.…”

Section: Introductionmentioning

confidence: 99%

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Subsequent therapy and outcomes in patients with newly diagnosed multiple myeloma experiencing disease progression after quadruplet combinations

Ravi,

Bal,

Joiner

et al. 2024

Br J Haematol

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SummaryThe combination of anti‐CD38 monoclonal antibodies to a proteasome inhibitor, an immunomodulatory agent and dexamethasone (quadruplet—QUAD) in sequence with autologous stem cell transplantation (ASCT) leads to deep and durable responses in newly diagnosed multiple myeloma (NDMM). Disease progression in the first year post‐QUADs is uncommon. We analysed 274 consecutive NDMM patients treated with QUADs + ASCT. After a median follow‐up of 21.3 months, 20 patients had disease progression <18 months and 21 had progression ≥18 months after the onset of a QUAD regimen. All patients received subsequent anti‐MM therapy, and 38 were evaluated for response. Nine (22.0%) received T‐cell redirecting therapy as the next treatment, and 21 (51.2%) at some point in the treatment course. Response to next therapy was 26.3% for patients with progression <18 months and 52.6% for those with progression ≥18 months after the onset of a QUAD regimen. Median PFS on the next therapy was 2.5 months (95% CI 1.5–3.4) for those with progression <18 months and 7.0 months (95% CI 3.6–10.5) for those with progression ≥18 months. Efforts should focus on the early deployment of therapies with new mechanism of action for patients experiencing treatment failure after QUADs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Subsequent therapy and outcomes in patients with newly diagnosed multiple myeloma experiencing disease progression after quadruplet combinations

Ravi,

Bal,

Joiner

et al. 2024

Br J Haematol

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“…and s.c. daratumumab as monotherapy in patients with relapsed or refractory MM. 4 The results of this pivotal NI trial along with supportive efficacy and safety data from two other clinical trials (NCT03412565 and NCT03180736), where s.c. daratumumab was evaluated in combination with various standard background therapies in MM, 5,6 enabled the approval of s.c. daratumumab as monotherapy and in combination with standard background medications for all of the indications established for i.v. daratumumab in the European Union and for five out of seven indications in the United States.…”

Section: Review Indication Extrapolationmentioning

confidence: 99%

Development of Therapeutic Proteins for a New Subcutaneous Route of Administration After the Establishment of Intravenous Dosages: A Systematic Review

Leu

et al. 2023

Clin Pharma and Therapeutics

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Therapeutic proteins may first be developed as intravenous (i.v.) therapies with new subcutaneous (s.c.) dosage forms being subsequently developed to provide an alternative route of administration. As of August 2022, there have been 9 therapeutic proteins which were developed as a new s.c. dosage form after the approval of the corresponding i.v. product. This article provides a systematic review of prior experiences in the i.v. to s.c. switch development programs. We describe what types of clinical studies were conducted to support the i.v. to s.c. switch for these nine therapeutic proteins. Publicly available scientific advice from health authorities is summarized, particularly regarding recommendations on overall development strategy, dose selection, immunogenicity assessment, and indication extrapolation. The clinical data from these i.v. to s.c. development programs demonstrate that: (1) when switching from i.v. dosing to s.c. dosing, trough drug concentration (Ctrough) from s.c. dosing should not be inferior to i.v. dosing with average drug concentration (Cavg; equivalent to AUC, area under the curve after correcting for dosing intervals between i.v. and s.c. administration) being matched or non‐inferior to i.v. dosing; and (2) with appropriate s.c. dose regimens, treatment with s.c. therapeutic proteins can generally achieve similar efficacy and safety as the corresponding i.v. products, suggesting that the much higher maximum concentration (Cmax) after i.v. infusion as compared with that from s.c. injection is often not relevant to the treatment effect.

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“…Recent OS updates from phase III APOLLO trial demonstrated a significant OS advantage for this triplet compared to the doublet pomalidomide-dexamethasone (Pd) with a median OS of 34.4 vs. 23.7 months, in a population of 304 RRMM patients with a median of 2 prior LOT (range 1–5), whose 79.6% was lenalidomide-refractory. The most common grade 3/4 AEs was neutropenia (68% vs. 51%) whereas pneumonia were reported in 15% vs. 8% of patients and lower respiratory tract infections in 12% vs. 9%, respectively [ 140 ]. Pomalidomide-based triplet isatuximab-pomalidomide-dexamethasone (Isa-Pd) was approved for the treatment of RRMM patients with ≥2 previous lines of therapy, on the basis of results of the phase III ICARIA trial, having randomized 307 RRMM patients to receive the triplet vs. Pd.…”

Section: Sequential Therapy In Relapsed/refractory MM In Light Of New...mentioning

confidence: 99%

Current Main Topics in Multiple Myeloma

Morè¹,

Corvatta²,

Manieri³

et al. 2023

Cancers

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Multiple Myeloma (MM) remains a difficult to treat disease mainly due to its biological heterogeneity, of which we are more and more knowledgeable thanks to the development of increasingly sensitive molecular methods that allow us to build better prognostication models. The biological diversity translates into a wide range of clinical outcomes from long-lasting remission in some patients to very early relapse in others. In NDMM transplant eligible (TE) patients, the incorporation of mAb as daratumumab in the induction regimens, followed by autologous stem cell transplantation (ASCT) and consolidation/maintenance therapy, has led to a significant improvement of PFS and OS.; however, this outcome remains poor in ultra-high risk MM or in those who did not achieve a minimal residual disease (MRD) negativity. Several trials are exploring cytogenetic risk-adapted and MRD-driven therapies in these patients. Similarly, quadruplets-containing daratumumab, particularly when administered as continuous therapies, have improved outcome of patients not eligible for autologous transplant (NTE). Patients who become refractory to conventional therapies have noticeably poor outcomes, making their treatment a difficult challenge in need of novel strategies. In this review, we will focus on the main points regarding risk stratification, treatment and monitoring of MM, highlighting the most recent evidence that could modify the management of this still incurable disease.

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Subcutaneous Daratumumab Plus Pomalidomide and Dexamethasone (D-Pd) Versus Pomalidomide and Dexamethasone (Pd) Alone in Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Overall Survival Results from the Phase 3 Apollo Study

Cited by 16 publications

References 0 publications

Subsequent therapy and outcomes in patients with newly diagnosed multiple myeloma experiencing disease progression after quadruplet combinations

Subsequent therapy and outcomes in patients with newly diagnosed multiple myeloma experiencing disease progression after quadruplet combinations

Development of Therapeutic Proteins for a New Subcutaneous Route of Administration After the Establishment of Intravenous Dosages: A Systematic Review

Current Main Topics in Multiple Myeloma

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