News of the Week

This review presents unified, evidence-based first-line treatment recommendations from the Intergroupe Francophone du Myélome (IFM), covering transplant-eligible (TE) and transplant-ineligible (TI) newly diagnosed multiple myeloma (MM) within a single framework and common methodology.

Key points:

• Anti-CD38-VRd quadruplets are now the standard of care for TE patients and an important option for TI patients. In TE patients, daratumumab plus bortezomib-lenalidomide-dexamethasone(VRd) and isatuximab-VRd, informed respectively by the PERSEUS and GMMG-HD7 trials, are now the reference induction regimens, followed by autologous stem cell transplantation (ASCT), optional consolidation, and daratumumab-lenalidomide maintenance. See Figure 2 in original paper.
• Duration: 4 to 6 cycles of 28 days. Option 1: 4 induction cycles + 2 post-ASCT consolidation cycles. Option 2: 6 induction cycles without consolidation.
• Stem cell collection should be performed after the 3rd induction cycle, with plerixafor if required; the usual target is a graft of 2–3 × 10⁶ CD34+ cells/kg. Treatment should not be switched in patients with only a partial response after 4–6 induction cycles: ASCT remains the most effective means of deepening response [strong recommendation].
• In TI patients, daratumumab lenalidomide-dexamethasone (DRd), informed by the MAIA trial, remains the treatment backbone. See Figure 1 in original paper.
• Stratify all TI patients according to frailty using a frailty score (the validated International Myeloma Working Group [IMWG] score, or the simplified IFM score used in routine French practice), to adapt treatment intensity, and define high-risk MM status by next-generation sequencing-based genomic profiling according to Consensus Genomic Staging [panel consensus; strong recommendation].
• In fit patients (up to age 80 years, without major functional impairment), anti-CD38-VRd quadruplets — Isatuximab-VRd or daratumumab-VRd — are the new standard of care, with weekly bortezomib to limit neurotoxicity [strong recommendation; high certainty]. Once-weekly bortezomib is an acceptable substitution for the twice-weekly schedule used in the IMROZ and CEPHEUS registrational trials, particularly to reduce the risk of peripheral neuropathy; a twice-weekly schedule may still be preferred during the first induction cycle in patients with high tumor burden, or with bone or renal complications, to achieve rapid antitumor activity.
  • Dexamethasone can be discontinued early (after 2 cycles, as evaluated in the IFM2017-03 trial), and bortezomib can be stopped at 12 months or earlier depending on the efficacy/tolerability balance [conditional recommendation; moderate certainty].
  • Daratumumab-Rd (or Isatuximab-Rd) remains an equivalent option in these patients, in the absence to date of a demonstrated progression-free survival superiority of Isatuximab-VRd or Daratumumab-VRd over Daratumumab-Rd [conditional recommendation; moderate certainty].
• In frail patients, the recommended strategy is corticosteroid-sparing DR (daratumumab + lenalidomide, with dexamethasone discontinued after the first two cycles), validated by IFM2017-03 11 [strong recommendation; moderate-to-high certainty].
• In certain clinical situations, starting lenalidomide from cycle 1 day 1 may be difficult to manage (e.g.,significant baseline cytopenias or renal impairment). In these situations, an anti-CD38 monoclonal antibody plus Vd (without lenalidomide) or Daratumumab-VMP (bortezomib-melphalan-prednisone) can be proposed, primarily for the first cycles, with a prompt return to a quadruplet or triplet anti-CD38-(V)Rd regimen once feasible [panel consensus].

Key points:

• Mantle cell lymphoma (MCL) has a heterogeneous clinical course, ranging from indolent to highly aggressive.
• With a median age of approximately 72 years at diagnosis, patient characteristics influence prognosis and treatment tolerability.
• TP53 mutations or deletions, blastoid histology, and a high Ki-67 proliferation index ( ≥30% [Europe] or ≥50% [USA] ) consistently identify patients at high risk of relapse.
• MCL is difficult to cure, relapses are common, and treatments can cause severe side-effects.
• Historically, treatment stratification has relied on age and transplant eligibility, commonly using a cutoff age of 65 years. As the field moves away from routine use of high-dose chemotherapy (in combination with CD20-directed monoclonal antibodies) and autologous stem-cell transplantation (consolidation therapy), this approach is increasingly inadequate.
• For young and fit patients, the experimental arm used in the TRIANGLE trial (induction chemotherapy [in combination with rituximab] plus Bruton tyrosine kinase inhibitor [BTKi] and maintenance rituximab) should be the preferred control arm.
• For patients who are frail, options for the standard arm are more diverse, but is likely a chemotherapy or chemotherapy-free treatment containing a BTKi.
• T-cell directed therapy with chimeric antigen receptor T-cell therapy and CD20 × CD3 bispecific antibodies have shown promising efficacy and are today moving into earlier lines of therapy.
• Positive measurable residual disease serves as a powerful surrogate endpoint to identify patients with an inadequate treatment response who might benefit from treatment modification. See Figure 3 in original paper.
• Patients who are treatment-naïve and relapsed or refractory should be analysed separately, as their biology and therapeutic receptiveness differ substantially.
• Markers of indolent MCL, toxicity, and tolerability need to be further refined and might permit chemotherapy-free approaches.

Highlights:

• Consolidation therapy for primary CNS lymphoma (PCNSL) includes high-dose chemotherapy with autologous stem-cell transplantation (HCT-ASCT), yet its efficacy compared with non-myeloablative chemoimmunotherapy remains uncertain.
• In the largest randomised trial in untreated PCNSL to date, HCT-ASCT significantly improved progression-free survival (PFS) and overall survival (OS) compared with non-myeloablative consolidation in patients who had completed induction treatment, establishing it as the preferred consolidation strategy in fit patients.
• Approximately one-third of patients in MATRix/IELSG43 did not reach randomisation due to induction toxicity or early progression, underscoring that optimisation of induction regimens is urgently needed.

The MATRix/IELSG43 trial (ClinicalTrials.gov; NCT02531841) is a multicentre study involving 56 centres across five European countries, and the first phase 3 trial to directly compare thiotepa-based HCT-ASCT with non-myeloablative R-DeVIC (rituximab plus dexamethasone, etoposide, ifosfamide, and carboplatin) consolidation after a uniform MATRix induction (high-dose methotrexate, high-dose cytarabine, thiotepa and rituximab) in patients with newly diagnosed PCNSL. 360 patients were enrolled, 346 (94%) started induction treatment, and 230 were randomly assigned; 229 patients were analysed (R-DeVIC group, n=115; HCT–ASCT group, n=114).  After a median follow-up of 45.3 months, among patients up to 70 years of age who had at least a partial response after MATRix, HCT-ASCT significantly improved 3-year PFS (primary endpoint) (78% vs 51%; hazard ratio [HR] 0.43; p=0.0003) and OS (86% vs 71%; HR 0.46) compared with R-DeVIC, with acceptable toxicity in experienced centres.

Highlights:

• Blinatumomab, a bispecific T-cell engager targeting the CD19 antigen on B cells, may offer an option to safely replace cycles of traditional chemotherapy in pediatric patients with newly diagnosed high-risk B-cell acute lymphoblastic leukemia (ALL).
• In children with newly diagnosed high-risk B-cell ALL, replacement of two cycles of highly toxic conventional chemotherapy with blinatumomab resulted in a significantly greater percentage of patients with event-free survival (EFS) at 4 years.

In this trial (AIEOP-BFM ALL 2017), 709 of 768 children with high-risk B-cell ALL were eligible for randomization (1:1 ratio), to receive two cycles of blinatumomab (blinatumomab group; n=358) or two cycles of chemotherapy (control group; n=351) after consolidation. A planned interim analysis at a median follow-up of 2.9 years showed an estimated 4-year EFS of 83.0% (95% confidence interval [CI], 77.4 to 87.4) in the blinatumomab group and 70.3% (95% CI, 63.8 to 75.9) in the control group (P=0.0002 in an intention-to-treat analysis). The estimated hazard ratio for a primary end-point event (blinatumomab vs. control) was 0.51 (95% CI, 0.35 to 0.73) as assessed with a Cox model. Infection related to the trial treatment occurred in 23.9% of patients in the blinatumomab group and in 69.4% of those in the control group (P<0.001). Neurotoxic events were reported in 12.0% and 3.2%, respectively (P<0.001). The pathogenesis of these neurotoxic events observed during blinatumomab administration may be due to blood–brain barrier dysfunction caused by overactivation of the peripheral immune response and endothelial inflammation. Cytokine release syndrome of grade 2 or higher occurred in 1.1% of patients in the blinatumomab group.