EHA–EMN Evidence-Based Guidelines for diagnosis, treatment and follow-up of patients with multiple myeloma

Key points: 

-        Both positron emission tomography-computed tomography and diffusion-weighted imaging magnetic resonance imaging are considered complementary to bone marrow minimal residual disease (MRD) for the evaluation of MRD negativity.

-        Urine-based tests are not obligatory for the assessment of response or during follow-up, but should be performed at diagnosis and at the time of each relapse to exclude other pathologies (such as light chain amyloidosis or free light chain deposition disease).

-        Patients with low-risk or intermediate-risk smoldering multiple myeloma (MM) should be evaluated every 6 months or every 3–6 months, respectively, to assess their risk of progression to MM; risk assessment should be performed using the International Myeloma Working Group (IMWG) classification models.

-        Although approval by regulatory agencies is pending at the time of writing, daratumumab monotherapy for 3 years can be considered in patients with high-risk smoldering MM.

-        In patients aged <70 years without comorbidities, induction therapy followed by high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT) is recommended.

-        Regarding induction therapy before ASCT, DaraVRd (daratumumab, bortezomib, lenalidomide, dexamethasone) and IsaVRd (isatuximab, bortezomib, lenalidomide, and dexamethasone) provide the best risk–benefit profile to date among quadruplets and are recommended as the new standard-of-care (SOC) regimens, despite not being approved yet by the European Medicines Agency (EMA). DaraVTd (daratumumab, bortezomib, thalidomide, and dexamethasone) is another valid option in this setting, although it has not been compared directly with DaraVRd. If the above regimens are not available, VRd can be used. For all induction regimens, four to six cycles are recommended.

-        Collection of hematopoietic stem cells should be performed after three or four induction cycles.

-        HDM (200 mg/m²) is the recommended SOC conditioning regimen before ASCT.

-        To date, consolidation therapy after ASCT has not been established as an SOC approach. In patients who have received only four cycles of DaraVRd induction, two cycles of DaraVRd consolidation should be considered.

-        Tandem ASCT might be suitable in patients with genetically defined high-risk disease or in all patients who have received induction with bortezomib, dexamethasone and cyclophosphamide.

-        Lenalidomide was considered the SOC maintenance treatment after ASCT in all patients with MM. On the basis of progression-free survival results from the PERSEUS trial, the addition of daratumumab to lenalidomide is the new SOC.

-        Patients who are not eligible for ASCT but have an IMWG frailty score (FS) of <2 and are <80 years old can receive two new SOC regimens: IsaVRd and DaraVRd, although at the time of writing, DaraVRd is pending approval by the EMA. DaraRd is a valuable option in all transplant-ineligible patients, especially those with an IMWG FS of ≥1. A dexamethasone-sparing strategy (DaraR) should be considered in patients with an IMWG FS of ≥2. If none of the above-mentioned options is available, DaraVMP (daratumumab, bortezomib, melphalan, prednisone) or VRd can be used.

Allogeneic Hematopoietic Cell Donor Selection: Contemporary Guidelines from the NMDP/CIBMTR

Key points: 

See Table 2 and Figure 2 in the original paper for the summary of recommendations. 

-        Searching for all donor types should be performed concurrently.

-        Search prognosis tools based on patient human leukocyte (HLA) and ancestry can identify patients who may benefit from early consideration of an alternative donor source (haploidentical [haplo], mismatched unrelated donor [MMUD] or cord blood).

-        Enrolling patients in clinical trials should always be considered.

-        A suitable matched sibling donor is generally the first choice.

-        Matched unrelated donors (MUD) are generally the second choice.

-        Haplo and MMUD have similar outcomes using post-transplant cyclophosphamide (PTCy), and these sources should be considered upfront in a patient with a very unlikely search prognosis score.

-        Factors to consider in selection between these donor sources include prioritizing younger donor, avoiding donor-specific antibodies (DSA), logistic concerns, and available clinical trials.

-        Donors with a high titer DSA target should not be used.

-        In the calcineurin inhibitor setting: Avoid HLA-DPB1 non-permissive mismatches in MUD.

-        In the PTCy setting: HLA-DRB1 mismatched haplos may be protective against relapse.

-        HLA-DPB1 T-cell epitope non-permissive mismatching may be associated with better survival in haplo.

-        MUD and MMUD 7/8 outcomes are similar.

-        There is insufficient evidence to recommend prioritization of specific HLA mismatches when selecting between MMUDs.

-        Highly MMUDs (4-6/8 matched) can be considered.

-        Donors ≤ 30 years old should be prioritized to maximize overall survival.

-        Donor/recipient ABO matching may reduce post hematopoietic cell transplantation (HCT) transfusion burden.

-        Major ABO mismatches should be avoided in haplo and when using bone marrow (BM) grafts.

-        Donor cytomegalovirus serostatus may be considered in specific clinical cases (e.g., Severe Combined Immunodeficiency)

-        A large patient-donor weight discrepancy should be avoided in the setting of BM HCT.

Efficacy and safety of immunosuppressive therapy versus cyclosporine combined with avatrombopag in older adults with severe aplastic anemia: a multicenter prospective study [Clinical trial]

Highlights:  

The combination of cyclosporine A (CsA) +  avatrombopag (AVA) achieved comparable efficacy with superior safety compared to the combination of antithymocyte globulin + CsA + AVA in older adults newly diagnosed with severe aplastic anemia (SAA).

This trial (NCT05996393) compared antithymocyte globulin (ATG) +CsA + AVA and CsA + AVA in older adults with SAA. The patients were randomized to receive either ATG + CsA + AVA or CsA + AVA. Of 84 included patients, 42 were treated with ATG + CsA + AVA and 42 with CsA + AVA.

The primary endpoint was the hematological response at 6 months, which was represented by the objective response rate (ORR), including complete (CR) and partial response (PR). CR was defined as HGB > 120 g/L for males (110 g/L for females), platelet count > 100×10⁹/L, and absolute neutrophil count > 1.5×10⁹/L. With a median follow-up of 13 (0.3–17) months, the ORR at 3, 6, and 12 months, and the end of follow-up was 53.7%, 65.9%, 80.6%, and 71.4% in the ATG + CsA + AVA group and 61.9%, 73.2%, 77.4%, and 64.3% in the CsA + AVA group, respectively (p>0.05 at any time point). Three-month ORR was an independent predictor of 6-month CR rates (p=0.019). Patients in the ATG + CsA + AVA group showed a higher incidence of adverse events than those in the CsA + AVA group (64.3% vs. 35.7%, p=0.009). The rates of relapse (p=0.667), mortality (p=1.000), and clonal evolution (p=1.000) were comparable between the groups.

Venesection and resolution of erythrocytosis are not associated with reduced thrombotic risk in secondary and idiopathic polycythaemia: Results from a dual centre, 5-year retrospective study

Highlights: 

-        In idiopathic polycythemia, there is weak evidence of increased thrombotic risk, and for secondary polycythemia, specifically, there is an absence of evidence informing thrombotic risk, although at a population level, higher haematocrit (Hct) is associated with thrombosis.

-        Venesection itself is not without risk: It can induce iron deficiency, syncope, and nerve injury.

-        This study suggests that venesection for secondary/idiopathic polycythemia may not affect thrombosis risk.   The use of venesection in this population is potentially harmful and has time and cost implications for health services and patients.

-        The authors did not examine the effect of venesection on symptoms attributable to polycythemia.

Of 2360 JAK2 V617F-negative patients screened, the authors collected data on 206 patients with British Society for Haematology-defined secondary polycythemia who had 5 years of follow-up data. The median Hct at diagnosis was 0.51 (female) and 0.54 (male). 26% and 49% of patients had definite and probable secondary polycythemia, respectively. One or more (median 3) venesections were performed in 83 (40%) patients, and 29% of patients undergoing >1 venesection had no target Hct documented. Modelling venesection as a time-dependent variable in Cox proportional hazards analysis found no evidence of an association with thrombosis (hazard ratio: 0.88, 95% confidence interval: 0.36–2.17, p=0.79). In a multivariable analysis of thrombosis, the only statistically significant (p<0.05) association was with prior venous thrombosis. There was no association with venesection when modeled as a time-dependent variable.

Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus   Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study

Highlight:

Isatuximab (Isa) using an on-body injector (OBI) was noninferior to intravenous (IV), with both arms achieving similar overall response rate (ORR) and equivalent Isa exposure. OBI patients had markedly lower infusion reaction incidence versus IV. Patient satisfaction was higher for OBI versus IV.

The open-label, phase III IRAKLIA trial (NCT05405166) included patients with ≥1 prior line of therapy who were randomly assigned 1:1 to Isa OBI or IV plus pomalidomide and dexamethasone and treated until progression, unacceptable toxicity, or patient request. After 12-month median follow-up, the ORR was 71.1% (OBI) and 70.5% (IV; relative risk, 1.008; 95% confidence interval [CI], 0.903 to 1.126); the lower CI exceeded noninferiority margin). Grade ≥3 treatment-emergent adverse event incidences were 81.7% (OBI) and 76.1% (IV); infusion reaction incidences were 1.5% and 25.0%. Injection site reactions occurred in 0.4% of OBI injections (all grade 1-2); 99.9% of injections completed without interruption.