Practice-changing updates on multiple myeloma: highlights from the 2024 ASH annual meeting

Abstract

Although multiple myeloma (MM) remains an incurable disease, the advancements in patient management are rapid and novel approaches emerge each year. At the last congress of the American Society of Hematology (ASH) 2024, several practice-changing studies were presented that challenge current standards of care for patients with multiple myeloma. The AQUILA study introduced monotherapy with daratumumab for patients with high-risk smoldering MM. For both transplant eligible and ineligible patients with symptomatic MM, anti-CD38-based quadruplets are now established as the primary standard regimens. Emerging data has demonstrated the utility of belantamab mafodotin, an anti-BCMA antibody drug conjugate, in combination with other standard therapies in early relapsed myeloma. Furthermore, a more simplified myeloma response assessment may be feasible. Overall, we provide a critical summary of key studies on MM from the last ASH meeting.

To the Editor,

Monitoring or treatment for smoldering myeloma?

The phase 3 AQUILA study evaluated the role of daratumumab monotherapy in delaying progression to active multiple myeloma (MM) in patients with high-risk smoldering MM (sMM) [1]. A total of 390 patients were randomized to receive either subcutaneous daratumumab for 3 years or active monitoring. At a median follow-up of 65.2 months, progression-free survival (PFS) was significantly improved in the daratumumab group compared to active monitoring (hazard ratio[HR] = 0.49; p < 0.0001). The median PFS was not reached for daratumumab, but it was 41.5 months for active monitoring, with 60-month PFS rates of 63.1% and 40.8%, respectively. Daratumumab significantly prolonged the median time to first-line anti-myeloma treatment (HR = 0.46; p < 0.0001). Positive trends were observed in favor of daratumumab for second progression-free survival and overall survival (OS). The 5-year OS rate was 93% versus 86.9% for daratumumab versus observation, respectively. The safety profile of daratumumab was acceptable, with grade 3/4 adverse events reported in 40% of patients, and low rates of treatment discontinuation. Severe infections were reported in 16.1% and 4.6% of the patients in the daratumumab and active surveillance group, respectively. These findings highlight the clinical benefit of early intervention with fixed-duration daratumumab monotherapy in preventing or delaying progression to active MM. However, defining the true high-risk patients who will derive benefit remains a challenge.

Can we stop maintenance after autologous transplant?

A prospective study assessed the outcomes of discontinuing lenalidomide maintenance in patients with newly diagnosed MM who achieved sustained measurable residual disease (MRD) negativity after autologous transplant [2]. Patients achieving sustained bone marrow MRD negativity for three years underwent PET/CT scans, and lenalidomide maintenance was discontinued if imaging confirmed MRD negativity. MRD testing continued every six months post-discontinuation. 51 among 194 (26.3%) evaluated patients fulfilled the criteria and discontinued maintenance. At a median follow-up of 32 months after discontinuation, 92% of patients remained MRD negative at 30 months, and 86% maintained negativity at three years. Eleven patients restarted lenalidomide after MRD conversion from negative to positive, with four progressing to second-line treatment. Prospective randomized trials are needed for validation.

New standards for first-line treatment

For transplant-eligible patients, the phase 3 GMMG-HD7 study showed the superiority of IsaVRd compared to VRd in terms of both MRD at 10^− 5 negativity rates (66% vs. 48%) and 3-year PFS rates (83% vs. 75%,p = 0.02) (Table 1) [3]. For transplant-ineligible patients, the phase 3 CEPHEUS study showed the superiority of DaraVRd compared to VRd in terms of MRD negativity rates at 10^− 5 and 10^− 6 (46.2% vs. 27.3%;p = 0.0001) in fit or intermediate-fit patients [4]. The estimated 54-month PFS rates were 81.0% and 69.5% for DaraVRd and VRd, respectively, in MRD-negative 10^− 5 patients.

Table 1 New treatment options for patients with newly diagnosed multiple myeloma

New standards for early relapse

Updated analyses of the DREAMM-7/8 studies confirmed the superiority of belamaf-bortezomib-dexamethasone (BelaVd) and belamaf-pomalidomide-dexamethasone (BelaPd) compared to daratumumab-bortezomib-dexamethasone (DVd) and pomalidomide-bortezomib-dexamethasone (PVd), respectively (Table 2) [5, 6]. The median PFS was prolonged with BelaVd compared to DVd (36.6 vs. 13.4 months, p < 0.001), as well as with BelaPd compared to PVd (not reached vs. 18.5 months, HR = 0.50, at first relapse). The MRD negativity rate was higher with BelaVd compared to DVd (25% vs. 10%), as well as with BelaPd compared to PVd (33% vs. 5%, at first relapse). Ocular adverse events were evident in more than 80% of the patients receiving belamaf.

Table 2 Belantamab mafodotin - based combinations for patients with multiple myeloma at early relapse

Furthermore, several studies on bispecific antibodies and novel chimeric antigen receptor (CAR) T-cells were presented, although there were no practice-changing phase 3 trials. Interestingly, autologous transplant before the administration of anti-BCMA CAR T-cells was associated with dismal outcomes [7], whereas the anti-GPRC5D bispecific antibody talquetamab emerged as a promising bridging therapy [8].

Can we simplify response assessment in multiple myeloma?

A secondary analysis of the phase 3 STAMINA study showed that omitting the 24 h urine response assessments changed less than 1% of the responses and this had no impact on PFS prediction [9]. A retrospective analysis of 434 patients enrolled in clinical trials showed that the simultaneous presence of at least two out of three criteria for disease progression (serum M-spike, urine U-spike, difference in serum free light chains) at a single timepoint was sufficient to establish myeloma progression without the need of a second confirmation [10].