GPRC5D: a promising target

As in previous years, the field of multiple myeloma (MM) and plasma cell diseases was amongst those with the highest numbers of workshops, published abstracts and presentations at the Annual Meeting of the American Society of Hematology (ASH) in December 2022. From a clinician’s point of view the focus was on precancerous stages of multiple myeloma (MGUS, smouldering myeloma), on the optimised use of established therapeutic options and, of course, on the area of novel therapeutics.

From the high amount of contributions and innovations concerning multiple myeloma I choose five that appear to be in particular relevant for our daily clinical practice in the treatment of patients with multiple myeloma.

Bone marrow sampling in MGUS

From the results of a large population-based study in Iceland we know that precancerous stages of multiple myeloma (MGUS) were found in approximately 5% of persons aged over 40. The Icelandic study group has subsequently developed and prospectively verified a model and risk assessment tool to predict the need for bone marrow sampling in individuals with MGUS. The model is based on information concerning clonal type, M protein, free light chains, IgA, IgG and IgM; the corresponding website is available online.¹

The model allows an accurate assessment of the predicted risk of an MGUS patient having more than 10% bone marrow plasma cells which would then qualify for smouldering myeloma. With a chosen threshold of 5% predicted risk, the negative predictive value of the model was 97%. This model represents a shift from a group-based approach to an individual risk-adapted approach and may allow to defer bone marrow sampling in approximately 30% of MGUS patients who show risk features according to the conventional approach of the Mayo-Clinic-based risk assessment. External validation in independent cohorts is still required.²

Duration of lenalidomide maintenance therapy

In the Myeloma XI trial, a British study group presented a large dataset to shed light on the optimal duration of lenalidomide maintenance after high-dose chemotherapy in patients with newly diagnosed myeloma.³ In particular, it addresses the fact that the optimal duration of therapy in different risk groups remains still unknown, as well as the preferred regimen and long-term side effects.

In the trial’s approach, >1200 patients with newly diagnosed myeloma after treatment with different national protocols comprising induction and high-dose chemotherapy were randomised to lenalidomide 10mg on days 1–21 of a 28-day cycle vs. observation. Annual landmark analysis after 2 to 5 years compared the risk of myeloma progression in each of the time windows between both arms.

The data suggest that the benefit of lenalidomide maintenance therapy towards progression-free survival (PFS) extends over the treatment period of 4 to 5 years both in the standard risk, as well as in the high-risk and ultrahigh-risk populations with a hazard ratio (HR) of approximately 0.5. Surprisingly, even the negative minimal residual disease (MRD) as well as the sustained MRD-negative populations benefit towards PFS from lenalidomide maintenance therapy of a duration of 2 to 3 years with a HR of approximately 0.6.

Although this trial did not directly address the question when to terminate lenalidomide maintenance therapy, it clearly demonstrates that a 10mg maintenance therapy in the 21/28-schedule is active and provides PFS benefits over treatment periods of 4 to 5 years lenalidomide maintenance in patients with standard-risk or high-risk myeloma; and accordingly with 2 to 3 years therapy in patients with MRD-negative or sustained MRD-negative myeloma after high-dose chemotherapy in the first-line setting.

Effect of daratumumab as first-line therapy on quality of life in frailpatients

The addition of daratumumab to first-line treatment, either in the context of high-dose chemotherapy or without high-dose chemotherapy, is increasingly becoming standard practice in Switzerland. The MAIA study had tested the effect of adding daratumumab to the standard lenalidomide/dexamethasone (Rd) backbone in phase III and had provided an impressive improvement of PFS and recently also overall survival (OS).

However, the effect of this triple therapy (D-Rd) on health-related quality of life (HRQOL) particularly in frail patients is clinically important and was not yet explored. Presented data showed that in general, D-Rd preserved HRQOL scores longer than Rd. It maintained physical functioning almost twice as long as Rd (68 vs. 39 months), provided faster improved levels of pain control, while not worsening fatigue or cognitive symptoms. The data thus support the use of the D-Rd triplet in first-line treatment also in frail patients.⁴

Treatment concept for ultra high-risk myeloma

With the incorporation of CD38-antibodies in induction and consolidation/maintenance therapy, PFS outcomes of patients with myeloma bearing one high-risk cytogenetic feature approach those of standard-risk myeloma. This result identifies patients with at least 2 high-risk cytogenetic aberrations, the ultra high-risk myeloma, as the new myeloma subgroup which still lacks improvement of outcome in an era of new therapeutic options with a medium PFS of 18 to 24 months after quadruplet based high-dose chemotherapy and maintenance.

A British study group has introduced a novel concept in this patient population: After penta-drug induction and bortezomib-augmented autologous stem cell transplantation (ASCT), consolidation is greatly intensified with daratumumab, bortezomib, lenalidomide and dexamethasone (Dara-VRd) consolidation for 18 months, followed by Dara-R maintenance. After follow-up of 41 months in this national trial, the PFS at 30 months was 70%, which is unprecedented in this population.

The trial is ongoing and results of the maintenance phase with daratumumab lenalidomide remain pending. The trial highlights that prolonged quadruplet-based consolidation is a valid therapeutic option in ultra high-risk myeloma and plasma cell leukaemia.⁵

Novel T-cell-redirecting therapies targeting GPRC5D

GPRC5D is following BCMA as novel antigen target in multiple myeloma. Besides a number of T-cell-redirecting bispecific antibodies against BCMA mostly showing characteristics similar to teclistamab, T-cell-redirecting antibodies and CAR-T-cells against GPRC5D were presented at the ASH meeting. Talquetamab showed an overall response rate of greater than 70% (approximately half of it complete response, CR) in heavily pretreated, mostly triple- and penta-drug-refractory myeloma patients in a phase II trial with close to 300 patients.⁶

The PFS on a biweekly schedule was a remarkable 1 year while the toxicity was well manageable: Grade 3 cytokine release syndromes (CRS) or immune-effector-cell-associated neurotoxicities (ICAN) were 3% and 1%, respectively, with grade 3 or higher haematologic toxicity in around 30%. Infections were relatively rarely observed in this population and type of treatment, with 25% infections of grade 3 and 4. Since the antigen is also expressed in keratocytes, skin- and nail-toxicity as well as dysgeusia are observed with this agent as a new type of toxicity to deal with. However, the rate of discontinuation due to adverse events (AE) was low and close to 5%.

Likewise, CAR-T-cells against the same antigen were presented in the dose escalation phase I trial (BMS–986393) in a population of heavily pretreated patients with relapsed multiple myeloma.⁷

While the expected toxicities of CAR-T-cells in multiple myeloma were observed, no severe skin- or nail-toxicity was identified with GPRC5D-targeting CAR-T-cells. The overall response rate was 90% for the entire trial with 19 patients.