Rajkumar Previews CAR-T Updates, Elranatamab Findings in Multiple Myeloma Ahead of ASH 2022

S. Vincent Rajkumar, MD

The 2022 ASH Annual Meeting will return to New Orleans, Louisiana for a hybrid meeting starting December 10 for 4 days packed with riveting and potentially practice-changing results across hematologic malignancies, including multiple myeloma, acute and myeloid leukemias, and myeloproliferative neoplasms, and more.

Specifically in multiple myeloma, data related to dexamethasone-sparing regimens, bispecific antibodies, and more are eagerly anticipated as the findings may hold the potential to shift clinical practice.

S. Vincent Rajkumar, MD, professor of medicine at Mayo Clinic and a 2019 Giant of Cancer Care® winner in the multiple myeloma category, previewed his top 5 abstracts in multiple myeloma with OncLive^® ahead of the meeting this weekend.

A dexamethasone sparing-regimen with daratumumab and lenalidomide in frail patients with newly diagnosed multiple myeloma: efficacy and safety analysis of the phase 3 IFM2017-03 trial (Abstract 569).

The phase 3 IFM2017-03 trial evaluated daratumumab (Darzalex) plus lenalidomide (Revlimid) without long-term dexamethasone and compared that with lenalidomide and dexamethasone (Rd) in frail patients with newly diagnosed multiple myeloma. In the analysis at the 2022 ASH Annual Meeting, investigators will present on response rates and safety.

In the abstract, data showed that the overall response rate (ORRs) was 89% with daratumumab and lenalidomide vs 77% with Rd, and the very good partial response rates were 58% and 42%, respectively. The dexamethasone-free regimen also showed a favorable safety profile.

“Dexamethasone is an important component of myeloma therapy but does carry significant side effects. Several years ago, we showed that low-dose dexamethasone [at 40 mg once a week] had less toxicity and better survival that the pulsed high dose dexamethasone that was commonly used at the time.1

But even low-dose dexamethasone can be challenging especially for elderly and frail patients. This randomized trial being presented at ASH shows that, in frail patients, you may be able to omit dexamethasone from frontline therapy. It is hard to do a randomized trial in frail patients, and I congratulate the IFM for doing such a trial, and for testing a dexamethasone-free regimen.”

Elranatamab, a BCMA targeted T-cell engaging bispecific antibody, induces durable clinical and molecular responses for patients with relapsed or refractory multiple myeloma (Abstract 158).

Elranatamab is being evaluated in the ongoing, phase 1 MagnetisMM-1 trial (NCT03269136) in patients with relapsed/refractory multiple myeloma. The subcutaneous BCMA T-cell engaging bispecific antibody led to clinical and molecular responses In this patient population, with a 64% ORR, a 38% complete response (CR) or better, and 100% of evaluable patients achieving minimal residual disease (MRD) negativity.

Beyond efficacy, results from the trial will also include safety, pharmacokinetics, and pharmacodynamics data with elranatamab.

“Data on numerous bispecific antibodies for the treatment of relapsed and refractory myeloma are being presented at ASH this year. They include bispecifics targeting BCMA ([ranatamab, teclistamab, alnuctamab, REGN5458, Abbv383), FcRH5 (cevostamab), and GPRC5D (talquetamab, RG6234). All of these are promising, and provides great hope for the future of myeloma therapy. I picked the elranatamab trial to highlight because it is in an advanced stage of development, and shows a 54% response rate in patients with prior BCMA-targeted therapy.”

Differences in single cells between BCMA-targeting CAR T-cell therapy responders and non-responders reveals initial resistance and acquired resistance are driven by different factors (Abstract 869)

Investigators conducted single-cell RNA sequencing and TCR-seq on bone marrow samples from patients treated with idecabtagene vicleucel (Abecma) in the KarMMa study (NCT03361748) using 59,194 cells (range 758 to 8543 per sample) and bulk whole-genome sequencing (n = 101) and bulk RNA sequencing (n = 161) of CD138-positive multiple myeloma cells.

Findings showed that by bulk whole-genome sequencing, a monoallelic loss of BCMA was detected in 4% of pretreatment samples. This increased to 12% at relapse; 6% of samples had a bi-allelic loss of BCMA at relapse. These data suggest that plasma cells’ baseline characteristics have an impact on initial response to CAR T-cell therapy.

“Despite the promise of CAR-T therapy in myeloma, we face issues with initial resistance in some patients, and eventual relapse in most. We need to understand the mechanisms of resistance to BCMA-directed CAR-T therapy in myeloma. This abstract investigates the mechanisms of resistance to BCMA-targeted CAR T-cell therapy using single-cell analysis. The authors show that initial resistance is not driven by dysfunctional immune system but baseline features of the myeloma cells themselves.”

Defining the optimal duration of lenalidomide maintenance after autologous stem cell transplant – data from the Myeloma XI trial (Abstract 570)

The randomized phase 3 Myeloma XI study enrolled newly diagnosed patients with multiple myeloma who have pathways for both transplant eligible and ineligible disease and evaluated the benefit of maintenance therapy with lenalidomide or observation.

While there appeared to be improved progression-free survival at 3 years, there seems to be a drop off in benefit around 4 to 5 years, which was found to be earlier in patients with MRD negativity.

“Maintenance therapy with lenalidomide is standard of care in myeloma. One issue we wrestle with due to cost and long-term toxicity is the optimal duration of maintenance. In this abstract, the authors analyzed the [United Kingdom] Myeloma XI trial to address this issue. They found that maintenance therapy for a period of 3 years benefited both MRD-positive and MRD-negative patients. However, after 4 to 5 years from starting maintenance, benefit diminishes, and does so earlier in MRD-negative patients than MRD-positive patients. This trial provides guidance for patient care in current clinical practice.”

Predicting the need for upfront bone marrow sampling in individuals with mgus: derivation of a multivariable prediction model using the prospective population-based Istopmm cohort (Abstract 107)

Because most patients with monoclonal gammopathy of undetermined significance (MGUS) do not have a multiple myeloma diagnosis, researchers developed a multivariable model to predict the risk of 10% or higher bone marrow plasma cells to inform the decision to obtain a bone marrow sample.

In the 1000-patient study of the multivariable model, data showed that, while it needs external validation, it shows the potential to decrease the number of patients who are unnecessarily exposed to bone marrow sampling. Authors noted in the abstract that it will also improve the efficiency and cost-effectiveness of the diagnostic evaluation of MGUS.

“Monoclonal gammopathy of undetermined significance [MGUS] is an asymptomatic plasma cell disorder present in approximately 5% of the general population above the age of 50. Due to increasing use of sensitive laboratory tests, the diagnosis of MGUS is encountered frequently in the clinic. Most represent low-risk MGUS with very low risk of progression. Not everyone with a presumptive MGUS needs a bone marrow biopsy. The iStopMM trial data being presented provides a new model that limits unnecessary bone marrow biopsies.”

Reference

1. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11(1):29-37. doi:10.1016/S1470-2045(09)70284-0