Patients With NDMM Who Fail QUAD Treatment Within 18 Months Show Poor Response to Subsequent Treatments

For patients with newly diagnosed multiple melanoma (NDMM), triplet therapy with a proteasome inhibitor, an immunomodulatory agent, and dexamethasone has been the standard therapy. Patients with relapsed or refractory MM have a choice of therapy that is primarily based on patients’ prior exposure and refractoriness to previous anti-MM agents; however, there is no high-level evidence that can guide the management of patients with NDMM who are eligible for transplant. Authors of a study published in the British Journal of Haematology analyzed a dataset of patients with NDMM who were treated with quadruplet regimens (QUADs) with the intent to proceed with stem cell transplantation (ASCT) treatment. The investigators determined which patients had relapsed or refractory disease after the induction of QUAD as well as outcomes of following therapeutic methods.

This retrospective analysis included patients with NDMM who are eligible for transplant (NDMM-TE) and beginning administration of QUAD therapy. Every 2 months, all patients underwent a follow-up with history, physical examination, serum, and urine protein quantification as well as a bone marrow examination when necessary. Within this patient population, individuals who had disease progression after the initiation of therapy or ASCT, regardless of the use of maintenance therapy, were identified. Further, patients who had a resurgence of minimal residual disease (MRD) after previously being MRD-negative without concomitant clinical or biochemical progression was not considered to be a treatment failure.

The enrolled patients were divided into 2 groups: those with treatment failure less than 18 months from the initiation of QUAD, and those with treatment failure either at or after 18 months from the initiation of QUAD. The timeline of 18 months was chosen due to the progression of initial therapy generally being considered as functional high-risk myeloma, regardless of other factors. The study’s primary objective was to describe the outcomes of patients with NDMM post-QUAD treatment failure, specifically progression-free survival (PFS) and overall survival.

A total of 274 patients who were treated with QUADs at the onset of therapy were enrolled in the study. The median follow-up from the onset of QUAD was 21.3 months (IQR 12.1-35.6), and among the enrolled patients, 78 (28.5%) had received QUAD in a clinical trial whereas the remaining 196 (71.5%) received the treatment as standard of care. Further, a total of 217 patients (79.2%) were treated with daratumumab, bortezomib, lenalidomide, and dexamethasone (D-VRd), and 57 (20.8%) were treated with daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd). The median follow-ups for patients who were treated with the daratumumab regimens were 18.0 months (D-VRd: IQR 11.1–27.4) and 46.9 months (D-KRd: IQR 36.6–57.3).

Further, the authors determined there were 41 patients with treatment failure after receiving QUAD, and among those, 14 had disease progression after D-KRd induction and 27 after D-VRd induction. In addition, there were 20 patients with progression less than 18 months—of which 14 occurred while either on QUAD or within 60 days after induction therapy—and 21 patients with progression either at or after 18 months from the induction of QUAD.

According to the authors, all patients who had experienced QUAD failure received following therapy, of which 38 have had longer than 1 month follow-up and were evaluated for their response to treatment. Among these patients, 11 (26.8%) received the next line of therapy as a participant in a clinical trial, and 20 (48.8%) participated in a clinical trial at some point while receiving subsequent therapies.

Further, 9 patients (22.0%) received a T-cell redirecting therapy as the first therapy employed after QUAD failure, and 21 (51.2%) received a T-cell redirecting therapy at some point during the treatment course. In addition, among those with progression either at or after 18 months who received an anti-CD38 monoclonal antibody as their next line of therapy, 16 were determined to not have anti-CD38-refractory disease. The median PFS for these patients was 5.5 months (95% CI 2.1-8.9). In addition, cytotoxic chemotherapy was used for 10 patients (50.0%) progressing before the 18-month point and was uncommon in patients progressing either at or after the 18-month onset of QUAD. The overall response rate was 39.5% (95% CI 24.0–56.6), and the likelihood of response increased as time progressed since the onset of QUAD and was 26.3% (95% CI 9.1–51.2) for patients with less than 18 months progression and 52.6% (95% CI 28.9–75.6) for patients with progression either at or beyond 18 months.

In addition, the median follow-up from QUAD failure was 7.2 months (IQR 3.3–15.9), 6.3 months (IQR 3.4–14.0) for those with progression before the 18-month mark, and 11.4 months (IQR 3.2–19.1) for those with progression either at or beyond 18 months. According to the investigators, there were 29 reported PFS events among the 41 patients. For the next line of therapy, the median PFS was 2.5 months (95% CI 1.5-3.4) for those with progression before 18 months, and 7.0 months (95% CI 3.6-10.5) for those with progression at or beyond 18 months (HR 2.78, 95% CI 1.29-5.98, p = 0.008).

Limitations of the study include the small number of patients despite the large cohort of QUAD-treated patients who were enrolled, the improper assessment of risk factors for treatment failure due to the heterogeneity of patients, and the lack of comparison between the daratumumab treatment regimens. Further, the authors note that many patients who were treated with QUADs were participants in clinical trials, of which a high proportion of patients had treatment failure (48.8%).

The study authors emphasize that the findings indicate a need to continue to refine the predictors of treatment failure for patients with NDMM. In addition, they note that the results highlight the limitations of clinical trial enrollment as well as the regulatory approval process based on the number of prior lines of therapy. The suggest that patients who are treated with QUAD and ASCT who experience progression prior to 18 months are a population with unmet needs that show be examined in additional research.

References

Ravi G, Bal S, Joiner L, Giri S, Sentell M, Hill T, et al. Subsequent therapy and outcomes in patients with newly diagnosed multiple myeloma experiencing disease progression after quadruplet combinations. Br J Haematol. 2024; 00: 1–7. https://doi.org/10.1111/bjh.19303