Identifying clinical response to daratumumab therapy in relapsed/refractory multiple myeloma using a patient-derived in vitro model.

Response to daratumumab in patients with relapsed/refractory multiple myeloma is heterogeneous, and a reliable biomarker of response is lacking. We aimed to develop a method that identifies response to daratumumab therapy. Patient-derived MM cells were collected before start of daratumumab treatment and were cultured in a hydrogel-based culture system. The extent of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro was associated with both clinical response and progression-free survival in corresponding patients. Together, our results demonstrate that in vitro sensitivity to daratumumab therapy in a hydrogel culture with primary MM cells might be used to identify patients most likely to benefit from treatment.

Direct P70S6K1 inhibition to replace dexamethasone in synergistic combination with MCL-1 inhibition in multiple myeloma.

Novel combination therapies have markedly improved the lifespan of patients with multiple myeloma (MM), but drug resistance and disease relapse remain major clinical problems. Dexamethasone and other glucocorticoids are a cornerstone of conventional and new combination therapies for MM, although their use is accompanied by serious side effects. We aimed to uncover drug combinations that act in synergy and, as such, allow reduced dosing while remaining effective. Dexamethasone and the myeloid cell leukemia 1 (MCL-1) inhibitor S63845 (MCL-1i) proved the most potent combination in our lethality screen and induced apoptosis of human myeloma cell lines (HMCLs) that was 50% higher compared with an additive drug effect. Kinome analysis of dexamethasone-treated HMCLs revealed a reduction in serine/threonine peptide phosphorylation, which was predicted to result from reduced Akt activity. Biochemical techniques showed no dexamethasone-induced effects on FOXO protein or GSK3 but did show a 50% reduction in P70S6K phosphorylation, downstream of the Akt-mTORC1 axis. Replacing dexamethasone by the P70S6K1 isoform-specific inhibitor PF-4708671 (S6K1i) revealed similar and statistically significant synergistic apoptosis of HMCLs in combination with MCL-1i. Interestingly, apoptosis induced by the P70S6K1i and MCL-1i combination was more-than-additive in all 9 primary MM samples tested; this effect was observed for 6 of 9 samples with the dexamethasone and MCL-1i combination. Toxicity on stem and progenitor cell subsets remained minimal. Combined, our results show a strong rationale for combination treatments using the P70S6K inhibitor in MM. Direct and specific inhibition of P70S6K may also provide a solution for patients ineligible or insensitive to dexamethasone or other glucocorticoids.

Therapeutic outcome of early-phase clinical trials in multiple myeloma: a meta-analysis.

Great progress in the treatment of patients with multiple myeloma (MM) has been made due to the development of novel drugs. Patients with relapsed/refractory MM (RRMM) can be enrolled in early-phase clinical trials, but their performance across the last decade is unknown. We conducted a meta-analysis on the overall response rate (ORR) and toxicity. PubMed, Embase, and Cochrane Library were systematically searched for phase I and phase II trials investigating an experimental compound as a single agent or in combination with dexamethasone, published from January 1, 2010 to July 1, 2020. Eighty-eight articles were included, describing 61 phase I trials involving 1835 patients and 37 phase II trials involving 2644 patients. There was a high degree of heterogeneity. Using a random-effects model, the 95% CIs of the estimated ORR were 8-17% for phase I trials and 18-28% for phase II trials. There were significant subgroup differences in ORR between the years of publication in phase I trials and between drug classes in both phase I and phase II trials. The ORR in early-phase clinical trials in RRMM is substantial, especially in phase II trials, but due to high heterogeneity a general assessment of clinical benefit before participation is difficult to offer to patients.

From MGUS to Multiple Myeloma, a Paradigm for Clonal Evolution of Premalignant Cells.

Multiple myeloma (MM) is a treatable, but incurable, malignancy of plasma cells (PC) in the bone marrow (BM). It represents the final stage in a continuum of PC dyscrasias and is consistently preceded by a premalignant phase termed monoclonal gammopathy of undetermined significance (MGUS). The existence of this well-defined premalignant phase provides the opportunity to study clonal evolution of a premalignant condition into overt cancer. Unraveling the mechanisms of malignant transformation of PC could enable early identification of MGUS patients at high risk of progression and may point to novel therapeutic targets, thereby possibly delaying or preventing malignant transformation. The MGUS-to-MM progression requires multiple genomic events and the establishment of a permissive BM microenvironment, although it is generally not clear if the various microenvironmental events are causes or consequences of disease progression. Advances in gene-sequencing techniques and the use of serial paired analyses have allowed for a more specific identification of driver lesions. The challenge in cancer biology is to identify and target those lesions that confer selective advantage and thereby drive evolution of a premalignant clone. Here, we review recent advances in the understanding of malignant transformation of MGUS to MM. Cancer Res; 78(10); 2449-56. ©2018 AACR.