Identification of treatment effect modifiers and prognostic factors in newly diagnosed and relapsed or refractory multiple myeloma.

An Investigation of Potential Treatment Effect Modifiers in Multiple Myeloma from Published Randomized Controlled Trials

Comparison of the Efficacy in Clinical Trials Versus Effectiveness in the Real-World of Treatments for Multiple Myeloma: A Population-Based Cohort Study

Advanced Risk Stratification in Multiple Myeloma Beyond Traditional FISH: The First Prospective Real-World Evidence for SKY92 Gene Expression Profiling

Identify high-risk disease in multiple myeloma through single-cell transcriptomic detection of highly proliferative (PR) cells

High-risk (HR) multiple myeloma (MM) patients still have a very poor prognosis. However, the definition of HR MM remains controversial. Currently, FISH is the most commonly used method for risk stratification in MM. According to the Second Revised International Staging System (R2-ISS), HR cytogenetics is defined as presence of at least one of the following: del(17p), t(4;14), and 1q CNA. In recent years, gene expression profiling (GEP) approaches, e.g. SKY92, have been developed for detection of HR patients. In the R2-ISS era, however, data on MM risk stratification applying SKY92 in combination with traditional FISH is still lacking. Therefore, we performed the first prospective study evaluating the prognostic value of the combined SKY92 and FISH HR detection in newly diagnosed (ND) and relapsed/refractory (RR) MM. We prospectively collected bone marrow (BM) samples and clinical data of 147 MM patients. Cytogenetics were analyzed on purified CD138 positive MM cells by FISH, and HR cytogenetics was defined according to the R2-ISS classification. SKY92 risk status was determined with MMprofiler gene expression assay. Whole genome sequencing (WGS) was performed to compare the both risk stratification systems SKY92 and FISH. We included 147 patients in our study (NDMM: n=51, RRMM: n=96). SKY92 classification was available for 121 (82.3%) patients. HR SKY92 was significantly enriched in RRMM (40/76) compared with NDMM (6/45) (P<0.0001). RRMM patients with HR SKY92 showed significantly shorter progression free survival (PFS) (P<0.0001) and overall survival (OS) (P=0.0004) than standard-risk (SR). In NDMM, HR SKY92 also indicated a significantly inferior PFS (P=0.001) in comparison with SR. Of note, samples of 26 (17.7%) patients, who showed significantly lower bone marrow infiltration than the remaining patients (median: 25% vs 55%, P=0.038), did not meet the SKY92 quality control criteria. We then combined the SKY92 classification with cytogenetic analyses by FISH, which were available in 99 patients (NDMM: n=33; RRMM: n=66). We noticed a discrepancy between both risk stratification systems, with 44 (44.4%) and 58 (58.6%) patients being classified as HR by SKY92 and FISH, respectively. In total, 28 (42.4%) RRMM patients and 6 (18.2%) NDMM patients displayed HR in both SKY92 and FISH (double-HR). Regarding survival outcome in RRMM, double-HR patients showed the worst PFS (P<0.0001) and OS (P=0.0007). In NDMM, double-HR presented a negative prognostic factor for PFS (P=0.01). To compare the FISH and SKY92 classifications, we performed WGS in 16 patients who exhibited either only HR SKY92 (n=7) or only HR FISH (n=9). Interestingly, 1 patient with bi-allelic TP53 inactivation (deletion + mutation) and 6 patients harbouring 1q CNA were determined as SR by SKY92 but as HR by FISH. The median PFS was not reached after a median follow up of 371 days in these 9 patients. Moreover, 4 out of 7 patients with only HR SKY92 but SR FISH displayed 1q CNA, which was detected only by WGS, and del1p32 was found in 1 patients. Interestingly, we found CRBN mutation in 3 out of 7 patients with only HR SKY92 but SR FISH. The remaining 2 patients did not show any known HR genomic alterations, suggesting that HR MM may be associated with other factors, e.g. epigenetic modifications. Here, we provide the first prospective evidence in the R2-ISS era that advanced risk stratification combining SKY92 and FISH may help to identify the highest-risk MM.

Progression-Free Survival as a Surrogate Endpoint for Overall Survival in Patients with Relapsed or Refractory Multiple Myeloma

Lyra: A Phase 2 Study of Daratumumab (Dara) Plus Cyclophosphamide, Bortezomib, and Dexamethasone (Cybord) in Newly Diagnosed and Relapsed Patients (Pts) with Multiple Myeloma (MM)

PACE as salvage therapy for relapsed or refractory multiple myeloma

Efficacy of Elotuzumab Based Combinations in Patients with Multiple Myeloma - a Systematic Review

Induction with Bortezomib Melphalan and Prednisolon (VMP) Is Associated with Unexpectedly High Discontinuation Rate in Elderly Multiple Myeloma Patients: First Analysis of the German Maintenance (GERMAIN) Trial

Outcomes for Older Patients in Stratus (MM-010), a Single-Arm, and Phase 3b Study of Pomalidomide + Low-Dose Dexamethasone in Refractory or Relapsed and Refractory Multiple Myeloma

Antibody Based Three-Drug Regimens for Multiple Myeloma - a Systematic Review of Phase II and Phase III Clinical Trials

Race and Outcomes of Autologous Hematopoietic Cell Transplantation for Multiple Myeloma

Background:The prognosis of multiple myeloma (MM) patients who are refractory to all currently available therapies, including anti‐CD38 monoclonal antibodies, remains poor, indicating that there is an unmet need for novel treatment strategies. Although data on G‐protein coupled receptor 5D (GPRC5D) protein expression is scarce, GPRC5D RNA levels are selectively elevated in MM cell lines and primary MM cells. This makes GPRC5D an attractive target for the novel anti‐MM JNJ‐7564 bispecific antibody.Aims:We determined GPRC5D protein expression levels on bone marrow (BM) mononuclear cells (MNCs) and MM cell lines. We also analyzed the impact of differential GPRC5D gene expression on overall survival (OS) and progression free survival (PFS) in MM patients. Furthermore, the preclinical activity of a new GPRC5DxCD3 bispecific antibody (JNJ‐7564) in development for the treatment of MM was evaluated, as well as biomarkers for in vitro JNJ‐7564 response.Methods:GPRC5D protein expression was assessed by flow cytometry on BM MNCs derived from healthy donors (HD) and MM patients. GPRC5D gene expression levels were analyzed in purified CD138+ MM cells derived from patients who participated in 5 large randomized clinical trials (HOVON65, MRC‐IX, TT2, TT3 and APEX). MM cell lysis by JNJ‐7564 (0.00064–4 μg/ml; 48 hour‐incubation) was evaluated in MM cell lines and whole BM samples from newly diagnosed (ND) and relapsed/refractory (RR) MM patients. At baseline, the MNCs were characterized for the composition of T‐cell subsets. T‐cell activation and degranulation were measured by flow cytometry based on expression of CD25 and CD107a, respectively.Results:GPRC5D protein expression was significantly higher on MM cells compared to other BM cells, including HD plasma cells (fig 1A). GPRC5D protein expression was positively correlated with BCMA expression (r = 0.44; P = 0.02), but was independent of tumor load, and CD38 or PD‐L1 expression on MM cells. Gene expression levels of GPRC5D were highly variable in MM, and independent of age and ISS stage, but were significantly higher in patients with t(4;14) or gain 1q. There was no association with OS or PFS in the 5 clinical trials (n = 1421). JNJ‐7564 effectively killed GPRC5D+ MM cell lines (MM1.S, UM9 (fig 1B) and RPMI8226) in a dose‐dependent manner using HD peripheral blood MNCs as effector cells. Co‐incubation with patient‐derived BM stromal cells resulted in a modest impairment of killing capacity in MM1.S and RPMI8226 cells. In MM patient samples (n = 20), the mean lysis of MM cells with 4.0 μg/mL JNJ‐7564 was 62% (range: −8–97%; fig 1C), while NK‐cell and T‐cell frequencies were not affected. JNJ‐7564 was also effective in samples from extensively pretreated daratumumab (DARA)‐refractory patients (DRMM; n = 6; median of 6 prior lines; mean lysis with 4.0 μg/mL: 70%; range: 44–97%). Maximal lysis of primary MM cells was not associated with the level of GPRC5D expression on MM cells, effector:target ratio, or frequency of regulatory T‐cells. JNJ‐7564‐mediated MM cell lysis was associated with activation and degranulation of CD4+ and CD8+ T‐cells (fig 1D).Summary/Conclusion:GPRC5D is highly and selectively expressed on MM cells, which makes it an attractive therapeutic target. The GPRC5DxCD3 bispecific antibody, JNJ‐7564, effectively lysed GPRC5D+ MM cell lines and primary MM cells in samples derived from both newly diagnosed and heavily pre‐treated patients, including DARA‐refractory patients. Altogether, this strengthens the preclinical rationale for an ongoing phase 1 study with JNJ‐7564 in RRMM.image

Network Meta-Analysis of Randomized Trials in Relapsed/Refractory Multiple Myeloma: Relative Efficacy for Patients Who Are Lenalidomide-Refractory