Faculty Bibliography

Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.

Newer treatments for multiple myeloma (MM) have improved response rates and survival for many patients. However, MM remains challenging to treat due to the propensity for multiple relapses, cumulative and emergent toxicities from prior therapies and increasing genomic complexity that arises due to clonal evolution. In particular, patients with relapsed/refractory MM often require increased complexity of treatment, yet still experience poorer outcomes compared with patients who are newly diagnosed. Additionally, several patient subgroups, including those with extramedullary disease and patients who are frail and/or have multiple comorbidities, have an unfavorable prognosis and remain undertreated. This review (based on an Updates-in-Hematology session at the 25th European Hematology Association Annual Congress 2020) discusses the management of these difficult-to-treat patients with MM.

Background: Daratumumab (Dara), ixazomib (I), carfilzomib (K), bortezomib (V), and elotuzumab (Elo) plus Rd, as well as Rd alone, are among the standards of care for RRMM treatment. In phase 3 RRMM trials, these regimens have been given as long-term/continuous therapy, with median DOTs ranging from 10.1 to 34.3 months. Longer DOT is associated with improved outcomes; however, the lengthy DOTs seen in clinical trials do not always translate to the real-world setting due to multiple pt- and treatment-related factors, emphasizing the importance of real-world data collection to aid in treatment decisions.
Aim(s): To estimate DOT with Rd-based regimens in RRMM pts in the global, prospective, observational INSIGHT MM study (NCT02761187).
Method(s): From July 2016 to June 2019, INSIGHT MM enrolled 4307 pts from 15 countries, including 1939 pts with >=2 prior lines of therapy (LOT). Prospective follow-up of >=2 years/pt is ongoing. DOT was defined as time from Rd-based treatment initiation within a LOT (index regimen) to time of discontinuation of index regimen. Kaplan-Meier analyses were used to determine DOT for each Rd-based regimen reported, overall, and by LOT and region (Europe+Israel [EUR]; North America [NA]). Exposure to prior therapies and reasons for treatment discontinuation were also examined.
Result(s): In total, 821 pts received 867 Rd-based LOT for RRMM (225 Rd, 211 Dara-Rd, 179 IRd, 108 KRd, 87 VRd, and 57 Elo-Rd; pts could be included more than once if they received an Rd-based treatment in >1 LOT), including 464/262/150 in 2nd/3rd/>=4th line (134/70/24 Rd, 115/58/39 Dara-Rd, 58/82/40 IRd, 67/25/18 KRd, 57/16/15 VRd, and 33/11/14 Elo-Rd; 9 pts received the same regimen >once). Overall, median DOT was longest with Dara-Rd and IRd (14.1 and 12.2 months); the proportions of pts in treatment at 12 months (12-month DOT rate) were 52.8% and 51.5%, respectively (Figure). Analysis by region showed higher 12-month DOT rates in EUR vs NA with Dara-Rd (57.1 vs 43.7%), IRd (55.3 vs 34.2%), and KRd (41.0 vs 30.7%), a lower rate in EUR with VRd (11.0 vs 30.7%), and similar rates with Rd (40.8 vs 40.0%) and Elo-Rd (37.0 vs 33.6%). These rates were not analyzed in Latin America and Asia-Pacific regions due to small pt numbers. Among 2nd/3rd/>=4th-line pts, 12-month DOT rates with Dara-Rd were 58.8%/56.1%/31.1%; with IRd, 49.8%/56.6%/47.4%; with KRd, 41.3%/44.3%/35.3%; with Elo-Rd, 40.8%/30.0%/27.7%; with Rd, 36.8%/36.2%/28.1%; and with VRd, 25.0%/40.0%/0%. Most regimens received immediately prior to Rd-based treatment were V-based (n=504, 58.1%). Overall, common prior regimens received included VCd (20.6%), VRd (10.3%), VTd (9.1%), Vd (8.9%), Rd (6.6%), and VMP (5.9%), used primarily as 1st and 2nd line. Prior therapies were more diverse in pts receiving Rd-based treatment beyond 3rd vs in earlier lines. Overall, 555/867 (64.0%) of the reported LOT were in R-na.ve pts and 312 (36.0%) were in pts exposed to R in any line prior to Rd-based treatment. At data cutoff, 530/867 (61.1%) Rd-based individual LOT had been discontinued; overall reasons for discontinuation (multiple reasons could be provided per LOT) included relapse in 224 pts (42.3% of 530), adverse events in 78 (14.7%), death in 33 (6.2%), and other reasons in 207 (39.1%). Summary/Conclusion: DOT with Rd-based treatment in the real-world setting of INSIGHT MM generally appeared shorter than in clinical trials. The longest DOTs were seen in 2nd and 3rd LOT with Dara-Rd and IRd. Thirty six percent of the reported LOT were in pts who received R in any prior line, while the most common therapies immediately prior to Rd-based therapy were V-based

Background: Autologous stem cell transplant (ASCT) remains standard of care for eligible newly diagnosed myeloma patients (TE NDMM). Induction prior to ASCT frequently includes lenalidomide, reported to have an adverse effect on peripheal blood stem cell (PBSC) harvest in some studies.
Aim(s): The UK NCRI Myeloma XI/+ study compared induction combinations including thalidomide or lenalidomide giving the opportunity to compare PBSC harvests between patients treated with different immunomodulatory agents.
Method(s): TE NDMM patients were randomised to triplet combinations, thalidomide or lenalidomide plus dexamethasone and cyclophosphamide (Tdc/Rdc) or the quadruplet combination carfilzomib+Rdc (KRdc). Induction was given for a min. of 4 cycles but continued to max. response. Patients who received Tdc/Rdc and achieved a max. response less than VGPR underwent response-adapted intensification therapy. PBSC harvest was planned to occur after the completion of induction+/- intensification. Stem cell mobilisation and harvest was performed according to local practice with advice to aim for the collection of sufficient cells for at least two transplants. The median number of CD34+ cells harvested was compared between patients randomised to Tdc, Rdc and KRdc and those who received 4, 5-6 or >6 cycles of induction. Mann-Whitney U Tests were used to compare groups. Only patients achieving >=VGPR to initial induction, completing >=4 cycles and proceeding directly to ASCT were included in this analysis to avoid any impact of response or intensification therapy on harvest outcome.
Result(s): Of the1543 patients included, 521 had received Tdc (51.0% of all patients randomised to Tdc), 610 Rdc (59.7%), 412 KRdc (78.3%). Of these patients 88.4% underwent harvest (Tdc 86.9%, Rdc 87.5%, KRdc 91.5%). The median number of CD34+ cells harvested was lower for those who had received lenalidomide compared to thalidomide. Patients who received Tdc harvested a median 4.6x10^6/kg CD34+ cells, Rdc 4.1, KRdc 4.2 (Rdc vs Tdc p=0.0002, KRdc vs Rdc p=0.1766, KRdc vs Tdc p=0.0210). There was also a reduction in the median CD34+ cells harvested for patients requiring >6 cycles of induction to achieve maximum response prior to harvest. 4 cycles 4.5 x10^6/kg CD34+ cells, 5-6 cycles 4.2, >6 cycles 4.1 (4 vs 5-6 p=0.1212, 5-6 vs >6 p=0.1839, 4 vs >6 p=0.0262). The reduction in CD34+ cells with increasing number of induction cycles appeared greater for those patients who received lenalidomide induction. Tdc: 4 cycles 4.9 x10^6/kg CD34+ cells, 5-6 cycles 4.6, >6 cycles 4.6. Rdc: 4 cycles 4.4, 5-6 cycles 4.0, >6 cycles 3.5. KRdc: 4 cycles 4.4, 5-6 cycles 4.1, >6 cycles 3.9. This corresponded to a reduction in the proportion of patients meeting the threshold for two ASCTs both between therapies and with increasing cycles. Tdc: 4 cycles 63.0%, 5-6 cycles 60.2%, >6 cycles 61.4%. Rdc: 4 cycles 54.3%, 5-6 cycles 47.4%, >6 cycles 46.2%. KRdc: 4 cycles 60.9%, 5-6 cycles 49.3%, >6 cycles 41.7%. Despite these differences, more than 96% of patients in all groups were considered to have enough stem cells and proceeded to first ASCT within the trial, with no differences between treatment groups. Summary/Conclusion: Lenalidomide-based induction therapy was associated with lower median CD34+ cells harvested than thalidomide-based induction. This had no impact on the proportion of patients able to undergo first ASCT. The reduction in median CD34+ cells with lenalidomide was most marked when >4 cycles were administered. This should be considered when planning the timing of harvests, especially if storage of sufficient cells for two ASCTs is desired

ABSTRACT:The summation of 20 years of biological studies and the comprehensive analysis of more than 1000 multiple myeloma genomes with data linked to clinical outcome has enabled an increased understanding of the pathogenesis of multiple myeloma in the context of normal plasma cell biology. This novel data have facilitated the identification of prognostic markers and targets suitable for therapeutic manipulation. The challenge moving forward is to translate this genetic and biological information into the clinic to improve patient care. This review discusses the key data required to achieve this and provides a framework within which to explore the use of response-adapted, biologically targeted, molecularly targeted, and risk-stratified therapeutic approaches to improve the management of patients with multiple myeloma.

Predicting patient outcome in multiple myeloma remains challenging despite the availability of standard prognostic biomarkers. We investigated outcome for patients relapsing early from intensive therapy on NCRI Myeloma XI. Relapse within 12 months of autologous stem cell transplant was associated with markedly worse median progression-free survival 2 (PFS2) of 18 months and overall survival (OS) of 26 months, compared to median PFS2 of 85 months and OS of 91 months for later relapsing patients despite equal access to and use of subsequent therapies, highlighting the urgent need for improved outcome prediction and early intervention strategies for myeloma patients.

Idecabtagene vicleucel (ide-cel, bb2121), a chimeric antigen receptor (CAR) T cell therapy, has been investigated in patients with relapsed and refractory multiple myeloma (RRMM) who have received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody in the single-arm phase 2 KarMMa clinical trial. Two therapies with distinct mechanisms of action - selinexor plus dexamethasone (Sd) and belantamab mafodotin (BM) - are currently approved in the United States for heavily pretreated patients, including those who are triple-class refractory. To compare ide-cel versus Sd and ide-cel versus BM, matching-adjusted indirect comparisons were performed. Ide-cel extended progression-free survival (PFS) and overall survival (OS) versus both Sd and BM (hazard ratio (HR); 95% confidence interval (CI)). PFS: ide-cel versus Sd, 0.46; 0.28-0.75; ide-cel versus BM, 0.45; 0.27-0.77. OS: ide-cel versus Sd, 0.23; 0.13-0.42; ide-cel versus BM, 0.35; 0.14-0.87. These results suggest ide-cel offers clinically meaningful improvements over currently approved regimens for patients with heavily pretreated RRMM.

INTRODUCTION/UNASSIGNED:: Survival in multiple myeloma (MM) has improved due to the ongoing revolution of therapeutic approaches. Nevertheless, many patients relapse, and additional novel approaches are required to prolong remissions and prevent disease progression. AREAS COVERED/UNASSIGNED:Considering the success of monoclonal antibodies (mAbs) against CD38 and SLAMF7 in relapsed/refractory MM (R/R MM), additional antigens expressed on malignant plasma cells are being investigated as treatment targets. Among these, many trials are focusing on B cell maturation antigen (BCMA), using either antibody-drug conjugates (ADCs), bispecific T cell engagers (TCE), or chimeric antigen receptor T cells (CAR-T). Other potential targets include the myeloma markers CD138, GPRC5D, FcRH5, the plasma cell differentiating factors APRIL, TACI and BAFF, and the immune checkpoint proteins CD47 and TIGIT. Additionally, novel immunomodulatory Cereblon E3 Ligase Modulators (CELMoDs) offer the potential to overcome resistance to conventional immunomodulatory agents. Based upon PubMed and abstract searches primarily from the past 4 years, here we review the data supporting novel immunotherapies for R/R MM. EXPERT OPINION/UNASSIGNED:: Overcoming disease resistance remains a challenge in R/R MM. Novel therapeutic approaches targeting MM antigens and/or enhancing immune cell function offer the potential to prolong survival and are actively being investigated in clinical trials.