Faculty Bibliography

Survival in multiple myeloma has improved greatly during the past 2 decades, but this change has primarily benefited patients who have standard-risk disease. Patients with high-risk disease remain a challenge to diagnose and treat. To improve their clinical outcomes, it is imperative to develop tools to readily identify them and to provide them with the most effective available treatments. The most widely used stratification system, the revised International Staging System, incorporates serum β-2 microglobulin, albumin, lactate dehydrogenase, and high-risk chromosomal abnormalities [del(17p), t(4;14), and t(14;16)]. Recent updates have included mutational status and chromosome 1q abnormalities. Plasma cell leukemia, extramedullary disease, circulating plasma cells, renal failure, and frailty are also associated with poor outcome. The treatment approach for a newly diagnosed patient with high-risk multiple myeloma should include induction therapy, autologous stem cell transplantation if appropriate, and maintenance therapy. Triplet therapy with a proteasome inhibitor, immunomodulatory drug, and steroid, with or without an anti-CD38 antibody, should be considered for induction, along with a proteasome inhibitor and/or immunomodulatory drug for maintenance. Aiming for a deep and sustained response is important. Similar principles apply at relapse, with close monitoring of response, especially extramedullary disease and active management of side effects, so that patients can continue therapy and benefit from treatment. Immune-based therapies, including autologous CAR T-cell-based therapies and bispecific antibodies, show promising activity in relapsed disease and are being actively explored in earlier disease settings. As the prognosis for high-risk disease remains poor, the future goal for this patient group is to develop specific clinical trials to explore novel approaches and therapies efficiently.

INTRODUCTION/BACKGROUND:Outcomes continue to improve in relapsed myeloma as more effective treatment options emerge. We report a multicenter single-arm phase 2 trial evaluating toxicity and efficacy of the histone deacetylase (HDAC) inhibitor vorinostat in combination with bortezomib and dexamethasone. PATIENTS AND METHODS/METHODS:days 1, 4, 8, and 11; dexamethasone 20 mg orally days 1-2, 4-5, 8-9, and 11-12; vorinostat 400 mg orally days 1-4, 8-11, and 15-18 of a 21-day cycle. After receipt of a minimum of 3 cycles of therapy, participants received maintenance vorinostat (400 mg days 1-4 and 15-18 of a 28-day cycle). RESULTS:Overall response was 81.3%: complete response occurred in 4 of 16, very good partial response in 2 of 16, and partial response 7 of 16. Clinical benefit response rate was 100%; median progression-free survival was 11.9 months. A total of 75% patients experienced a dose reduction or stopped treatment as a result of intolerability. CONCLUSION/CONCLUSIONS:Although toxicity and dose reductions were observed, this study demonstrates that the combination of vorinostat, bortezomib, and dexamethasone is effective in relapsed myeloma with good response rates, suggesting there is an ongoing rationale for further optimization of HDAC inhibitor-based combinations in the treatment of myeloma to improve tolerability and enhance efficacy.

Circulating cell-free DNA (cfDNA) has the potential to capture spatial genetic heterogeneity in myeloma (MM) patients. We assessed whether cfDNA levels vary according to risk status defined by the 70 gene expression profile (GEP70). cfDNA levels in 77 patients were significantly higher in the GEP70 high-risk (HR) group compared to the low-risk (LR) group and correlated weakly with clinical markers including lactate dehydrogenase, β₂ -microglobulin, and ISS. Patients with high cfDNA levels were associated with a worse PFS (hazard ratio 6.4; 95% CI of ratio 1.9-22) and OS (hazard ratio 4.4; 95% CI of ratio 1.2-15.7). Circulating tumor DNA (ctDNA) was elevated in the HR group and ctDNA correlated strongly with GEP70 risk score (Spearman r = .69, P = .0027). cfDNA concentrations were significantly elevated between days 3-5 after chemotherapy before falling back to baseline levels. ctDNA in two patients showed a similar spike in levels between days 3 and 5 after chemotherapy with a concomitant increase in allele fraction of KRAS mutations. We assessed cfDNA levels in 25 patients with smoldering myeloma with serial samples and showed increased allele fraction of mutated KRAS at progression in cfDNA. Our study shows that cfDNA is a dynamic tool to capture genetic events in myeloma.

Smoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5-8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.

BACKGROUND:Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy. METHODS AND FINDINGS/RESULTS:The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51-0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19-5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10-5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world. CONCLUSIONS:The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov ISRCTN49407852.

The treatment landscape for multiple myeloma (MM) has dramatically changed over the last three decades, moving from no US Food and Drug Administration approvals and two active drug classes to over 19 drug approvals and at least eight different active classes. The advances seen in MM therapy have relied on both a structured approach to obtaining new labels and cautious off-label drug use. Although there are country and regional differences in drug approval processes, many of the basic principles behind off-label drug use in MM can be summarized into four main categories: 1) use of a therapy prior to the current approval regulations; 2) widespread use of a therapy following the release of promising clinical trial results but prior to drug approval; 3) use of a cheap therapy supported by clinical safety and efficacy data but without commercial backing; and 4) niche therapies for small well-defined patient populations where large clinical trials with sufficient power may be difficult to perform. This review takes a historical approach to discuss how off-label drug use has helped to shape the current treatment approach for MM.

Introduction: Patients (pts) with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed (TCE) to IMiDs, proteasome inhibitors, and anti-CD38 monoclonal antibodies have poor clinical outcomes. Ide-cel is a CAR T cell therapy under development for this patient population. Literature review of published efficacy data for TCE RRMM pts identified MAMMOTH, a large, retrospective observational study (Gandhi UH, et al. Leukemia 2019;33:2266-2275). Pts in both MAMMOTH and KarMMa were TCE. This analysis aimed to compare efficacy outcomes observed with ide-cel treatment in KarMMa and conventional care (CC) receiving pts in MAMMOTH.
Method(s): Individual patient-level data (IPD) with a median follow-up of 13.3 months were available for KarMMa (data cutoff 14th Jan 2020) while study-level data were available for MAMMOTH. Unanchored matching-adjusted indirect comparisons (MAICs) were conducted to compare efficacy outcomes from the 2 studies. IPD from MAMMOTH were reconstructed based on published Kaplan-Meier curves for time-to-event outcomes. Propensity score models were used to weight the treated population from KarMMa to match the baseline characteristics of treated pts in MAMMOTH in order to predict outcomes for ide-cel in a population corresponding to the one evaluated in MAMMOTH.
Result(s): Ide-cel was associated with a significantly higher ORR compared with CC in a population matched to the one treated in MAMMOTH (odds ratio (OR) 5.11, 95% CI 2.92-8.94, P < 0.001) (Table 1). Similarly, ide-cel significantly extended PFS (hazard ratio (HR) 0.55, 95% CI 0.42-0.73, P < 0.001) and OS (HR 0.36, 95% CI 0.24-0.54, P < 0.001) versus CC. In MAMMOTH, the individual CC regimens involving targeted therapies (CFZ, DARA, and ELO) were associated with a median OS between 8.3 and 12.7 months. The weighted median OS times for ide-cel are consistently longer than those associated with the individual CC regimens in MAMMOTH (Table 2), similar to the results for the overall treated population.
Conclusion(s): Ide-cel provides clinically and statistically significant efficacy benefits over CC, including combination regimens involving targeted agents