Faculty Bibliography

Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.

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.

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

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:Sex differences in the incidence and outcomes of several cancers are well established. Multiple myeloma (MM) is a malignant plasma cell dyscrasia accounting for 2% of all new cancer cases in the UK. There is a clear sex disparity in MM incidence, with 57% of cases in males and 43% in females. The mechanisms behind this are not well understood and the impact of sex on patient outcomes has not been thoroughly explored. PATIENTS AND METHODS/METHODS:We investigated the association of sex with baseline disease characteristics and outcome in 3894 patients recruited to the phase III UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated. RESULTS:Females were significantly more likely to have the molecular lesions t(14;16) and del(17p) and were more likely to meet the cytogenetic classification of high-risk (HiR) or ultra-high-risk disease (UHiR). There was no difference in progression-free survival (PFS) or overall survival (OS) between the sexes in the overall population. CONCLUSION/CONCLUSIONS:Our data suggest that the genetic lesions involved in the initiation and progression of MM may be different between the sexes. Although females were more likely to have the poor prognosis lesions t(14;16) and del(17p), and were more likely to be assessed as having HiR or UHiR disease, this was not associated with reduced PFS or OS. In female patients the trial treatment may have been able to overcome some of the adverse effects of high-risk cytogenetic lesions. MicroAbstract Multiple myeloma (MM) is more common in males compared to females but the reasons behind this are not well understood and the impact of sex on patient outcomes is unclear. This study demonstrates fundamental differences in genetic lesions underlying the biology of MM between males and females. However, we found that progression-free survival and overall survival were the same in both sexes.

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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.