Richardson, Paul G.

Abstract Solitary plasmacytoma of bone (SPB) is a localized plasma cell neoplasm associated with a substantial risk of progression to multiple myeloma (MM), yet the role of adjuvant systemic therapy following definitive radiation therapy (RT) remains undefined. We conducted a randomized phase III trial (Alliance A061402) to evaluate whether the addition of systemic therapy with ixazomib, lenalidomide, and dexamethasone (IXA-LEN-DEX) to zoledronic acid (ZA) improves outcomes compared with ZA alone in patients with SPB and minimal (< 10%) bone marrow plasma cell involvement following RT. Patients were randomized to receive six 28-day cycles of IXA-LEN-DEX-ZA or ZA alone. The primary endpoint was time to progression (TTP) to MM. The study was closed early due to poor accrual after enrolling 11 patients (IXA-LEN-DEX-ZA, n = 5; ZA, n = 6). All patients completed RT and planned treatment without dose reductions. The combination regimen was well tolerated, with limited grade ≥ 3 toxicities, including hypophosphatemia and lymphopenia. At follow-up extending beyond 4 years, the 1- and 4-year progression rates to MM in the IXA-LEN-DEX-ZA arm were 0% and 33%, respectively, compared with 37.5% and 58.3% at 1 and 2 years in the ZA-alone arm. Although underpowered, these findings demonstrate the feasibility and tolerability of an all-oral adjuvant systemic regimen in SPB and provide prospective data supporting further investigation of systemic strategies to delay progression to MM.

Objectives To estimate the proportion and correlates of self-reported financial difficulty among patients with multiple myeloma (MM) or chronic lymphocytic leukaemia (CLL). Setting Sixty-six US community and minority oncology practices affiliated with the National Cancer Institute Community Oncology Research Programme (NCORP). Participants A total of 521 patients (=18 years) with MM or CLL consented and 416 responded to a survey (completion rate=79.8%). Respondents had a MM diagnosis (74.0%), an associate degree or higher (53.4%), were White (89.2%), insured (100%) and treated with clinician-administered drugs (68.0%). Study design Observational, theoretical model and protocol-based patient survey administered between May 2019 and June 2020. Primary and secondary outcome measures Financial difficulty was assessed using a single-item measure, the EORTC QLQC30: Has your physical condition or medical treatment caused you financial difficulties in the past year? and using an any-or-none composite measure of 22 items assessing financial difficulty, worries and the use of cost-coping strategies. Multivariable logistic regression models assessed the association of financial difficulty with diagnosis, socioeconomic and treatment characteristics. Results About 16.8% reported experiencing financial difficulty using the single-item measure and 60.3% using the composite measure. Most frequently endorsed items in the composite measure were financial worry about having to pay large medical bills related to cancer and difficulty paying medical bills. Financial difficulty using the single-item measure was associated with having MM vs CLL (adjusted OR (aOR), 0.34; 95% CI, 0.13 to 0.84; p=0.02), having insurance other than Medicare (aOR, 2.53; 95% CI, 1.37 to 4.66; p=0.003), being non-White (aOR, 2.21; 95% CI, 1.04 to 4.72; p=0.04) and having a high school education or below (aOR, 0.36; 95% CI, 0.21 to 0.64; p=0.001). Financial difficulty using the composite measure was associated with having a high school education or below (aOR, 0.62; 95% CI, 0.41 to 0.94; p=0.03). Conclusions US patients with MM and CLL report financial difficulty, especially those with low socio-economic status. Interventions are needed to mitigate patients financial difficulty. Trial registration number NCT03870633 .

7540 Background: The combination of a proteasome inhibitor (PI) with lenalidomide (R) and dex (d) has been a common initial therapy for newly diagnosed myeloma (NDMM). We designed a randomized phase 3 trial to examine if carfilzomib (K), a next generation PI, improved progression free survival (PFS) compared with bortezomib (V) when either is combined with Rd for initial treatment of NDMM. Initial analysis at a median follow up of 15.3 months (mos) showed comparable PFS for both triplets. We present the long-term results of the trial with ~70 months median follow up. Methods: Patients (Pts) with NDMM, were randomized 1:1 to receive VRd or KRd for 36 weeks followed by a 2 nd randomization (1:1) to indefinite versus 2 yrs of R maintenance. Pts without del17p, t(14;16), t(14;20), plasma cell leukemia or high-risk GEP70 profile, were enrolled. VRd arm included V 1.3 mg/m 2 on days(d) 1, 4, 8, and 11 (d1, 8 for cycles 9-12), R 25 mg d1-14, and d 20 mg d1, 2, 4, 5, 8, 9, 11, 12 of a 3-week (wk) cycle for 12 cycles, while pts in the KRd arm received K 36 mg/m 2 d1, 2, 8, 9, 15, 16 with R 25 mg daily on d1-21 and d 40 mg wkly, in 4 wk cycles for 9 cycles. Maintenance used 15 mg R d1-21 q4 wks. Results: The study accrued 1087 pts (VRd=542, KRd=545). Median age was 65y; baseline characteristics including intent to transplant were similar across the arms. Median induction duration (mos; IQR) was 7.2 (3.4-8.9) and 8.4 (5.1-9.1) for VRd and KRd, respectively; 59.8% in VRd and 45.3% in KRd did not proceed to Step 2. Median PFS (mos) was VRd=41.9 and KRd=44.6; HR = 0.89 (0.76-1.04). Toxicity data, PFS sensitivity analyses and OS probabilities are as in the table. Conclusions: In this randomized trial, with median follow up of nearly 6 years, KRd and VRd had comparable PFS and OS in an intent to treat analysis. While similar numbers proceeded to SCT in the 2 arms, more did so during induction in the VRd arm while more patients in the KRd arm went to SCT later. VRd remains a standard triplet induction regimen in standard and intermediate risk NDMM, and a suitable backbone for 4 drug combinations. Clinical trial information: NCT01863550 . N (%) VRd(n=527) KRd(n=526) SCT anytime 186 (34.3) 183 (33.6) SCT without Step 2 registration 146 112 Median Time to SCT (mos; range) 7.7 (3.5-83.9) 10.6 (3.7-70.6) Grade 3-4 Treatment-Related Toxicity 315 (59.8) 344 (65.4) Grade 5 Treatment-Related Toxicity 2 (0.4) 9 (1.7) Grade 5 All Events 11 (2.1) 20 (3.8) Survival outcomes HR Median (95% CI) Median (95% CI) PFS Primary: PD or death within 3 months of last evaluation as events 0.89(0.76-1.04) 41.9(35.7, 50.3) 44.6(38.2, 51.9) PFS Sensitivity: All deaths as events, 0.87(0.75-1.02) 39.5(34.9, 46.0) 42.8(37.4, 49.7) PFS Sensitivity: Censor at alternate Rx 0.83(0.69-0.99) 35.0(31.3, 42.6) 38.7(34.7, 49.0) PFS Sensitivity: Event at alternate Rx 0.84(0.73-0.97) 18.0(14.2, 23.0) 24.4(20.9, 27.9) Overall survival 0.92(0.75-1.12) 119(100, NE) 118(103-NE)

Background: Cemsidomide (formerly CFT7455) is a novel, rationally designed, highly potent Ikaros Family Zinc Finger Protein 1/3 (IKZF1/3) MonoDACTM cereblon-based degrader. Cemsidomide has demonstrated best-in-class activity in multiple myeloma (MM) preclinical models and has also been shown to stimulate immune activation, providing combination rationale for various novel and standard of care therapies in MM. Methods: CFT7455-1101(NCT04756726) is an open-label, phase 1/2, multi-center, first-in-human study evaluating safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of cemsidomide in patients (pts) with MM and non-Hodgkin's lymphoma who have relapsed from and/or are refractory to standard of care options. Eligible MM pts must have received lenalidomide, pomalidomide, a proteasome inhibitor, and an anti-CD38 antibody. The primary objective of the MM phase 1 portion of the study is to characterize the safety and tolerability of cemsidomide alone and in combination with dexamethasone (DEX) and to determine the maximum tolerated dose (MTD) and/or recommended doses for phase 2. Secondary objectives include assessments of antitumor activity according to the International Myeloma Working Group (IMWG) response criteria, PK, and PD. Dose escalation is guided by a Bayesian logistic regression model with an initial cohort size of 3-6 pts and a provision for additional pts to be enrolled in expansion cohorts at doses deemed safe. We report initial results from our ongoing cemsidomide plus DEX dose escalation arm. Results: As of July 3rd, 2024, 32 pts have been treated with cemsidomide at various doses plus DEX (20 or 40 mg weekly) in the ongoing dose escalation portion of the study. The median age was 64 (range 40-82) and pts had received a median of 6 prior lines of therapy (range 3-17). 21/32 (66%) of pts received prior treatment with a CAR-T or a bispecific antibody. 9/32 (28%) of pts had high-risk disease at screening and 6/32 (19%) of pts had extramedullary disease. Cemsidomide doses explored in dose-escalation and expansion cohorts included 50 µg MWF (n=6), 37.5 µg QD (n=12), 62.5 µg QD (n=10), and 75 µg QD (n=4), all on a 14 day on/14 day off dosing schedule. Systemic exposure of cemsidomide increased dose proportionally. At all dose levels, cemsidomide produced expected degradation of IKZF1 and IKZF3. To date only one dose-limiting toxicity has been observed (one pt in the 62.5 µg QD cohort experienced Grade 4 neutropenia lasting &gt;7 days). 59% of pts experienced a grade ≥3 TEAE. Grade 3-4 TEAEs occurring in ≥10% of patients included neutropenia (34%), anemia (28%), infections (19%), lymphopenia (16%), and thrombocytopenia (13%). No pts experienced grade 3/4 fatigue, nausea, or vomiting. 5 pts have had treatment-related SAEs and 3 pts had an AE resulting in treatment discontinuation. As of the July 25th, 2024 efficacy cutoff, IMWG responses have been observed at all dose levels. The overall response rate among the 32 pts treated in dose escalation and expansion cohorts is 22% (1 sCR, 1 VGPR, and 5 PRs) with an additional 5 pts achieving minimal response (MR) for a clinical benefit rate of 38% (MR or better). To date, 2/4 (50%) pts in the 75 µg cohort have had a PR with expansion at 75 µg ongoing. Conclusions: Initial results from this ongoing phase 1 trial of cemsidomide in combination with DEX demonstrate encouraging efficacy and tolerability as an all-oral therapy in a heavily pre-treated MM population, with the majority of pts having received a CAR-T or bispecific antibody. As anticipated in MM, grade 3-4 toxicities consist largely of myelosuppression, which has been manageable. Given a favorable emerging safety profile and promising anti-myeloma activity, cemsidomide is potentially well suited to combine with other modalities, including proteosome inhibitors, monoclonal antibodies, antibody drug-conjugates and bispecific antibodies. Dose escalation will continue until an MTD and/or the recommended phase 2 doses are identified. Updated data will be presented at the conference.

Abstract Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM), despite common toxicities, including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 mg once weekly was associated with lower mortality than higher doses. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM has not been fully characterized. We conducted a secondary pooled analysis of the SWOG 0777 and SWOG 1211 studies of NDMM, which used lenalidomide and dexamethasone (Rd) alone, with or without bortezomib, and with or without elotuzumab. The planned dexamethasone intensity was 40 to 60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for grade 3+ toxicities per both study protocols). Of the 541 evaluated patients, the LD-DEX group comprised 373 patients (69%). There were no differences in PFS or OS between the FD-DEX and LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in the multivariate models were treatment arm, age ≥70 years, and thrombocytopenia. FD-DEX did not significantly improve either outcome. Our study suggests that dexamethasone dose reductions are common in multiple myeloma, even within clinical trials. Given the many toxicities and unclear benefits of dexamethasone in the era of modern treatment regimens, dexamethasone dose reduction during NDMM induction warrants further prospective studies. These trials were registered at www.clinicaltrials.gov as #NCT00644228 and NCT01668719.

AbstractObjectivesCluster of differentiation 38 (CD38) is a key target on multiple myeloma (MM) cells. This multi‐centre, Phase 1, single‐agent study (NCT04000282) investigated SAR442085, a novel fragment crystallisable (Fc)‐modified anti‐CD38 monoclonal antibody (mAb), with enhanced affinity towards Fc‐gamma receptor on effector cells in patients with relapsed and/or refractory (RR) MM.MethodsThis study comprised two parts: Part‐A (dose‐escalation involving anti‐CD38 mAb pre‐treated and naïve patients) and Part‐B (dose expansion). Primary endpoints were maximum tolerated dose and recommended Phase 2 dose (RP2D).ResultsThirty‐seven heavily pre‐treated patients were treated in Part A. Part‐B (dose‐expansion) was not studied. Seven dose‐limiting toxicities were reported at DL3, DL5, DL6, and DL7. RP2D was determined to be 5–7·5 mg/kg. Most common treatment‐emergent adverse events were infusion‐related reactions in 70·3% (26/37) patients. Grade ≥3 thrombocytopenia was reported in 48·6% (18/37). Overall response rate was 70% in anti‐CD38 mAb naïve and 4% in anti‐CD38 pre‐treated patients, with a median progression‐free survival of 7·62 (95%CI: 2·858; not calculable) months and 2·79 (95%CI: 1·150; 4·172) months and, respectively.ConclusionsThe efficacy of SAR442085 was promising in anti‐CD38 mAb naïve patients but did not extend to the larger cohort of anti‐CD38 mAb pre‐treated patients. This observation, along with transient high‐grade thrombocytopenia, could potentially limit its clinical use.

Introduction: Preclinical studies have suggested synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a master transcriptional factor that regulates myeloma cell survival. Single agent oral IBR combined with dexamethasone proved well tolerated and active in advanced, steroid refractory relapsed MM as part of a large Phase1/2 study in 60 patients, with durable stabilization and minimal response seen in most evaluable patients (Richardson PG et al, BJH 2018). LEN is considered a standard of care in newly diagnosed MM, as maintenance and in relapsed disease, and a backbone of oral therapy in the MM treatment paradigm (Laubach JP et al, Leukemia 2016). Methods: We therefore conducted a 3+3 phase I trial to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least 2 prior lines of therapy. Three dose levels (DL) were planned. Cycle length was 28 days. IBR was administered orally daily at 560mg on DL1-2 and 840mg on DL3, LEN orally days 1-21 at 15mg on DL1 and 25mg on DL2-3, and DEX orally days 1, 8, 15, and 22 at 40 mg if age &lt; 75 or 20 mg if ≥75 for DL1-3. Patients with GFR ≥ 30 and &lt; 60 were treated according to manufacturer's instructions with lenalidomide dosed at 10mg/d. Dose limiting toxicities (DLT) included grade 4 thrombocytopenia; grade 4 neutropenia lasting more than 5 days or febrile neutropenia; grade 4 nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; grade 3-4 hyperglycemia or thrombotic/embolic event, treatment delays ≥ 21 days for toxicity; and treatment related death. Due to changes in standard of care during the study, eligibility was modified to allow the enrollment of patients with RRMM who had at least 1 prior line of therapy. Response was assessed using IMWG/Uniform Criteria. Results: Fourteen patients (DL1-6 pts; DL2-3 pts; DL3-5 pts) registered to the study from March 2019 to May 2023, prior to its closure due to slow accrual. One patient on DL3 cancelled participation prior to start of treatment due to disease progression (PD). The remaining 13 patients are included in summary of toxicities and response but 2 patients on DL3 are excluded from determination of MTD due to discontinuing cycle 1 treatment due to COVID and receiving 280 mg/day of IBR instead of assigned 840 mg/day dose during cycle 1, respectfully. Twelve patients were evaluable for response. The median number of prior lines of therapy was 3 (range: 2-9), reflecting a heavily pretreated relapsed and refractory population. One of the 6 patient on DL1 developed a DLT, grade 3 non-viral hepatitis. None of the 3 patients on DL2 or the 2 patients on DL3 had a DLT. One patient on DL1 remains on treatment with stable disease for 42+ cycles. The median number of cycles administered was 3 (range: 1-42+). Severe toxicities reported included grade 3 lymphocytopenia (3), anemia (2), alanine aminotransferase increase (1), aspartate aminotransferase increase (1), blood bilirubin increase (1), hypocalcemia (1), hypokalemia (1) hypophosphatemia (1), febrile neutropenia (1), chronic kidney disease (1), non-viral hepatitis (1), soft tissue infection (1), and fatigue (1); grade 4 lymphocytopenia (1), and grade 5 sepsis (1). End of treatment reasons included: PD (7), toxicity (2), death [soft tissue infection that turned into sepsis considered to be likely related to DEX] (1), and concomitant conditions (2). Stable disease (SD) or better was achieved in 10 of 12 evaluable patients (83%), including one patient who achieved disease control for over 3.5 years. One patient (8%) on DL3 had a complete response (CR) but stopped treatment after 2 cycles due to reversible toxicity and comorbid conditions, based upon physician advice and patient choice. Conclusions: The combination of lenalidomide with Ibrutinib as an all-oral approach in RR MM proved feasible and generally tolerable, with the majority of discontinuation seen in this Phase I study due to disease progression. No COVID related - mortality was seen. SD or better was achieved in 83% of patients, including one CR. Potential future directions include combination approaches with next generation IMids such as pomalidomide, as well as other orally bioavailable novel agents with potent immune activating properties, such as CelMoDs. Support: AFT; Pharmacyclics; Clinicaltrials.gov Identifier: NCT03702725

AbstractBackgroundCD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved—daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites.AimAmong the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38‐mediated T‐cell activation. Patients who respond to anti‐CD38 targeting treatment experience more marked changes in T‐cell expansion, activity, and clonality than nonresponders.ImplicationsResistance mechanisms that undermine the immunomodulatory effects of CD38‐targeting therapies can be tumor intrinsic, such as the downregulation of CD38 surface expression and expression of complement inhibitor proteins, and immune microenvironment‐related, such as changes to the natural killer (NK) cell numbers and function in the bone marrow niche. There are numerous strategies to overcome this resistance, which include identifying and targeting other therapeutic targets involved in, for example, adenosine production, the activation of NK cells or monocytes through immunomodulatory drugs and their combination with elotuzumab, or with bispecific T‐cell engagers.

AbstractDeeper responses are associated with longer survival in multiple myeloma (MM); however, limited data exist on the impact of response kinetics on outcomes. We investigated progression‐free survival (PFS) and duration of response (DOR) by response depth and in early (best confirmed response 0–4 months; n = 424) versus late responders (best confirmed response >4 months; n = 281). Newly diagnosed patients enrolled in TOURMALINE‐MM2 receiving ixazomib‐lenalidomide‐dexamethasone (IRd) (n = 351) or placebo‐Rd (n = 354) were evaluated post hoc. Deeper responses were associated with longer PFS (complete response [CR] not reached [NR], very good partial response [VGPR] 37.2 months, partial response [PR] 16.4 months) and DOR (CR NR, VGPR 42.6 months, PR 15.4 months). Among patients with a PFS (n = 511) or DOR (n = 484) of ≥6 months who achieved ≥PR, median PFS was prolonged among late versus early responders receiving IRd (59.7 vs. 17.9 months) or placebo‐Rd (56.6 vs. 12.4 months), as was median DOR (IRd, NR vs. 20.9 months; placebo‐Rd, 58.2 vs. 11.7 months). While the treatment paradigm for newly diagnosed MM is treatment to progression, our findings suggest slowness of response to a proteasome inhibitor‐immunomodulatory drug‐steroid combination is not a negative predictor of outcome.

Abstract Introduction: CFT7455 is a highly potent and novel Ikaros Family Zinc Finger Protein 1/3 (IKZF1/3) degrader. In xenograft models, CFT7455 has more potent IKZF1/3 degradation compared to other degraders. Early observations from the FIH clinical trial (NCT04756726) along with supporting translational studies are presented here. Methods: Pre-clinical studies comparing CFT7455 and CC-92480 in both in vitro and xenograft models were performed. The pre-clinical studies’ results coincided with observations from the on-going clinical trial. The clinical trial is an open-label, Phase 1/2, multi-center, FIH study in heavily pretreated relapsed/refractory (R/R) MM and non-Hodgkin’s lymphoma (NHL) patients evaluating safety, tolerability, and PK of CFT7455. Eligible MM patients are R/R to therapy and are not candidates for regimens known to provide clinical benefit. A starting dose of 50 μg QD 21 days on/7 days off (21/7) in 28-day cycles was administered. Results: CFT7455 and CC-92480 showed similar cereblon binding profiles and in vitro IKZF1/3 degradation kinetics, translating into sub-nanomolar GI50 values in proliferation assays across a panel of MM cell lines. In the NCI-H929 xenograft model, 100 μg/kg/day of CFT7455 resulted in durable tumor regressions, while 1000 μg/kg/day of CC-92480 gave tumor stasis. Similar results were seen in a systemic model of MM, MM1.S. Both compounds achieved &gt;95% IKZF3 degradation in tumors 4h post dose. At 48h post dose, CFT7455 was more effective than CC-92480 in maintaining IKZF3 degradation (65% vs. 6% respectively). When levels of CFT7455 and CC-92480 in plasma and tumor were compared, CFT7455 concentrations were &gt; DC80 in tumor 48h post dose, while CC-92480 levels were undetectable in tumor and plasma, demonstrating CFT7455 has longer exposure resulting in sustained IKZF1/3 degradation in pre-clinical models. In cohort A, 5 heavily pre-treated MM patients (pts) received single agent CFT7455. 4 pts have received at least 3 cycles, with 2 pts receiving 5 cycles. Neutropenia (grade 4) was observed in 3/5 pts without coincident fever or infection. Additionally, a 2-4 fold accumulation in plasma CFT7455 exposure at steady state was observed. Early pharmacodynamic (PD) data demonstrates deep persistent degradation of IKZF3 (~100%) and serum free light chain reduction (up to 72%) in response to treatment. Stable disease has been observed in 34 pts, suggesting clinical benefit. Conclusions: While CFT7455 showed clinical benefit at 50 ug with deep target degradation, neutropenia was dose limiting. PK/PD modeling suggests alternative dosing regimens may result in increased tolerability with preserved efficacy, and evaluation of them is underway. Updated results will be presented at the meeting. Citation Format: Sagar Lonial, Shambavi Richard, Jeffrey V Matous, Andrew J. Yee, Urvi Shah, Neha Mehta-Shah, Thomas Martin, Eli Muchtar, Sikander Ailawadhi, Paul G. Richardson, Manisha Bhutani, Samantha Perino, Jason Kirby, Roman V. Agafonov, Prasoon Chaturvedi, Bradley Class, Matthew Schnaderbeck, Michael R. Palmer, Cathleen Gorman, Oliver Schoenborn-Kellenberger, Amanda Hoerres, Stewart L. Fisher, Roy M. Pollock, Adam Crystal, Michelle Mahler, Jesus Bardeja. Pharmacokinetic (PK) profile of a novel IKZF1/3 degrader, CFT7455, enables significant potency advantage over other IKZF1/3 degraders in models of multiple myeloma (MM) and the results of the initial treatment cohort from a first-in-human (FIH) phase 1/2 study of CFT7455 in MM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT186.