Orlowski, Robert Z.

Abstract Both the phase 3 MAIA and ALCYONE studies demonstrated significant survival benefit with the addition of daratumumab to standard-of-care Rd (Revlimid [lenalidomide] and dexamethasone; D-Rd) or to VMP (Velcade [bortezomib], melphalan, and prednisone; D-VMP), respectively, vs Rd or VMP alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). Patients with NDMM are highly susceptible to infection; therefore, gaining a greater understanding of infection incidence may help to mitigate future risk. We conducted a pooled analysis of infection incidence, timing, and management strategies from MAIA and ALCYONE. The median (range) age of the pooled population was 72 (40-93) years. Incidence was higher with D-Rd/D-VMP vs Rd/VMP for grade 3/4 (36.9% vs 22.4%) and grade 5 (3.0% vs 1.5%) infections; however, exposure-adjusted incidence rates were generally comparable between groups. Any-grade infections led to the discontinuation of study treatment in ∼2% of patients across treatment groups. Of the timing intervals explored, the highest incidence of grade 3/4 infection occurred within the first 6-month interval of study treatment initiation in both groups. Median time to the first onset of grade 3/4 infections (per Kaplan-Meier estimates) was 83.3 months and not estimable in the D-Rd/D-VMP and Rd/VMP groups, respectively. Although the rates of D-Rd/D-VMP treatment discontinuation due to infection remained low in MAIA and ALCYONE, clinicians should remain vigilant about infections throughout treatment and follow local guidelines and International Myeloma Working Group recommendations to minimize the risk of infection. These trials were registered at www.ClinicalTrials.gov as NCT02252172 (MAIA) and NCT02195479 (ALCYONE).

Abstract Background: Multiple myeloma (MM) is always preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage or high tumor cell burden (i.e. SLiM criteria, SV Rajkumar Lancet Onc 2014), as morphology and cytogenetics cannot reliably distinguish them. Methods: To identify genomic features underlying clinical behavior in MGUS and SMM, a total of 374 patients with SMM (n= 290) or MGUS (n=84) with available whole exome (whole exome sequencing, WES, n=190) or whole genome sequencing (whole genome sequencing WGS, n=184) were included in the study. Overall, none of the patients had evidence of SLiM or CRAB criteria at the time of the biopsy. Based on the center of origin and availability of WES and WGS, 227 and 97 patients were used to form our study training and validation set. The study was designed in two parts: 1) defining a new classification for MM precursor conditions; 2) integrating genomics to existing prognostic score to improve accuracy in identifying patients at imminent risk of progression. Overall, 68 patients in the training set were either lost to follow-up or enrolled in a clinical trial and they were only included in the classification part of the study. Results: By leveraging the distribution of established MM-defining genomic events (Maura et al. JCO 2024) in the training set, we developed a workflow that differentiates MGUS and SMM into two genomically distinct entities: one with evidence of neoplastic transformation (i.e., genomic MM) and one without (i.e., genomic MGUS). Overall, 39% of MGUS and 91% of SMM cases had genomic evidence of neoplastic transformation in the training set (i.e., genomic MM). When we applied the same workflow and classification to the validation set, 46% and 83% of MGUS and SMM had evidence of neoplastic transformation, respectively. Importantly, none of the patients classified as genomic-MGUS progressed to MM in either the training or validation cohorts, with a median follow-up of 40 and 61 months, respectively. Moreover, all patients with IMWG 2/20/20 high risk SMM were classified as genomic MM in both the training and validation set. Interestingly, 5 out of 62 (8%) patients enrolled in early intervention trials for high risk SMM were genomically classified as genomic-MGUS. Overall, these data demonstrated that the MM genomic background and neoplastic transformation can be acquired very early in time, even before the SMM phase, in line with what observed in solid tumors. To avoid overestimating the prognostic impact of myeloma-defining genomic events—which are, by definition, enriched in the genomic-MM group compared to genomic-MGUS—we restricted our prognostic analysis to patients in whom transformation has already occurred (genomic-MM). In fact, distinct genomic drivers may predict malignant transformation but not necessarily the risk of imminent progression to MM once transformation has occurred. After running 5-fold cross validations corrected for IMWG 2/20/20, only presence of RAS mutations, genomic events involving MYC, presence of neoplastic copy number variant (CNV) signatures and APOBEC mutagenesis were predictive of early progression in the training set. Adding the presence of high-risk myeloma-defining genomic events to the IMWG 2/20/20 model (i.e., genomic-IMWG) significantly improves the accuracy of predicting MM progression in both the training (c-index 0.69 vs. 0.74) and validation sets (c-index 0.74 vs. 0.79), compared to the IMWG 2/20/20 alone. Conclusion: By leveraging comprehensive genomic profiling integrated with the clinical IMWG 2/20/20 risk score, we propose a novel classification and prognostication system for MM precursor conditions, which will better define patients who may benefit from early therapeutic intervention versus watch-and-wait monitoring.

Abstract Background and Significance: Waldenström's Macroglobulinemia (WM) is an indolent B cell disorder characterized by proliferation of clonal lymphoplasmacytic lymphocytes in the bone marrow, lymph nodes, as well as liver and spleen, and secreting a monoclonal IgM Protein. WM is a rare disorder with about 1,700 cases diagnosed in the U.S. each year. There have been significant advances in the management of patients with WM in the last decade, with Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib and zanubrutinib) emerging as a major treatment advancement in this disease. Currently, both BTK inhibitors are approved for the treatment of WM patients with newly diagnosed as well as relapsed/refractory (R/R) disease. BTK inhibitors are effective for the therapy of WM, especially among patients with MYD88 mutation, although the response rates are lower in patients with CXCR4 mutations. In addition, these drugs can cause cardiac side effects such as atrial and ventricular arrhythmias as well as an increased risk of bleeding/bruising. Thus, these drugs can be difficult to use in patients who are older and have cardiac comorbidities. BCL-2 overexpression is well described in a number of B cell malignancies, including WM, leading to inhibition of apoptosis of malignant cells. BCL-2 inhibition with venetoclax has been tested in patients with R/R WM and showed excellent activity with an overall response rate (ORR) of 85% and very good partial response (VGPR) rate of 19%. The therapy was overall well tolerated with no evidence of cardiac toxicity. Given the excellent activity and tolerability of Venetoclax in WM, we are conducting a national cooperative group randomized phase 2 trial comparing ibrutinib+rituximab (IR) vs. venetoclax+rituximab (VR) in patients with newly diagnosed WM. Our hypothesis is that with this trial, we have the potential to develop a more effective therapy targeting BCL-2 for patients with untreated WM, that does not have cardiac or hemostatic toxicity. In addition, we are testing use of a fixed duration therapy with these regimens. Study design and methods: The ongoing clinical trial () is being conducted through the Southwest Oncology Group (SWOG) and is enrolling at multiple SWOG, ECOG, and ALLIANCE centers throughout the US. Major inclusion criteria include 1) newly diagnosed WM confirmed by biopsy and measurable disease (≥0.5 g/dl IgM type paraprotein), 2) meeting WM-related clinical criteria to initiate therapy (cytopenias, B symptoms, bulky lymphadenopathy, neuropathy, hyperviscosity) 3) adequate blood counts (ANC >1000, HGB ≥7.5, PLT ≥50,000), 4) eGFR ≥30 ml/min, 5) adequate liver function tests (total bilirubin ≤1.5 x ULN and AST, ALT and alkaline phosphatase ≤3 x ULN), 6) Zubrod performance status ≤2, 7)prior treatment with single-agent R allowed as long as >6 months prior to registration. Once enrolled the patients will be randomized 1:1 to IR vs. VR. I will be started at 420 mg daily at start of therapy while V will be given at 400mg daily during cycle 1 week 1 and then increased to 800 mg daily from cycle 1 day 8 onwards. R will be given weekly x 4 in cycles 2 and 5. Dose adjustments for both I and V can be done depending on toxicity. Therapy will be given for 2 years and then the patients will be observed off treatment. Patients with disease progression during these 2 years of therapy can cross-over to the other arm. The primary endpoint of the study is rate of VGPR or better. With 41 eligible participants per arm (total N=82), this design has 80% power to reject the null hypothesis of a 25% VGPR rate, given the alternative of a 50% VGPR rate, with a one-sided alpha of 10%. To account for an anticipated 10% ineligibility rate, approximately 46 participants will be accrued per arm (92 total). Current enrollment stands at 15 patients. The secondary end points include ORR, complete response rate, major response rate, progression free and overall survival rates.

Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage as morphology and cytogenetics cannot reliably distinguish them. In this study, using genomic data from 374 patients with MGUS or SMM (277 training, 97 validation), to our knowledge, we demonstrate for the first time the ability to identify malignant transformation in MGUS and SMM. We introduce the concept of genomic MM and genomic MGUS to differentiate the subsets of MGUS and SMM that are biologically malignant with genomic features indistinguishable from MM from the subset that is premalignant and unlikely to progress to malignancy. Importantly, we find that most SMM has biological features of malignant transformation indistinguishable from MM. As expected, this subset that we consider having genomic MM is associated with a high risk of progression to MM although some patients remained progression-free beyond 5 years. Conversely, 60% of MGUS and 10% of SMM have no evidence of malignant transformation (genomic MGUS), with no progression during follow-up. Integration of genomic features with the 2/20/20 International Myeloma Working Group model significantly improved the prediction of progression among genomic MM. These findings support the use of genomic criteria to refine the classification and the risk stratification in myeloma precursor conditions.

Abstract Isatuximab is an immunoglobulin G1κ monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells. Anti-CD38 antibodies have shown efficacy as monotherapy and in combination in a variety of settings for patients with multiple myeloma and light chain (AL) amyloidosis. This multicenter, cooperative group phase 2 trial was designed to evaluate hematologic response, organ response, and safety of isatuximab monotherapy for the treatment of relapsed AL amyloidosis. Isatuximab at 20 mg/kg was administered IV weekly during the first 28-day cycle, and then every other week during cycles 2 to 24. Forty-three patients were registered, with 35 patients being evaluable for response. The overall hematologic response rate was 77.1%, with 57% of patients achieving a very good partial response (VGPR) or better. The median time to partial response (PR) or better was 1.1 months. Renal response occurred in 50% (7/14) of patients with renal involvement, and cardiac response occurred in 57% (8/14) of patients who were evaluable utilizing N-terminal pro b-type natriuretic peptide (NT-proBNP) with cardiac involvement. The most common treatment-related grade ≥3 adverse events included lymphopenia (n = 3, 8.5%) and infection (n = 2, 6%). Isatuximab demonstrated substantial efficacy in previously treated patients with AL amyloidosis, and was associated with a good safety profile. This trial was registered at www.clinicaltrials.gov as #NCT03499808.

Despite significant improvements in survival of patients with multiple myeloma (MM), outcomes remain heterogeneous, and a significant proportion of patients experience suboptimal outcomes. Importantly, traditional prognostic factors based on data from patients treated with older therapies no longer capture prognosis accurately in the contemporary era of novel triplet or quadruplet therapies. Therefore, risk stratification requires refinement in the context of available and investigational treatment options in routine practice and clinical trials, respectively. The current identification of high-risk MM (HRMM) in routine practice is based on the Revised International Staging System, which stratifies patients using a combination of widely available serum biomarkers and chromosomal abnormalities assessed via fluorescence in situ hybridization. In recent years, a substantial body of evidence concerning additional clinical, biological, and molecular/genomic prognostic factors has accumulated, along with new MM risk stratification tools and consensus reports. The International Myeloma Society, along with the International Myeloma Working Group, convened an Expert Panel with the primary aim of revisiting the definition of HRMM and formulating a practical and data-driven consensus definition, based on new evidence from molecular/genomic assays, updated clinical data, and contemporary risk stratification concepts. The Panel proposes the following Consensus Genomic Staging (CGS) of HRMM which relies upon the presence of at least one of these abnormalities: (1) del(17p), with a cutoff of >20% clonal fraction, and/or TP53 mutation; (2) an IgH translocation including t(4;14), t(14;16), or t(14;20) along with 1q+ and/or del(1p32); (3) monoallelic del(1p32) along with 1q+ or biallelic del(1p32); or (4) β2 microglobulin ≥5.5 mg/L with normal creatinine (<1.2 mg/dL).

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)

ABSTRACTObjectivesThis final post hoc analysis evaluated patient‐reported outcomes from the Phase 3 MAIA study of daratumumab, lenalidomide, and dexamethasone (D‐Rd) versus lenalidomide and dexamethasone (Rd) after median 64.5‐month follow‐up in transplant‐ineligible patients with newly diagnosed multiple myeloma (NDMM), including patient subgroups.MethodsKey scales from the EORTC QLQ‐C30 (global health status [GHS], physical functioning, pain, and fatigue) were assessed. Scores were evaluated every 3 months for 1 year, then every 6 months until disease progression.ResultsThe intent‐to‐treat population (n = 737) included 46.3% frail, 35.4% 70 to < 75 years old, and 43.6% ≥ 75 years old. D‐Rd‐treated patients showed improvements from baseline that were sustained over 5 years in the intent‐to‐treat population and across subgroups by age, frailty, and bone lesions. Greater proportions of patients treated with D‐Rd versus Rd achieved minimally important changes for improvement at cycle 36 (year ~3) in GHS (odds ratio, 1.84 [95% CI, 1.16–2.91]), physical functioning (1.93 [1.18–3.14]), pain (1.41 [0.90–2.22]), and fatigue (2.00 [1.24–3.23]). Greater proportions of patients with bone lesions improved with D‐Rd versus Rd on GHS and physical functioning.ConclusionsIn transplant‐ineligible patients with NDMM, D‐Rd improved health‐related quality of life over a 5‐year period versus Rd. Trial Registration: ClinicalTrials.gov: NCT02252172

Background: Isatuximab is an IgG1κ monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells in light chain (AL) amyloidosis. Anti-CD38 antibodies have shown efficacy alone and in combination in a variety of settings for patients with multiple myeloma and light chain (AL) amyloidosis. Here we report the final analysis of a multi-center, cooperative group prospective phase II study of isatuximab in previously treated patients with AL amyloidosis (NCT03499808). Methods: Eligibility included: age ≥18 years, relapsed or refractory systemic AL amyloidosis, ≥1 prior line of therapy, measurable disease, ≥1 organ involved, not refractory to daratumumab, Eastern Cooperative Oncology Group performance status ≤2, creatinine clearance ≥25 mL/min, and NT-proBNP ≤8500 pg/mL. Patients received isatuximab intravenously 20 mg/kg weekly during the first 28-day cycle and every other week during cycles 2 through 24 for a maximum of 24 cycles. The primary objective was hematologic response with secondary objectives of organ response, safety, progression free survival, and overall survival. Results: Forty-three patients were registered, with 35 patients being eligible for response. The median age of the evaluable patients was 70 years (range, 40.1-79.5) with the majority (66%, n=23) having a lambda clonal plasma cell dyscrasia. The most common cytogenetic abnormality using fluorescence in situ hybridization was translocation t(11;14) observed in ten patients (29%). The most common prior treatment was a proteasome inhibitor (94%, n=33) while 46% (n=16) had undergone autologous stem cell transplant. Eighteen patients (51%) had single organ involvement while 17 (49%) had multiple organs involved. The distribution of organ involvement was typical for AL amyloidosis with cardiac involvement in 25 patients (71%) and renal involvement in 14 (40%). As of December 30, 2022, no new safety concerns were identified. The most common treatment related grade ≥3 adverse events included lymphopenia (n=3, 8.5%) and infection (n=2, 6%). The overall hematologic response rate was 77.1% with a rapid median time to partial response or better of 1.1 months. Two patients (6%) achieved a hematological complete response (CR), 18 (51%) had a very good partial response (VGPR), and 7 (20%) had a partial response (PR). At 24 months from hematologic response, the rate of patients still in response was estimated at 81% (95% confidence interval (CI): 67, 96). The 24-month estimated overall survival was 85% (95% CI: 73%, 97%). Renal response occurred in 50% (7/14) of patients with renal involvement with a median time to response of 18.5 months. Cardiac response occurred in 56% (14/25) of patients with cardiac involvement with a median time to response of 16.6 months. Conclusions: Isatuximab monotherapy resulted in high rates of hematologic response in relapsed AL amyloidosis which translated into organ responses. Treatment appears safe and was well tolerated. Support: NIH/NCI/NCTN grant awards U10CA180888, U10CA180819, CA180820, and CA180821; and in part by Sanofi-Aventis (Sanofi US)