High-risk Chromosomal Abnormalities Research Articles

Use of daratumumab in combination with lenalidomide and dexamethasone (D-Rd regimen) in therapy of elderly patients with newly diagnosed multiple myeloma with high-risk cytogenetics. Clinical observation

Multiple myeloma (MM) is a B cell lymphoproliferative disease characterized by clonal proliferation of plasma cells and heterogenous progression. Successes in MM therapy are in large part based on the study of molecular and genetic features of disease pathogenesis and identification of high-risk chromosomal abnormalities determining prognosis and antitumor response. Elderly patients with newly diagnosed MM with high-risk cytogenetics who are not candidates for autologous stem cell transplantation should receive programs of antitumor therapy which increase progression-free survival and overall survival with satisfactory tolerability and minimal toxicity. Use of monoclonal antibodies in triplets at early stages allow to achieve deeper antitumor response, the absence of minimal residual disease in a greater number of observations, and improve survival in all patient subgroups.A clinical observation of a 75-year-old female patient with newly diagnosed MM with high-risk cytogenetics and multiple bone plasmacytomas with massive extraosseous components is presented. During D-Rd regimen therapy, after 8 daratumumab administrations very good partial remission was achieved which has been maintained for 20 months. Significant improvement in quality of life with satisfactory treatment tolerability and absence of adverse events are observed

Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long-term outcomes in the Phase 3 IKEMA study.

Gain/amplification of 1q21 (≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma, can negatively affect prognosis, due to its involvement in resistance to anti-myeloma therapy and disease progression. In this updated subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285) in relapsed/refractory multiple myeloma (RRMM), we evaluated progression-free survival (PFS) and depth of response with the anti-CD38 antibody isatuximab plus carfilzomib-dexamethasone (Isa-Kd) versus Kd, in 1q21+ patients and related subgroups, at long-term follow-up (44.2months). Our analysis included patients with 1q21+ (≥3 copies, with/without high-risk chromosomal abnormality [HRCA]), isolated 1q21+ (≥3 copies, without HRCA), gain(1q21) (3 copies, with/without HRCA), and amp(1q21) (≥4 copies, with/without HRCA). PFS benefit was achieved with Isa-Kd versus Kd in patients with 1q21+ (HR 0.58, 95% CI: 0.37-0.92), with isolated 1q21+ (HR 0.49, 95% CI: 0.27-0.92), with gain(1q21), or amp(1q21), consistent with the overall population and prior interim 1q21+ subgroup analyses. Median PFS with Isa-Kd versus Kd was 25.8 versus 16.2months in 1q21+ patients and 38.2 versus 16.2months in patients with isolated 1q21+. Clinically meaningful, higher rates of very good partial response or better, complete response or better (≥CR), minimal residual disease (MRD) negativity, and MRD negativity and ≥CR were reached with Isa-Kd versus Kd in patients with 1q21+, isolated 1q21+, gain(1q21), or amp(1q21). In Isa-Kd and Kd, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in 1q21+ patients, 36.2% versus 12.9% in patients with isolated 1q21+, 27.9% versus 13.5% in patients with gain(1q21), and 31.3% versus 20.0% in patients with amp(1q21), respectively. In conclusion, addition of Isa to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd, in 1q21+ patients at higher risk of progression, including patients with isolated 1q21+, gain(1q21), and amp(1q21), thus supporting Isa-Kd an effective treatment option for patients with RRMM.

Abstract B020: Genetic markers, first-line treatment, and survival among Hispanic patients with multiple myeloma: A population-based study in Puerto Rico

Abstract Background: Research on the genetic markers, treatment, and survival of multiple myeloma (MM) among Hispanics is limited. Most population-based registries do not comprehensively collect cancer-related biological and genetic markers, which limits the use of these registries to address critical research questions. We used the Puerto Rico Central Cancer Registry (PRCCR) and the PRCCR-Health Insurance Linkage Database (PRCCR-HILD) to evaluate these factors among patients diagnosed with MM in Puerto Rico (PR). Methods: A retrospective cohort study was conducted among MM patients in PR between 2015 and 2019. We developed a robust sub-database that expands the quality and quantity of data regularly collected by the PRCCR and health insurance claims by integrating data from PRCCR’s cancer database, Electronic Medical Records, Pathology Reports database, and PRCCR-HILD. Descriptive statistics were used to present an epidemiological profile of the study group. Bivariate analyses were performed to evaluate associations between treatment patterns and patient characteristics. Multivariable Cox regression models were used to estimate the magnitude of the association between overall mortality among patients with MM and different characteristics. Results: The study cohort consisted of 716 patients; 49.6% were male, the median age at diagnosis was 69 years, and 76.7% had a comorbidity index score ³2. High-risk chromosomal abnormalities (HRCAs), which include at least one of t(4;14), t(14;16), Del(17p), and t(14;20), were found in 23.2% of patients. Around 88% of MM patients had documented evidence of treatment, and nearly half of all patients began treatment after 30 days (49.1%) of diagnosis. The most common treatment was bortezomib-based triplet (29.1%), followed by bortezomib-based doublet (25.9%). Based on the multivariable Cox models, the risk of dying was greater among patients who had chromosome 1 abnormalities (C1As) (HRAdjusted: 1.28, 95% CI: 0.99-1.66) or HRCAs (HRAdjusted: 1.39, 95% CI: 1.04-1.86) than patients without C1As or HRCAs, respectively. Furthermore, the risk of dying was lower among those receiving treatment after controlling by potential confounders (HRAdjusted: 0.44, 95% CI: 0.32-0.61). Among those receiving treatment, the bortezomib triplet showed better results than dexamethasone (HRAdjusted: 2.62, 95% CI: 1.63-4.20) and bortezomib-based doublet (HRAdjusted: 1.72, 95% CI: 1.14-2.60). Conclusion: This study provides the first description of the prevalence of genetic markers in patients with MM in PR, integrating epidemiological, clinical, and health claims data. Our analysis confirms that HRCAs and C1As remain as important predictor factors in determining the outcomes of MM patients. In addition, treatment patterns in PR Hispanic population suggest a longer median time to treatment initiation than other US studies, which warrants follow-up. These findings highlight the importance of establishing a broader understanding of the genetic and treatment-related factors associated with MM outcomes in different racial/ethnic groups. Citation Format: Tonatiuh Suárez Ramos, Maira A. Castañeda-Avila, Carlos R. Torres-Cintrón, Axel Gierbolini-Bermúdez, Guillermo Tortolero-Luna, Karen J. Ortiz-Ortiz. Genetic markers, first-line treatment, and survival among Hispanic patients with multiple myeloma: A population-based study in Puerto Rico [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B020.

Patterns of Change in Multiple Myeloma (MM) Clone Size with Autologous Hematopoietic Stem Cell Transplantation (ASCT) Assessed By Next Generation Sequencing (NGS) in Patients (pts) Receiving Modern Therapy

Background Measurable residual disease (MRD) is a quantitative, dynamic prognostic marker of progression free and overall survival in MM. With modern triplet and quadruplet induction strategies deep responses are the norm and the incremental effect of ASCT impact may vary substantially among pts and be influenced by disease and treatment features. However, the accurate characterization of the impact of ASCT is diluted by measuring a disease surrogate (paraprotein) instead of clone size. We examine the quantitative impact of ASCT on MM clone size by serial NGS testing before and after ASCT and evaluate disease and induction treatment features that modulate this impact. Methods We included pts with newly diagnosed MM from five US centers, who received modern triplet and quadruplet induction followed by single melphalan ASCT between 3/2018 and 5/2023 with MRD testing (ClonoSEQ®) pre and post ASCT. ClonoSEQ® platform utilizes NGS to quantify unique immunoglobulin genes rearrangements associated with MM clone, therefore directly capturing clone size. We excluded pts with clone size <10 -5 prior to ASCT. We explored patient-, disease-, and treatment features influencing clone size reduction with AHCT by 1 log 10. We used binary logistic regression to identify factors associated with ≥1 log 10 clone reduction (60-100 days post ASCT). Results One hundred and forty-nine pts with NDMM had pre and post ASCT results and pre ASCT MRD ≥10 -5 and met the inclusion criteria. The median age was 63 years (35-79), 37 pts (25%) ≥70 years, 62% male, 27% Black, 23% ISS3 and 16% RISS3. Seventy-three pts (49%) had high risk chromosomal abnormalities [HRCA, gain/amp(1q), t(4;14), t(14;16), t(14;20) or del(17p)]); 72 pts (48%) had 0 HRCA, 50 (34%) had 1 HRCA, and 23 (15%) had 2+ HRCA. AntiCD38 monoclonal antibody (mAb) was part of induction in 125 (84%) pts [68 pts quadruplet containing carfilzomib; 53 pts quadruplet containing bortezomib], 28 pts received triplets. Eighty-seven pts (58%) had >1log 10 reduction in MRD burden with ASCT. The median log reduction in MRD burden was 1.15 (IQR 0.65-1.75). For pts with 0, 1 and 2+ HRCA, 47% (34/72), 68% (34/50), 74% (17/23) had a >1 log 10 reduction in clone size and the median reduction was 0.96 log 10 (IQR 0.47-1.66), 1.24 log 10 (IQR 0.89-1.91) and 1.5 log 10 (IQR 0.89-2.20), respectively (Figure). Among pts without HRCA, those with hyperdiploid MM had a trend towards less frequent ≥1 log 10 clone size reduction with ASCT (38% vs. 57%, p=0.18). Overall, we saw reduction ≥1 log 10 in clone size in 61% of pts receiving anti-CD38 mAb in induction (N=125) vs. 46% among those who did not (N=24, p= 0.18). Among pts treated with melphalan 200 mg/m 2 (N=113) compared to those who received 140 mg/m 2 (N=36), ≥1 log 10 reduction in clone size was noted in 61% vs. 50% (p=0.25), respectively. In multivariable analysis that included stage, antiCD38 mAb in induction, use of carfilzomib in induction, HRCA and melphalan dose, the presence of HRCA was the only factor associated with greater than 1 log 10 reduction in MRD burden with ASCT [1 HRCA, OR 2.34 (1.07-5.14); ≥2 HRCA, OR 2.71 (0.91-8.03); p=0.049]. Conclusions The impact of high dose melphalan and AHCT on MM clone size is heterogeneous, of greater magnitude in pts with one or more high-risk chromosome abnormalities, and less pronounced in pts with standard risk disease, particularly hyperdiploid MM. The use of antiCD38 mAb in induction regimens or dose of melphalan does not impact the effect of ASCT on MM clone size, likely owing to the distinct mechanism of action of melphalan. This dataset provides context to explore risk- and response-adapted use of ASCT and use of new cellular and non-cellular immunotherapies as post-induction consolidative strategies.

Definers and drivers of functional high-risk multiple myeloma: insights from genomic, transcriptomic, and immune profiling.

Traditional prognostic models for newly diagnosed patients with multiple myeloma (MM), including International Staging System criteria and number of high-risk chromosomal abnormalities, are based on disease characteristics at diagnosis. However, the identification of patients at risk of more rapidly progressive MM is inherently a dynamic assessment. In a subset of patients with MM, adverse disease biology only becomes evident after the failure of first-line therapy. We define this entity as functional high-risk MM (FHRMM), encompassing relapse within 18 months of treatment initiation and/or within 12 months of frontline autologous stem cell transplantation. FHRMM is not adequately captured by traditional prognostic models, and there is a need for better understanding of mechanisms or risk factors for early relapse or progression. In this review, we explore potential definitions of FHRMM before delving into its underlying drivers based on genetic, transcriptomic, and immune cell profiling studies. Emerging data suggest that specific features of both myeloma cells and immune cells can enable the FHRMM phenotype. We conclude our review by discussing ongoing and future studies that seek to identify and intervene upon patients with FHRMM preemptively.

Single-agent lenalidomide maintenance after upfront autologous stem cell transplant for newly diagnosed multiple myeloma: The MD Anderson experience.

The optimal duration of lenalidomide (Len) maintenance for patients with multiple myeloma (MM) after autologous stem cell transplantation (autoHCT) is unknown. We conducted a retrospective single-center analysis of adult MM patients that received upfront autoHCT between 2005 and 2021, followed by single-agent Len maintenance. A total of 1167 patients were included with a median age of 61.4 (range 25.4-82.3) years, and high-risk chromosomal abnormalities in 19%. Median duration of maintenance was 22.3 (range 0.03-139.6) months. After a median follow-up of 47.9 (range 2.9-171.7) months, median PFS and OS for the entire cohort were 56.6 (95% CI 48.2-61.4) months and 111.3 (95% CI 101.7-121.5) months, respectively. In MVA, high-risk cytogenetics was associated with a worse PFS (HR 1.91) and OS (HR 1.73) (p < .001 for both). Use of KRD induction and achievement of MRD-negative ≥ VGPR before autoHCT were associated with an improved PFS (HR 0.53 and HR 0.57, respectively; p < .001 for both). Longer maintenance duration, even with a 5-year cutoff, was associated with superior PFS and OS (HR 0.17 and 0.12, respectively; p < .001 for both). A total of 106 patients (9%) developed a second primary malignancy (SPM), mostly solid tumors (39%) and myeloid malignancies (30%). Longer maintenance duration was associated with a higher risk of SPM, reaching statistical significance after >2 years (odds ratio 2.25; p < .001). In conclusion, outcomes with Len maintenance were comparable to those reported in large clinical trials. Longer duration of maintenance, even beyond 5 years, was associated with improved survival.

Long-term outcomes with isatuximab-carfilzomib-dexamethasone (Isa-Kd) in relapsed multiple myeloma patients with 1q21+ status: Updated results from the phase 3 IKEMA study.

8029 Background: Gain or amplification of 1q21 (1q21+, ≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma (MM), has a negative impact on prognosis due to its potential involvement in resistance to MM therapy and disease progression. In the prespecified, long-term analysis of the Phase 3 IKEMA trial in relapsed MM patients (pts), treatment with Isa-Kd showed continued, significant improvement in progression-free survival (PFS) vs Kd (HR 0.58; 95.4% CI 0.42–0.79), with meaningful increase in depth of response (complete response or better [≥CR] 44.1% vs 28.5%; minimal residual disease negativity [MRD-] 33.5% vs 15.4%, MRD- ≥CR 26.3% vs 12.2%), and a manageable safety profile. In this subgroup analysis of IKEMA, we evaluated efficacy of Isa-Kd in pts with 1q21+ status (with or without high-risk chromosomal abnormalities [HRCA]) and related subgroups – isolated 1q21+ (≥3 copies without HRCA), gain(1q21), amp(1q21) – at long-term follow-up (44.2 months). Methods: Pts with 1–3 prior lines of therapy were randomized to Isa-Kd (n=179) or Kd (n=123). Assessment was prespecified (at 30% cut-off by FISH) for 1q21+ status as ≥3 copies, gain(1q21) as 3 copies, and amp(1q21) as ≥4 copies. Results: In the Isa-Kd and Kd arms, 41.9% and 42.3% of pts had 1q21+ status, 26.3% and 25.2% isolated 1q21+, 24.0% and 30.1% gain(1q21), 17.9% and 12.2% amp(1q21) respectively. Greater PFS benefit was achieved with Isa-Kd vs Kd in pts with 1q21+ status (HR 0.58, 95% CI 0.37–0.92) and in pts with isolated 1q21+, gain(1q21), or amp(1q21) (Table). Responses deepened by adding Isa to Kd, with increased rates of very good partial response or better (≥VGPR), ≥CR, MRD-, and MRD- ≥CR (Table). Conclusions: 1q21 abnormalities affect PFS in MM pts. Our results at long-term follow-up of pts with 1q21+ status (with or without HRCA) in the IKEMA study continue to show greater PFS benefit and deeper responses with Isa-Kd than Kd, consistent with the overall population and earlier 1q21+ subgroup interim analyses. Thus, they support Isa-Kd as an effective treatment option also for difficult-to-treat, 1q21+ pts with relapsed MM. Clinical trial information: NCT03275285.[Table: see text]

Impact of clonal plasma cells in autografts on outcomes in high-risk multiple myeloma patients

Most patients with multiple myeloma (MM) undergoing autologous hematopoietic stem cell transplantation (autoHCT) eventually relapse, perhaps due to the presence of clonal plasma cells (CPC) in the autograft. We conducted a retrospective analysis to evaluate the impact of CPC in the autograft on the outcomes of high-risk chromosomal abnormalities (HRMM) patients undergoing autoHCT between 2008 and 2018. Patients were divided into CPC+ or CPC− in the autograft by next-generation flow cytometry (NGF). There were 75 CPC + autografts (18%) and 341 CPC− (82%). The CPC + group was less likely to achieve MRD-negative complete remission post-transplant (11% vs. 42%; p < 0.001). Median progression free survival (PFS) and overall survival (OS) were (12.8 vs. 32.1 months) and (36.4 vs. 81.2 months) in the CPC + and CPC− groups, respectively (both p < 0.001). Also in the subset of patients with MRD-negative ≥VGPR prior to autoHCT, those with CPC + autografts had inferior PFS (HR 4.21, p = 0.006) and OS (HR 7.04, p = 0.002) compared to CPC-. In multivariable analysis, the degree of CPC positivity in the autograft was independently predictive of worse PFS (HR 1.50, p = 0.001) and OS (HR 1.37, p = 0.001). In conclusion, both the presence and degree of CPC in the autograft were highly predictive of inferior PFS and OS.

Multiple myeloma with t(11;14): impact of novel agents on outcome

Multiple myeloma (MM) patients with t(11;14) present unique biological features and their prognosis is not well established. We report a retrospective study of 591 MM patients, 17.3% of whom had t(11;14). It was designed to determine the prognostic impact of this abnormality and the effect of novel agents on the response and outcomes. Three groups were established based on their cytogenetics: (1) t(11;14); (2) high-risk chromosomal abnormalities; and (3) standard risk (SR). After 80.1 months (1.2–273.8 months) of follow-up, no differences were observed in overall survival (OS) between the t(11;14) and SR groups (75.8 vs. 87.2 months; P = 0.438). Treatment of MM t(11;14) with novel agents did not improve their overall response rate (ORR) or complete response (CR) compared with those who received conventional therapy (ORR: 87.2 vs. 79.5%, P = 0.336; CR: 23.4 vs. 12.8%, P = 0.215). This effect translated into a similar PFS (39.6 vs. 30.0 months; P = 0.450) and OS (107.6 vs. 75.7 months; P = 0.175). In summary, MM t(11;14) patients did not benefit from the introduction of novel agents as much as SR patients did, indicating that other therapies are needed to improve their outcomes.

Real-world assessment of the treatment patterns and outcomes among patients with multiple myeloma across different risk stratification criteria in the United States: a retrospective cohort study

This study evaluated prognostic performance of International Staging System (ISS), revised ISS, and chromosomal abnormalities (CA) in newly diagnosed multiple myeloma patients to describe treatment patterns (cohort 1; n = 1979) and survival outcomes (cohort 2; n = 1382). In both cohorts, ∼18%, 41%, and 37% of patients were high-risk according to the R-ISS, ISS, and high-risk CA criteria, respectively. Across all risk stratification criteria, 60% of patients received triplets. In cohort 2, the median modified progression-free survival decreased with each increasing risk stage (23.5, 12.1, and 8.8 months in R-ISS I, II, and III, respectively, and 16.0, 12.7, and 10.4 months in ISS I, II, and III). Similar trends were observed in the proportions of two-year overall survival. In conclusion, R-ISS has greater discriminatory power than ISS or high-risk CA alone and can be implemented in a real-world setting. Accordingly, a more risk-adapted approach can be feasible, with a greater population-level impact.

Daratumumab Plus Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) in Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): Final Analysis of Griffin Among Clinically Relevant Subgroups

Introduction: Daratumumab (DARA) is approved across lines of therapy for multiple myeloma. In the primary analysis of the randomized phase 2 GRIFFIN trial (NCT02874742) (median follow-up, 13.5 mo), addition of DARA to RVd improved the stringent complete response (sCR) rate by end of post-autologous stem cell transplant (ASCT) consolidation (D-RVd, 42.4% vs RVd, 32.0%; odds ratio [OR], 1.57; 95% CI, 0.87-2.82; 1-sided P = 0.068, which met the pre-specified 1-sided α of 0.1) (Voorhees PM, et al. Blood. 2020). Here, we present an end-of-study post hoc analysis of clinically relevant subgroups in GRIFFIN (≥65 years; International Staging System [ISS] stage III disease; high cytogenetic risk [defined as ≥1 of the following: del17p, t(4;14), or t(14;16)]; revised high cytogenetic risk [defined as ≥1 of the following high-risk chromosomal abnormalities (HRCA): del17p, t(4;14), t(14;16), t(14;20) or gain/amp1q (≥3 copies of chromosome 1q21)]; gain/amp1q; 1 HRCA (per the revised definition); gain/amp1q plus 1 HRCA; and ≥2 HRCA). The final analysis of GRIFFIN (median follow-up, 49.6 mo) occurred after all pts completed ≥1 year of long-term follow-up after completion of study treatment, discontinued, or withdrew. Methods: In GRIFFIN, pts with transplant-eligible NDMM were randomized 1:1 to D-RVd or RVd. All pts received 4 D-RVd/RVd induction cycles, ASCT, 2 D-RVd/RVd consolidation cycles, and maintenance with lenalidomide (R) ± DARA for 24 months. All pts received 21-day cycles of R (25 mg PO on Days [D] 1-14), bortezomib (1.3 mg/m2 SC on D1, 4, 8, 11), and dexamethasone (40 mg PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-4 and D1 in Cycles 5-6). During maintenance (Cycles 7-32; 28-day cycles), pts received R (10 mg PO on Days 1-21; if tolerated, 15 mg in Cycles 10+) ± DARA (16 mg/kg IV Q8W/Q4W or 1800 mg SC Q4W per protocol amendments). The primary endpoint was the sCR rate by end of consolidation. Results: 207 pts were randomized (D-RVd, n = 104; RVd, n = 103); each subgroup had a similar number of pts per arm: ≥65 years (n = 28; n = 28), ISS stage III disease (n = 14; n = 14), high cytogenetic risk (n = 16; n = 14), revised high cytogenetic risk (n = 42; n = 37), gain/amp1q (n = 34; n = 28), 1 HRCA (n = 32; n = 29), gain/amp1q plus 1 HRCA (n = 9; n = 6), and ≥2 HRCA (n = 10; n = 8). Outcomes for pts with baseline extramedullary plasmacytomas (D-RVd, n = 1; RVd, n = 2) were explored but not included due to small pt numbers. Among response-evaluable pts, the rate of sCR at the end of maintenance therapy was numerically higher for D-RVd versus RVd among pts with age ≥65 years (63.0% vs 40.7%; OR, 2.47; 95% CI, 0.83-7.39), high cytogenetic risk (50.0% vs 38.5%; OR, 1.60; 95% CI, 0.36-7.07), gain/amp1q plus 1 HRCA (55.6% vs 33.3%; OR, 2.50; 95% CI; 0.29-21.40), and ≥2 HRCA (50.0% vs 37.5%; OR, 1.67; 95% CI, 0.25-11.07), but similar for D-RVd and RVd pts with ISS stage III disease (64.3% vs 61.5%; OR, 1.13; 95% CI, 0.24-5.37), revised high cytogenetic risk (56.1% vs 55.6%; OR, 1.02; 95% CI, 0.42-2.52), gain/amp1q (57.6% vs 57.1%; OR, 1.02; 95% CI, 0.37-2.82), and 1 HRCA (58.1% vs 60.7%; OR, 0.90; 95% CI, 0.32-2.54). MRD-negativity (10-5) rates at the end of maintenance favored D-RVd over RVd across all subgroups (Figure A). At 49.6 months of median follow-up, PFS rates among subgroups favored D-RVd over RVd except for pts with ≥2 HRCA (Figure B). In pts ≥65 years, grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 88.9% of D-RVd and 77.8% of RVd pts; the most common grade 3/4 TEAEs (≥20%) were neutropenia (D-RVd, 37.0%; RVd, 29.6%) and lymphopenia (25.9%; 11.1%). TEAEs led to study treatment discontinuation in 37.0% of D-RVd and 25.9% of RVd pts. In pts ≥65 years, death as outcome of a TEAE occurred in 1 D-RVd pt (pneumonia; unrelated to study treatment). Conclusions: In this final analysis of GRIFFIN by clinically relevant subgroups, addition of DARA to RVd induction/consolidation and R maintenance, with ASCT, was associated with higher MRD-negativity (10-5) rates for all subgroups and PFS estimates favored all high-risk groups except pts with ≥2 HRCA. Among pts ≥65 years, the rates of grade 3/4 TEAEs and TEAEs leading to study treatment discontinuation were slightly higher for the D-RVd group, although only 1 pt died due to a TEAE unrelated to study treatment. Results of this subgroup analysis support the use of DARA in transplant-eligible pts with NDMM among both clinically and cytogenetic high-risk subgroups, although larger studies are needed, especially in pts with ≥2 HRCA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Presence and Amount of Clonal Plasma Cells in Autografts Affect Outcomes in High-Risk Multiple Myeloma Patients Undergoing Autologous Hematopoietic Stem Cell Transplant

Introduction: Autologous hematopoietic stem cell transplantation (autoHCT) is considered standard of care for patients with multiple myeloma (MM). However, most patients eventually relapse, perhaps due to the presence of clonal plasma cells (CPC) in the autograft. The significance of CPC in the autograft has not been clearly established. MM patients with high-risk chromosomal abnormalities (HRMM) by florescent in situ hybridization (FISH) have worse outcomes compared to patients with standard-risk disease. We conducted a single center retrospective analysis to evaluate the impact of CPC in the autograft on the outcomes of patients with HRMM undergoing an autoHCT at our institution. Methods: Eligible patients had HRMM, received an autoHCT between 2008 and 2018 at our institution, and had 8-color next-generation flow cytometry (NGF) performed on the collected apheresis product for CPC. HRMM was defined as having del17p, t(4;14), t(14;16) and 1q21 gain or amplification by FISH. Patients were divided into two groups: CPC+ or CPC- in the autograft by NGF. Since not all collected autograft products are infused at autoHCT, and some bags may be CPC+ or CPC- for the same patient, we also evaluated the impact of infusion of CPC+ autograft products on patient outcomes. Minimal residual disease (MRD) status on the bone marrow biopsy was evaluated using 8-color next generation flow cytometry with sensitivity of 1/10-5 cells. Results: We analyzed the autograft products of 416 patients: 75 CPC+ (18%) and 341 CPC- (82%). 57% patients were male, and median age at autoHCT was 62 (range 32-83) years. Fewer patients in the CPC+ group received the VRD regimen as induction prior to transplant compared to the CPC- group (25% vs. 44%, p=0.003) and fewer achieved ≥VGPR after induction compared to the CPC- group (32% vs. 62%, p<0.001). Patient and clinical characteristics are presented in Table 1. Median follow up for the whole cohort was 35.7 (range 0.3-139.5) months. 100-day and best post-autoHCT CR rates in the CPC+ and CPC- groups were 8% vs. 19% (p<0.001), and 33% vs. 54% (p<0.001), respectively. The CPC+ group was also less likely to achieve MRD-negative CR post-transplant (11% vs. 42%; p<0.001). Median PFS in the CPC+ vs. CPC- group was 12.8 vs. 32.1 months (p<0.001), and median OS was 36.4 vs. 81.2 months (p<0.001). The degree of autograft CPC involvement was inversely associated with post-transplant day 100 response: mean maximal autograft CPC level was 0.02% (SD 0.02) for patients who achieved ≥VGPR vs. 1.04% (SD 2.59) for those who achieved ≤PR at day 100 post-transplant. Similarly, degree of autograft CPC level was inversely associated with best post-transplant response: mean maximal autograft CPC level was 0.06% (SD 0.16) for patients who achieved ≥VGPR vs. vs. 1.55% (SD 3.17) for those who achieved ≤PR. In patients achieving ≥VGPR prior to autoHCT, those with CPC+ autograft had inferior PFS (hazard ratio (HR) [95% CI]: 3.38 [2.05-5.58], p<0.001; Figure 1C) and OS (HR 2.29 [1.20-4.40], p=0.013; Figure 1D) compared to the CPC- group. Also in patients who achieved MRD- negative CR or VGPR prior to autoHCT, those with CPC+ autograft had inferior PFS (HR 4.35 [1.87-10.16], p<0.001) and OS (HR 6.14 [2.10-17.96], p<0.001) compared to the CPC- group. In a multivariable analysis (MVA), the degree of CPC positivity in the autograft was independently predictive of worse PFS (HR 1.50 [1.12-1.99]; p=0.006) and OS (HR 1.35 [1.08-1.67]; p=0.007). The MVA also showed that infusion of CPC+ autograft products was predictive of worse PFS (HR 2.78 [1.85-4.15]; p<0.001) with a trend towards worse OS (HR 1.66 [0.99-2.78]; p=0.054). Conclusions: Our study shows a major impact of CPC in the autograft on post-autoHCT outcomes in HRMM. Both the presence and degree of CPC in the autograft were highly predictive of inferior PFS and OS, even in patients who had achieved ≥VGPR and MRD-negative CR/VGPR prior to autoHCT. Novel strategies for ex-vivo purging of CPC could improve patient outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Daratumumab (Dara), Cyclophosphamide, Thalidomide and Dexamethasone for Transplant Eligible Newly Diagnosed Multiple Myeloma (TE NDMM) Patients: Response Rate Impacts on PFS

Background: The introduction of monoclonal antibodies (mAb) such as daratumumab created a new landscape for MM treatment. The four-drug combo has becoming one of the main induction treatment for TE NDMM patients (pts). We conducted a phase 2 study to assess the safety and preliminary efficacy of Cyclophosphamide (C), thalidomide (T), dexamethasone (d)-(CTd) and Dara combination. MAXDARA study has shown in the primary analysis with 21 included patients (pts), 4 and 8 pts MRD negativity after four induction cycles and two consolidation cycles post transplant, respectively. (Crusoe E et al ASH 2020, 2416 poster presentation). In the present analysis we evaluate the effect of deep response rate on PFS. Primary endpoint of the study was to evaluate the VGPR after two consolidation cycles post-autologous stem cell transplantation (ASCT). Methods: This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, creatinine clearance > 30 ml/min, normal cardiac, renal and liver function and the Easter Cooperative Oncology Group (ECOG) performance status = 0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg oral (PO) on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose intravenous (IV) on days 1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 - 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16mg/Kg and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara at 16mg/Kg was used monthly as maintenance until progression or limiting toxicity. The MRD was evaluated by next-generation flow (NGF) 10-6 and PET-CT was performed when the patient obtained NGF negativity or finished consolidation. PFS outcome was estimated using Kaplan-Meier method and PFS analysis were performed based on the different response rates. ( Data cut-off was April 2022) Results: A total of 24 pts were included. The median age being 58 (range 37- 67 years), 15 (62.5%) pts were female, 23 (92%) were non-white, 6 (25%) had an R-ISS = 1, 12 (50%) had an R-ISS = 2 and 4 (16%), an R-ISS = 3. Sixteen (66.7%) pts were IgG isotype and Six (25%) had high-risk chromosomal abnormalities [1q+, del17p, t(4;14) or t(14;16)]. To date, 23 pts have completed induction, 21 performed transplant and 14 are still in treatment after one year of dara maintenance. No stem cell mobilization failure was observed, and six (30%) pts needed plerixafor use. By ITT analysis, 22 pts (91.6%) achieved (> PR) after 4 induction cycles. One pts achieved SD, one MR and one sCR. Eleven (39%) pts achieved PR, and 10 (35.7%) VGPR. After two consolidation cycles, ORR was 68%, 8 (28.6%) and 11 (39.3%) pts obtained sCR and VGPR, respectively. The best response during any time of the treatment were PR in 3 (12.5%) pts, VGPR in 12 pts (50%) and sCR in 8 (33.3%) pts. In a ITT analysis, NGF MRD 10-6 negativity were observed in 4(16.6%) after four induction cycles, and in 17 (70.8%) pts after two consolidation cycles post-ASCT. In a ITT analysis, after a median follow up (FU) of 26 months, the PFS was 37months for the entire group. The median PFS comparing sCR vs < VGPR were 37m vs 27m (p=0.021), respectively, and comparing MRD negative by NGF vs no, had impacted even more on PFS with a median of 37m vs 16m (p=0.004), respectively. The OS was not yet achieved and 83% of the patients still alive after a median FU of 27 months. Four pts died from infection, two of them related with covid infection (one before transplant and one during maintenance). Another case post-transplant, considered not related to the investigational agent and one after consolidation, related to the investigational agent. Summary/Conclusion: The Daratumumab - CTd protocol is an active and safe regimen capable of producing deep and sustainable responses. The deeper response rate impacted on PFS, confirm that MRD negativity is critical to patient outcome. Clinical trial information: NCT03792620.

The Co-Occurrence of 1q21+/1q23+ and t(4;14) Abnormalities with Specific Clone Size Is Predictive of Shorter Response to Transplant in Patients with Multiple Myeloma

Introduction: The presence or absence of recurrent chromosomal abnormalities (CA) as detected by karyotype and/or fluorescence in-situ hybridization (FISH) has emerged as one of the most clinically relevant prognostic factors for patients with newly diagnosed multiple myeloma (MM). The Revised-International Staging System (R-ISS) defined high-risk disease as the presence of at least one of the following: deletion(17p), translocation t(4;14)(p16;q32), or translocation t(14;16)(q32;q23). Amplification or gain of chromosome 1q (1q21+/1q23+) has also been growing in its clinical relevance, with 1q21+ found in approximately 35-40% of patients. As a result, this study evaluated differences in survival outcomes and disease characteristics in patients with both 1q+ (1q21+ or 1q23+) and t(4;14), compared to those patients with only 1q+ or t(4;14). Methods: A retrospective chart review was performed on 243 newly diagnosed MM patients with the cytogenetic abnormalities of interest obtained from established FISH data from bone marrow aspirate samples at diagnosis. Primary endpoints were Progression-Free Survival (PFS) and Overall Survival (OS) after autologous stem cell transplant (ASCT), and Kaplan Meier methods were used to calculate PFS and OS. Secondary endpoints included the identification of disease characteristics between single CA and combined abnormalities. To specifically analyze the quantitative CA cutoff values and the correlation of clone size to survival outcomes, we established subgroupings with positivity defined as 1q21+ or 1q23+ present in more than 20% of cells and t(4;14) present in more than 30% of cells. Patients who satisfied both cutoff criteria were labeled as 'double-hit', and patients with CA present, but clone sizes less than the prespecified cutoffs for both CA, were denoted as 'CA(low)'. All tests were two-sided with p-values <0.05 considered statistically significant. Results: The median age at diagnosis was 61.5 years, 54% were male, and 84% of patients identified as non-Hispanic White. Of the total cohort and independent of quantitative CA cutoff, 1q+ (1q21+ or 1q23+) only was the most prevalent CA in 198 (81%) of patients, t(4;14) only in 13 (5%) patients, and both 1q+ (1q21+ or 1q23+) and t(4;14) in 32 (13%) patients. One hundred seventy (70%) patients underwent ASCT, followed by maintenance therapy in 85% of them. Pre-transplant best hematologic responses did not differ amongst CA groups. There was no difference in baseline hemoglobin, serum creatinine, calcium, albumin, lactate dehydrogenase, or beta-2 microglobulin amongst the CA groups. No differences in outcomes were noted without including size clone cutoffs. There was a statistically significant difference in univariable analysis in PFS and OS from ASCT in patients with 1q21+ and t(4;14) 'CA(low)’ (n=76, 31%) having better survival outcomes compared to the corresponding 'double-hit’ group (n=25, 10%) (PFS: HR=0.52, 95% CI: 0.30-0.92, p=0.025; OS: HR=0.41, 95% CI: 0.21-0.81, p=0.010). This pattern in PFS and OS after ASCT was also seen in patients with 1q23+ and t(4;14) 'CA(low)’ (n=119, 49%) faring better compared to its 'double-hit’ group (n=19, 8%) (PFS: HR=0.47, 95% CI:0.26-0.83, p=0.009; OS: HR=0.34, 95% CI:0.18-0.66, p=0.001). Patients with t(4;14) only (>30%) (n=19, 8%) within the 1q23+ cohort also demonstrated longer PFS and OS after ASCT as compared to its 'double-hit’ group (PFS: HR=0.42, 95% CI:0.20-0.91, p=0.027; OS: HR=0.38, 95% CI:0.15-0.94, p=0.037). After adjusting for age and R-ISS staging, the difference between 1q23+ and t(4;14) 'CA(low)’ vs 'double-hit’ and t(4;14) only within the 1q23+ cohort vs 'double-hit’ remained significant in multivariable analysis in PFS after ASCT ('CA(low)’ group: HR=0.50, 95% CI:0.25-0.99, p=0.048; and t(4;14) only group: HR=0.41, 95% CI:0.18-0.98, p=0.045). Conclusion: Our findings reveal the differences seen in MM patients with single CA compared to the combined high-risk aberrations with both 1q21+/1q23+ and t(4;14). The effects of quantitative clone sizes on survival outcomes were displayed as patients with smaller clone sizes (i.e. 'CA(low)’ subsets) had superior survival outcomes than those patients with 'double-hit’ 1q21+ (or 1q23+) >20% and t(4;14) >30%. It is thus imperative for clinicians to be mindful of not only the presence of high-risk CA but also the size of the aberrant clone influencing subsequent MM disease characteristics.

MM-403 Impact of Clonal Plasma Cells in Autografts on the Outcome of High-Risk Multiple Myeloma Patients Undergoing Autologous Hematopoietic Stem Cell Transplant

Almost all patients with multiple myeloma (MM) undergoing an autologous hematopoietic stem cell transplantation (autoHCT) eventually relapse, and the risk is highest in patients with high-risk chromosomal abnormalities (HRMM). The significance of clonal plasma cells (CPC) in the autograft has not been clearly established. To determine the impact of CPC in the autograft on outcomes of patients with HRMM undergoing autoHCT. Adult patients with HRMM, defined as del17p, t(4;14), t(14;16), 1q21 gain or amplification by FISH, who underwent autoHCT between 2008-2018 and had 8-color next-generation flow cytometry (NGF) on the apheresis product for CPC were included, and divided into NGF+ or NGF- groups for CPC in the autograft. 416 patients, 341 in the NGF- and 75 in the NGF+ groups, were included. Fewer patients in the NGF+ group achieved ≥VGPR after induction vs. the NGF- group (32% vs. 62%). Median follow up for the whole cohort was 35.7 (range 0.3-139.5) months. 100-day and best post autoHCT CR rates in the NGF+ and NGF- groups were 8% vs. 19% (p<0.001) and 33% vs. 54% (p<0.001), respectively. The NGF+ group also had lower rates of post-transplant MRD negativity (23% vs. 57%; p<0.001). Higher CPC number in the autograft was associated with inferior day 100 (p=0.017) and best post autoHCT (p=0.048) response rates. Median progression free survival (PFS) in the NGF+ vs. NGF- group was 12.8 vs. 32.1 months, respectively (p<0.001), and median overall survival (OS) was 36.4 vs. 81.2 months (p<0.001). In the subset of patients with ≥VGPR prior to transplant, those with NGF+ had inferior PFS (HR 3.38 [2.05-5.58], p<0.001) and OS (HR 2.29 [1.20-4.40], p=0.013) compared to the NGF- group. In multivariable analysis, the number of CPC in the autograft was predictive of worse PFS (HR 1.50 [1.12-1.99]; p=0.006), and worse OS (HR 1.35 [1.08-1.67]; p=0.007). Both the presence and the number of CPC in the autograft were highly predictive of post-transplant outcomes including PFS and OS in patients with HRMM. Novel strategies for ex-vivo purging of CPC could potentially improve patient outcomes.

DARATUMUMAB (DARA), CYCLOPHOSPHAMIDE, THALIDOMIDE AND DEXAMETHASONE FOR TRANSPLANT ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA (TE NDMM) PATIENTS: RESPONSE RATE IMPACTS ON PFS

The four-drug combo has becoming one of the main induction treatment for TE NDMM patients (pts). We conducted a phase 2 study to assess the safety and preliminary efficacy of Cyclophosphamide (C), thalidomide (T), dexamethasone (d)-(CTd) and Dara combination. MAXDARA study has shown in the primary analysis with 21 included patients (pts), 4 and 8 pts MRD negativity after four induction cycles and two consolidation cycles post transplant, respectively. (Crusoe E et al ASH 2020, 2416 poster presentation). In the present analysis we evaluate the effect of deep response rate on PFS. This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, creatinine clearance > 30 ml/min, normal cardiac, renal and liver function and the ECOG performance status = 0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg oral (PO) on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose intravenous (IV) on days 1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 – 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16mg/Kg and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara at 16mg/Kg was used monthly as maintenance until progression or limiting toxicity. The MRD was evaluated by next-generation flow (NGF) 10−6 and PET-CT was performed when the patient obtained NGF negativity or finished consolidation. PFS outcome was estimated using Kaplan–Meier method and PFS analysis were performed based on the different response rates. (Data cut-off was April 2022) A total of 24 pts were included. The median age being 58 (range 37– 67 years), 15 (62.5%) pts were female, 22 (92%) were non-white, 6 (25%) had an R-ISS = 1, 12 (50%) had an R-ISS = 2 and 4 (16%), an R-ISS = 3. Sixteen (66.7%) pts were IgG isotype and Six (25%) had high-risk chromosomal abnormalities [1q+, del17p, t(4;14) or t(14;16)]. To date, 23 pts have completed induction, 21 performed transplant and 14 are still in treatment after one year of dara maintenance. By ITT analysis, 22 pts (91.6%) achieved ( > PR) after 4 induction cycles. One pts achieved SD, one MR and one sCR. Eleven (39%) pts achieved PR, and 10 (35.7%) VGPR. After two consolidation cycles, ORR was 68%, 8 (28.6%) and 11 (39.3%) pts obtained sCR and VGPR, respectively. The best response during any time of the treatment were PR in 3 (12.5%) pts, VGPR in 12 pts (50%) and sCR in 8 (33.3%) pts. In a ITT analysis, NGF MRD 10−6 negativity were observed in 4(16.6%) after four induction cycles, and in 17 (70.8%) pts after two consolidation cycles post-ASCT. In a ITT analysis, after a median follow up (FU) of 26 months, the PFS was 37months for the entire group. The median PFS comparing sCR vs < VGPR were 37m vs 27m (p = 0.021), respectively, and comparing MRD negative by NGF vs no, had impacted even more on PFS with a median of 37m vs 16m (p = 0.004), respectively. The OS was not yet achieved and 83% of the patients still alive after a median FU of 27m. Four pts died from infection, two of them related with covid infection (one before transplant and one during maintenance). Another case post-transplant, considered not related to the investigational agent and one after consolidation, related to the investigational agent. The Daratumumab - CTd protocol is an active and safe regimen capable of producing deep and sustainable responses. The deeper response rate impacted on PFS, confirm that MRD negativity is critical to patient outcome.

Heterogeneity in long-term outcomes for patients with Revised International Staging System stage II, newly diagnosed multiple myeloma.

In the era of personalized treatment in multiple myeloma, high-risk patients must be accurately identified. The International Myeloma Working Group recommends using the Revised International Staging System (R-ISS) to pick out high-risk patients. The main purpose of our work was to explore the heterogeneity of outcome among R-ISS stage II patients assessing the impact of International Staging System (ISS) stage, chromosomal abnormalities and lactate dehydrogenase level in this subgroup. Data were collected from 1,343 patients up to 65 years old with newly diagnosed myeloma, enrolled in three clinical trials implemented by the Intergroupe Francophone du Myélome. All patients were eligible for intensive treatment. Patients in R-ISS stage II but ISS stage I had 1.6 times higher risk of death than patients in R-ISS stage I (adjusted hazard ratio=1.6; 95% confidence interval: 1.1-2.2; P=0.01) and patients in R-ISS stage II but with ISS stage III had a better overall survival than patients in R-ISS stage III (adjusted hazard ratio=0.7; 95% confidence interval: 0.4-0.9, P=0.02). However, among patients classified in R-ISS II, ISS stage and chromosomal abnormalities (del[17p] and t[4;14]) were still relevant prognostic factors for death. Dividing R-ISS stage II into three subgroups: ISS I with standard-risk chromosomal abnormalities, ISS II or III with standard-risk chromosomal abnormalities and patients with high-risk chromosomal abnormalities, median overall survival times were, respectively, not reached, 112 months and 71 months (P<0.001). In conclusion, stratification of patients in the R-ISS stage II group can be improved by taking into account chromosomal abnormalities and ISS. However, this does not improve predictive performance of survival models.

Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high-risk cytogenetics: IKEMA subgroup analysis.

The presence of high-risk chromosomal abnormalities [t(4;14), del(17p), and t(14;16)] has been linked with inferior outcomes in patients with multiple myeloma (MM). A prespecified interim analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d; Isa-Kd) significantly improved progression-free survival (PFS) versus Kd in patients with relapsed MM. This prespecified subgroup analysis of IKEMA examined efficacy and safety in patients with high-risk cytogenetics. High-risk cytogenetics was assessed by central laboratory and patients were classified as high risk if abnormalities were present in ≥1 of the following: del(17p): 50% cutoff; t(4;14), and/or t(14;16): 30% cutoff. Of the randomized patients, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk chromosomal abnormality. A PFS benefit was seen in favor of Isa-Kd for patients with standard-risk (HR 0.440; 95% CI 0.266-0.728) and high-risk cytogenetics (HR 0.724; 95% CI 0.361-1.451). Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd (85.7%) versus Kd (63.3%) in patients with high-risk cytogenetics; however, the incidence of serious TEAEs (64.3% vs. 66.7%) was similar. Isa-Kd is a new treatment option for the difficult-to-treat subgroup of patients with relapsed MM and high-risk cytogenetics.

Lenalidomide-Based Maintenance after Autologous Hematopoietic Stem Cell Transplantation for Patients with High-Risk Multiple Myeloma

Maintenance therapy with single-agent lenalidomide (Len) after autologous hematopoietic stem cell transplantation (autoHCT) for multiple myeloma (MM) is associated with improved progression-free survival (PFS). However, MM patients with high-risk chromosomal abnormalities (HRMMs) may need a more intense regimen. We hypothesized that adding another antimyeloma drug to Len maintenance would lead to improved outcomes. We conducted this retrospective single-center chart review analysis of adult HRMM patients who underwent autoHCT between 2008 and 2018, followed by Len-based maintenance therapy. High-risk cytogenetics were defined as del(17p), t(4;14), t(14;16), 1q21 gain or amplification by fluorescence in situ hybridization. We divided patients into those who received either single-agent Len maintenance (Len-only) or Len-based combinations (Len-combo). We compared nonrelapse mortality, day 100 and best post-transplantation responses, minimal residual disease status, PFS, and overall survival (OS) between the 2 groups. We also performed sensitivity analyses using inverse probability weights to correct for potential bias owing to nonrandomization of the 2 groups. A total of 231 patients with HRMM were included in our analysis, with a median age of 62.4 years (range, 33.5 to 79.9 years), and 55% were male. There were 153 patients in the Len-only group and 78 in the Len-combo group. Len-combo regimens were either doublets (Len with dexamethasone [dex] [n=10], elotuzumab [n=28], or ixazomib [n=14]) or triplets (Len with bortezomib/dex [n=10], ixazomib/dex [n=10], or carfilzomib/dex [n=6]). More patients in the Len-combo group had ≥2 high-risk cytogenetic abnormalities compared with the Len-only group (32% versus 12%: P < .001). The median duration of follow-up was 40.7 months in the Len-only group and 37.0 months in the Len-combo group. For all patients, the median PFS was 25.5 months, and the median OS was 82.6 months. There was no significant between-group difference in PFS (hazard ratio [HR] 1.01; 95% confidence interval [CI], .71-1.44; P=.94) or OS (HR, .84; 95% CI, .49 to 1.43; P=.52). However, for patients with high-risk cytogenetic abnormalities other than 1q+, there was a trend toward better PFS in the Len-combo group (HR, .59; 95% CI, .32 to 1.09; P=.09), but no difference in OS (HR, .79; 95% CI, .37 to 1.65; P=.53). In this single-center retrospective analysis, the use of Len-based combinations for post-transplantation maintenance was not associated with improved outcomes in HRMM patients; however, there was a trend toward improved PFS in patients with high-risk abnormalities other than 1q+.

Recent advances in the management of older adults with newly diagnosed multiple myeloma in Japan.

Multiple myeloma is a cancer of plasma cells; the incidence rate of multiple myeloma is high among older adults. Although significant advances have been made in the clinical management of multiple myeloma driven by the introduction of novel drugs, such as proteasome inhibitors, immuno- modulators and antibodies, multiple myeloma remains incurable. Hence, the current therapeutic goal for multiple myeloma is to achieve long-term survival while maintaining a good quality of life. In this context, personalized treatment to balance the efficacy and safety of therapies is important, especially for older adults as they display diverse physical, cognitive or organ functioning. Furthermore, old age is also often associated with frailty. Several tools for evaluating frailty in older adults with multiple myeloma are now available, and frail patients defined by these tools have shown a poor prognosis and more treatment-related toxicities. In addition, it is important to evaluate other factors, such as the International Staging System, high-risk chromosomal abnormalities and treatment response, to predict the clinical course of patients. Further investigations are required to determine how these factors can optimize the treatment for multiple myeloma. In this review, we present a detailed account on the developments and issues related to the current treatment approaches for older adults with newly diagnosed multiple myeloma. We also discuss the ongoing phase III clinical study conducted by the lymphoma study group of the Japan Clinical Oncology Group, which targeted older adults with newly diagnosed multiple myeloma.