ABSTRACT
Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with faorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improed response rate and progression free-surial in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improed outcome of HR TE NDMM patients (EMN02, STAMINA). Aims: The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is ealuating an intensie strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensie strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with preiously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n=20, 40%), t(4;14) (n=26, 52%) or t(14;16) (n=10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to seere aderse eent (COVID-19 infection, n=1 ;drug-induced hepatitis, n=1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related aderse eent (>5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-ein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Oerall response rate was 96%, including 92 % > ery good partial response. Among 37/46 ealuable patients post induction, Minimal Residual Disease negatiity rate (NGS, 10-5) was 62%. Summary/Conclusion: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to ealuate safety and efficacy of the oerall strategy with Dara-KRD induction and consolidation plus double transplant in this subset of HR patients.
ABSTRACT
Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with favorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improved response rate and progression free-survival in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improved outcome of HR TE NDMM patients (EMN02, STAMINA). The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is evaluating an intensive strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara- KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensive strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with previously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n = 20, 40%), t(4;14) (n = 26, 52%) or t(14;16) (n = 10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to severe adverse event (COVID-19 infection, n = 1 ;drug-induced hepatitis, n = 1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related adverse event (> 5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-vein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Overall response rate was 96%, including 92 % > very good partial response. Among 37 (/46) evaluable patients post induction, Minimal Residual Disease negativity rate (NGS, 10-5) was 62%. Conclusions: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to evaluate safety and efficacy of the overall strategy with Dara- KRD induction and consolidation plus double transplant in this subset of HR patients.
ABSTRACT
Background: Proteasome inhibitors (PIs) & monoclonal antibodies are backbones of RRMM treatment;Ixa is approved with lenalidomide-dex for pts with ≥1 prior therapy, & Dara is approved in various regimens, including with bortezomib-dex (DVd). In CASTOR (DVd vs Vd), Vd was limited to 8 cycles;however, prolonged PI therapy is associated with improved outcomes. The IDd regimen with oral Ixa may enable longer-term PI therapy than with DVd. We evaluate IDd using a treat-to-progression approach. Methods: Ixa/Dara-naive RRMM pts receive Ixa 4 mg (days 1, 8, 15), Dara 16 mg/kg (days 1, 8, 15, 22, cycles 1–2;days 1, 15, cycles 3–6;day 1, cycles 7+), & dex 20 mg (days 1, 2, 8, 9, 15, 16, 22, 23) in 28-day cycles. The primary endpoint is ≥ very good partial response (VGPR) rate;secondary endpoints include overall response rate (ORR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), & safety. We report data from the 2nd IA, conducted after ~50% of PFS events had occurred (data cutoff: 1/1/2021). Results: 61 pts were enrolled (median age 69 y, 19.7% aged ≥75 y;19.7% International Staging System stage III;26.2% high-risk cytogenetics [del(17p), t(4;14), t(14;16)], 42.6% expanded high-risk cytogenetics [high-risk &/or amp1q21]);59.0/26.2/14.8% of pts had received 1/2/3 prior lines. At data cutoff, pts had received a median of 16 IDd cycles;37.7% were ongoing. Relative dose intensity (RDI) of Ixa, Dara, & dex was 20%) TEAEs were diarrhea (39.3%), anemia (27.9%), thrombocytopenia (26.2%), & fatigue (21.3%);common (>5%) G≥3 TEAEs were pneumonia (11.5%), thrombocytopenia (11.5%), & anemia (8.2%). Infections & Infestations TEAEs were seen in 57.4% of pts (G≥3 24.6%) and were serious in 26.2%, including pneumonia (9.8%) and COVID-19/pneumonia (4.9%). Rate of peripheral neuropathy (PN) was 18.0% (1.6% G≥3). PN was 28.6% & 12.5%in pts with & without history of PN, respectively. Study drug dose modifications, reductions & discontinuations due to TEAEs were required in 57.4% (Ixa 36.1%, Dara 34.4%, dex 41.0%), 32.8%, & 9.8%of pts, respectively. Four pts died on study due to sudden death, COVID-19 pneumonia, septic shock, & COVID-19 (none were considered study drug-related). Conclusion: These IA data suggest IDd has a positive risk-benefit profile in RRMM pts, with a ≥VGPR rate of 30.5%, median PFS of 17.0 m, & a low rate of discontinuation due to TEAEs. The final analysis of this ongoing study is expected in 2022.
ABSTRACT
Background: Ibrutinib (ibr) is a once-daily Bruton's tyrosine kinase (BTK) inhibitor approved in the US for patients (pts) with mantle cell lymphoma (MCL) who have received ≥1 prior therapy. Venetoclax (ven) is a BCL-2 inhibitor approved for pts with CLL or previously untreated AML. Ibr + ven have shown synergistic antitumor activity in preclinical models and complementary clinical activity in early phase studies (Zhao Br J Haematol 2015;Tam NEJM 2018;Jain NEJM 2019). The ongoing phase 3 SYMPATICO study (PCYC-1143-CA, NCT03112174) evaluates the safety and efficacy of ibr + ven in pts with relapsed/refractory (R/R) MCL. A safety run-in (SRI) was conducted to inform whether a 1-month (mo) ibr lead-in would be implemented for the randomized portion of the study;initial data from the SRI evaluating tumor lysis syndrome (TLS) events and dose-limiting toxicities (DLTs) concluded that the study would proceed with concurrent ibr + ven, with no ibr lead-in (Wang ICML 2019). Updated safety and efficacy from the SRI are presented. Methods: The phase 3 SYMPATICO study is comprised of an open-label SRI and a double-blind randomized period. Key eligibility criteria were pathologically confirmed MCL with measurable disease, 1-5 prior therapies, and no prior treatment with BTK or BCL inhibitors. In the SRI, pts received oral, once-daily 560 mg ibr + ven in a 5-week ramp-up to 400 mg ven. Ibr + ven are dosed concurrently for 2 years;thereafter, ven is discontinued in all pts and ibr is continued until progressive disease (PD) or unacceptable toxicity. The primary endpoint of the SRI was occurrence of TLS events and DLTs. Secondary endpoints included complete response (CR) and partial response (PR) per the 2014 Lugano criteria, progression-free survival (PFS), and duration of response (DOR). Rates of undetectable minimal residual disease (MRD) were assessed in bone marrow and peripheral blood. Efficacy and safety were analyzed by TLS risk (low or high). TP53 mutational status was determined by next-generation sequencing. Results: Twenty-one pts were enrolled in the SRI, with a median time on study of 22 (range, 2-31) mo. The median age was 68 (range, 53-84) years, and the median number of prior therapies was 2 (range, 1-4);6 pts were considered at low risk for TLS and 15 pts were considered at high risk for TLS. All pts had at least 1 lesion >2 cm at baseline;11/21 (52%) had baseline detectable MRD in peripheral blood or bone marrow. Of the 11 pts with available TP53 mutation data, 4 (36%) had mutated TP53. Median time on treatment was 18 (range, <1-28) mo. During the 5-week ven ramp-up, 3 pts had DLTs, and 1 pt at high risk for TLS had a laboratory TLS (Wang ICML 2019);no additional TLS events occurred during follow-up. The most common treatment-emergent adverse events (TEAEs) were diarrhea (n=16 [76%]) and fatigue (n=11 [52%]). Grade 3/4 TEAEs occurred in 17 pts (81%). Four pts (19%) discontinued study drugs because of TEAEs. Two treatment-emergent deaths occurred: 1 from a retroperitoneal hemorrhage unrelated to ibr or ven that was related to disease progression and 1 from COVID-19 in a pt with CR. The overall response rate (ORR) was 81% (17/21) in all pts, with an ORR of 83% (5/6) in the cohort at low risk for TLS and 80% (12/15) in the cohort at high risk for TLS (Figure). Sixty-two percent (13/21) of pts had CR (low risk for TLS, 67% [4/6];high risk for TLS, 60% [9/15]), 19% (4/21) of pts had PR (low risk for TLS, 17% [1/6];high risk for TLS, 20% [3/15]);5% (1/21) of all pts had stable disease, and 10% (2/21) had PD;1 pt was unevaluable. The median DOR has not been reached (95% CI, 17.5 mo-NE). The median PFS per investigator assessment was not reached (95% CI, 13.7 mo-NE);estimated PFS at 18 mo was 75% (95% CI: 50%-89%) (Figure). All 11 pts with detectable MRD at baseline achieved undetectable MRD, including 7 pts who achieved CRs. Conclusions: Ibr + ven is an all-oral, once-daily, chemotherapy-free regimen being studied for treatment of pts with R/R MCL. With a median of 22 mo on study, no new safety signals we e observed;TLS events and DLTs were rare. Ibr + ven had sustained efficacy, with an ORR of 81%, CR rate of 62%, and the median PFS not reached. All MRD-assessable pts achieved undetectable MRD. The ongoing randomized portion of the SYMPATICO study is evaluating the efficacy and safety of ibr + ven compared with ibr + placebo in pts with R/R MCL;additionally, a single-arm, open-label cohort in previously untreated pts, including pts with TP53 mutations, is ongoing. [Formula presented] Disclosures: Tam: AbbVie: Honoraria, Research Funding;Janssen: Honoraria, Research Funding;BeiGene: Honoraria, Research Funding;Pharmacyclics LLC, an AbbVie Company: Honoraria. Ramchandren: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding;Janssen: Research Funding. Chen: Autolus Therapeutics: Current Employment. Karlin: Sanofi: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees;Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support;AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support;Celgene: Other: Personal fees;GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees. Chong: Hutchison Medipharma: Research Funding;Bayer: Research Funding;Pharmacyclics LLC, an AbbVie Company: Research Funding;Servier: Research Funding;Isofol: Research Funding;Merck Serono: Research Funding;Bristol-Myers Squibb: Research Funding. Jurczak: AstraZeneca, Epizyme: Consultancy;BeiGene: Consultancy, Research Funding;Sandoz Novartis: Consultancy;Janssen: Consultancy, Research Funding;Acerta: Consultancy;Loxo: Consultancy;TG Therapeutics, Acerta, Bayer, MeiPharma: Research Funding;Merck: Research Funding;Pharmacyclics LLC, an AbbVie Company,: Research Funding;Roche: Research Funding;Takeda: Research Funding. Bishton: AbbVie: Research Funding;Gilead: Other: Travel/accomodations/expenses, Research Funding;Roche: Other: Travel/accommodations/expenses, Research Funding;Takeda: Other: Travel/accommodations/expenses, Research Funding;Janssen: Consultancy. Collins: Novartis: Consultancy, Honoraria, Speakers Bureau;ADC Therapeutics: Consultancy, Honoraria;Celleron: Consultancy, Honoraria, Research Funding;BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau;Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau;Amgen: Research Funding;Celgene: Research Funding;MSD: Consultancy, Honoraria, Research Funding;Gilead: Consultancy, Honoraria, Speakers Bureau;Pfizer: Honoraria;Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau;BeiGene: Consultancy. Szafer-Glusman: Pharmacyclics LLC, an AbbVie Company: Current Employment. Lee: AbbVie: Current equity holder in publicly-traded company;Pharmacyclics LLC, an AbbVie Company: Current Employment. Eckert: Pharmacyclics LLC, an AbbVie Company: Current Employment;AbbVie: Current equity holder in publicly-traded company. Neuenburg: Pharmacyclics LLC, an AbbVie Company: Current Employment;AbbVie: Current equity holder in publicly-traded company. Wang: Targeted Oncology: Honoraria;InnoCare: Consultancy;Oncternal: Consultancy, Research Funding;Nobel Insights: Consultancy;Guidepoint Global: Consultancy;Dava Oncology: Honoraria;Acerta Pharma: Research Funding;Verastem: Research Funding;OMI: Honoraria, Other: Travel, accommodation, expenses;Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Molecular Templates: Re earch Funding;AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;OncLive: Honoraria;Lu Daopei Medical Group: Honoraria;Beijing Medical Award Foundation: Honoraria;MoreHealth: Consultancy;Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding;Loxo Oncology: Consultancy, Research Funding;Pulse Biosciences: Consultancy;Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding;Juno: Consultancy, Research Funding;VelosBio: Research Funding;BioInvent: Research Funding. OffLabel Disclosure: Ibrutinib in combination with venetoclax is not approved in any indication