Gina Mauro

The triplet regimen of of ixazomib (Ninlaro), cyclophosphamide, and dexamethasone (ICd) elicited higher rates of efficacy compared with ixazomib/dexamethasone, followed by single-agent ixazomib maintenance, in patients with transplant-ineligible newly diagnosed multiple myeloma, according to updated results of the phase 2 EMN10-UNITO trial (NCT02586038). Findings were presented during the 2nd European Myeloma Network Meeting.

“Based on safety and efficacy data, ixazomib, cyclophosphamide, and dexamethasone [were] the most promising triplet. Ixazomib maintenance confirmed the promising data reported in the previous TOURMALINE-MM4 study,” said lead study author Roberto Mina, MD, of the myeloma unit in the Division of Hematology at the University of Torino in Italy, in a virtual presentation of the data during the meeting.

Findings showed that the median progression-free survival (PFS) was 17.9 months with the combination of ixazomib, cyclophosphamide, and dexamethasone and 12.3 months with the regimen of ixazomib, thalidomide, and dexamethasone (ITd). For patients who received ixazomib, bendamustine, and dexamethasone (IBd), the median PFS was 13.9 months; with ixazomib/dexamethasone (Id) alone, the median PFS was 10.3 months.

The 2-year PFS rates were 39%, 27%, 40%, and 31%, respectively. The 2-year overall survival rates were 75%, 78%, 89%, and 85%, respectively.

From the start of ixazomib maintenance, the overall median PFS was 15.1 months; the differences in median PFS were not significant in the intermediate-fit (HR, 0.92) and frail patients (HR, 1.14) versus fit patients. The 2-year PFS rate was 34%, which did not meet the study’s primary end point (≥ 65%).

Ixazomib is currently approved by the FDA for use in combination with lenalidomide (Revlimid) and dexamethasone as a treatment for patients with multiple myeloma who have received at least 1 prior therapy.

In the EMN10-UNITO study (n = 171), investigators evaluated ixazomib in various combinations: Id (n = 41), ICd (n = 59), ITd (n = 60), and IBd (n = 11) in transplant-ineligible newly diagnosed myeloma. All combinations were given as induction therapy followed by single-agent ixazomib maintenance therapy.

Patients enrolled on the study were at least aged 65 years and ineligible for transplant. Additional criteria for eligibility included an ECOG performance status of 0 to 2, creatinine clearance of at least 30 ml/min, and adequate bone marrow and hepatic function.

The median age was 74 years. Using the International Staging System (ISS), 24.75% of patients were stage 1, 50% stage II, and 25.5% stage III. Using the revised ISS, 31.5% of patients were stage I, 72% stage II, and 12% stage III. Chromosomal abnormalities were found in 24.25% of patients overall. More patients were fit (51.75%) compared with intermediate fit (26%), and frail (21.75%).

Ixazomib was administered at 4 mg on days 1, 8, and 15; dexamethasone at 40 mg on days 1, 8, 15, and 22; cyclophosphamide at 300 mg/m2 orally on days 1, 8, 15; thalidomide at 100 mg daily; and bendamustine at 75 mg/m2 intravenously on days 1 and 8. All induction therapies were given in 9 cycles. Ixazomib was then given as maintenance at a 4-mg dose on days 1, 8, and 15 for up to 2 years.

The primary end point was 2-year PFS rate; secondary end points were second progression–free survival, overall survival, and safety. The trial had dual stopping rules with an efficacy end point of below a very good partial response (VGPR) and a predefined toxicity related to ixazomibin 5-patient cohorts in each arm during the first 4 cycles.

The IBd and Id arms were prematurely closed due to low enrollment and high risk of inefficacy, respectively.

At a median follow-up of 27 months, results showed that a partial response or better was achieved in 57%, 75%, 84% and 64% in the Id, ICd, ITd, and IBd arms, respectively. A VGPR or better was achieved in 24% of the Id arm, 46% of the ICd arm, 48% with ITd, and 27% with IBd. Complete responses or better were achieved in 10%, 10%, 5%, and 9% with Id, ICd, ITd, and IBd, respectively (

Minimal residual disease negativity was achieved in 10% or better, 4% or better, 10% or better, 9% or better of the Id, ICd, ITd, and IBd, respectively.

Additional data showed that after induction, the response rates were similar in fit, intermediate-fit, and frail patients at 71%, 74%, and 76%, respectively. No significant differences were noted in these groups regarding median PFS, at 14.1 months, 14.8 months and 12.2 months, respectively. Sixty percent (n = 102) of patients completed the induction phase of treatment and then proceeded to maintenance therapy with ixazomib; 18% of patients upgraded their response during maintenance. Grade 3/4 nonhematological adverse events (AEs) were highest in the ITd arm (45%) compared with the ICd (17%), IBd (36%), and Id (17%) arms. Nonhematological AEs in the induction phase occurred more often in frail patients (37%) compared with the intermediate-fit (26%) and fit (24%) patients. Frail patients also had a higher risk of treatment discontinuation (21%) vs intermediate-fit (9%) and fit patients (11%).

Mina R, Larocca A, Corradini P, et al. Ixazomib-based induction followed by single-agent ixazomib maintenance in transplant ineligible, newly diagnosed multiple myeloma patients: updated results of the EMN10-UNITO trial. Presented at: 2nd European Myeloma Network Meeting; March 3-6, 2021; virtual. Abstract P28.

Articles

Ixazomib plus cyclophosphamide, and dexamethasone elicited higher rates of efficacy compared with ixazomib/dexamethasone, followed by single-agent ixazomib maintenance, in patients with transplant-ineligible newly diagnosed multiple myeloma/









Study Identifies Ideal Ixazomib Triplet Regimen for Newly Diagnosed Multiple Myeloma

Investigators reported an objective response rate (ORR) of 73% for the anti–B-cell maturation antigen (BCMA) teclistamab (formerly JNJ-64007957) in patients with relapsed/ refractorymultiple myeloma, according to results from an ongoing study (NCT03145181) presented during the 2nd European Myeloma Network Meeting.1 Findings also demonstrated a tolerable safety profile.

In addition, results from the phase 1 study showed that the agent had a very good partial response rate (VGPR) or better at 55%, which includes the complete response (CR) rate (23%) and the VGPR rate (32%).

The agent was also found to be well tolerated at the recommended phase 2 dose (RP2D), which was 1500 μg/kg given subcutaneously (SC); the maximum-tolerated dose was not identified, and all reports of cytokine release syndrome (CRS) were grades 1/2 and generally confined to step-up doses and the first full doses of treatment.

“Teclistamab is an off-the-shelf therapy targeting BCMA, [and it] showed promising efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma,” said lead study author Alfred L. Garfall, MD, an assistant professor of medicine at the Hospital of the University of Pennsylvania, in a virtual presentation of the data.

There continues to be an unmet need for patients with relapsed/refractory multiple myeloma, he explained; for those who progress on available therapies, the ORR is approximately 30%, the median progression-free survival is estimated at 3 months, and the median overall survival ranges from 6 to 11 months.

Teclistamab is a bispecific humanized IgG4 antibody targeting both BCMA and CD3. The agent induces the T-cell–mediated killing of myeloma cells from both preclinical models and heavily pretreated patients.

Prior data of the phase 1 study, which were presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program, showed that teclistamab was found to be safe and effective in this patient population.

In the updated results of the study, Garfall presented additional data of teclistamab administered intravenously (IV) or SC in patients with relapsed/refractory multiple myeloma. To be eligible for enrollment, patients had to have measurable myeloma that was relapsed/refractory or intolerant to established treatment, a hemoglobin level of at least 8 g/dL, a platelet count of at least 75 × 10

/L, and white blood cell counts of at least 1.0 × 10

The study included 2 cohorts: IV (n=84) and SC (n=65) administration. The dosing schedule in each cohort comprised 1 to 3 step-up doses prior to week 1, followed by full doses from weeks 1 to 3. In the IV cohort, doses increased from 0.3 to 19.2 μg/kg with a maximum dose of 720 μg/kg; the SC cohort started at 80 μg/kg and increased up to 3000 μg/kg. The initial every-2-week IV dose was switched to weekly IV or SC plus or minus step-up dosing. Investigators selected 1500 μg/kg as the RP2D.

Premedication with dexamethasone was limited to the step-up doses and the first full dose, and there was no steroid requirement following the first full dose.

In the overall study population (n=149), the median age was 63 years (range, 24-84), and 22% of patients were 70 years and older; 54% of patients were male. Twenty-five percent of patients had at least 60% of bone marrow plasma cells, 12% had at least 1 extramedullary plasmacytomas, and the median years since diagnosis was 7. A total 32% of patients had high-risk cytogenetics, and 85% had prior transplantation.

The median number of prior lines of therapy was 6 (range, 2-14), most patients (96%) were exposed to 3 classes of therapy, and 69% were penta-refractory. Patients were refractory to carfilzomib (Kyprolis; 66%), pomalidomide (Pomalyst; 77%), and anti-CD38 antibodies (93%), and 91% of patients were refractory to their last line of therapy.

Baseline characteristics were similar overall and in the cohort of patients on the RP2D (n = 33), except there were fewer patients with bone marrow plasma cells at 60% or more (10%) in this cohort.

The primary end point in part 1 of the trial was the RP2D; in part 2, the key objective was safety and tolerability at the RP2D, as well as antitumor activity, pharmacokinetics, and pharmacodynamics.

The updated findings also showed that at the RP2D, the median time to first confirmed response was 1 month (range, 0.3-3); 70% of patients who were triple-class refractory responded to treatment, and 75% of patients who were penta-refractory responded.

Most of the active doses were reported to be between 270 to 720 ug/kg given IV and 720 to 3000 μg/kg given SC. At these doses, the ORR was 69% and 59% of patients had a VGPR or greater, with a CR or better occurring in 26% of these patients. In the IV cohort (n=27) and SC cohort (n=41), the ORRs were 67% and 71%, respectively.

Responses in the SC Cohort In the SC cohort, the ORR was 46% at the 80 μg/kg plus 240 μg/kg dose (n=13), 60% at the 720 μg/kg dose (n=15), and 73% at the 1500 μg/kg (n=22), in which the VGPR or better was 55%.

Of 11 evaluable patients across the IV and SC doses thus far, 8 patients had a minimal residual disease (MRD)–negative CR at 10-6 and 1 patient experienced this at 10-5 sensitivity.

Responses were found to be durable and deepen over time. Among responders who received the RP2D (n=16), at a median follow-up of 3.9 months, 94% of patients were alive and progression free. Of those in the SC cohorts (n=35), 91% of patients were on treatment with ongoing responses at the median follow-up of 6.5 months.

Patients receiving the active IV and SC doses (n=47) remained on treatment with ongoing responses (94%) at a median follow-up of 6.5 months. All 5 evaluable patients across the IV and SC cohorts showed sustained MRD negativity.

The pharmacokinetic data supported the RP2D. Regarding the SC dosing, exposure was dose proportional following the first treatment dose (80 μg/kg to 3000 μg/kg SC), and 1500 μg/kg SC was found to have low peak/trough ratio and maintained exposure over the max EC90. This leads to the opportunity for less frequent SC dosing, Garfall added. Two of 107 patients (2%) had antidrug antibodies of low titer, and soluble BCMA was not found to impact teclistamab exposure, as seen in the preliminary population pharmacokinetic analysis. Pharmacodynamics also supported the RP2D.

Safety Profile The safety profile was similar in both the overall and RP2D population. Overall, the most common (≥ 20%) all-grade and grade 3 or higher adverse events (AEs) were neutropenia (57% and 46%, respectively), anemia (55% and 32%), thrombocytopenia (40% and 22%), and leukopenia (28% and 14%). Nonhematologic allgrade AEs were all-grade CRS (55%), pyrexia (30%), diarrhea (23%), nausea (22%), fatigue (22%), headache (22%), and cough (21%). Grade 3 or higher AEs were cough (2%) and diarrhea, nausea, and fatigue (1% each).

In the RP2D cohort, hematologic AEs were neutropenia (all-grade, 52%; grade≥3, 33%), anemia (39% and 21%, respectively), thrombocytopenia (33% and 22%), and leukopenia (33% and 18%). Nonhematologic AEs were CRS (64%), pyrexia (18%), diarrhea (12%), nausea (18%), fatigue (24%), headache (12%), and cough (3%). There was 1 nonhematologic AE that was grade 3 or higher, which was fatigue (3%).

There were 2 dose-limiting toxicities (DLTs) across all doses but none at the RP2D. The DLTs were grade 4 delirium, which occurred at the 20 μg/kg IV step-up dose, and grade 4 thrombocytopenia at the 180 μg/kg IV dose.

Infections occurred in 52% of patients, and 27% occurred at the RP2D; 15% of these patients had grade 3 or higher infections across all doses, and 6% had grade 3 or higher infections at the RP2D.

Neurotoxicity events occurred in 7 patients (5%), with 1 (3%) occurring at the RP2D. Two grade 3 or higher neurotoxicity occurred at the IV dose, and none were reported with SC dosing. One treatment-related AE, grade 5 pneumonia at 80 μg/kg after 16 cycles, led to death; no treatment-related deaths occurred at the RP2D. CRS occurred in 55% of patients overall; the median time to CRS onset was 2 days (range, 1-5 days), and the median duration of CRS was 2 days (range, 1-8). Fifty-one percent of patients had supportive measures to treat CRS: tocilizumab (Actemra; 23%), steroids (13%), low-flow oxygen (6%), and single low-dose vasopressor (1%).

There were no treatment discontinuations due to CRS; CRS was generally confined to the stepup and first full doses. CRS occurred in 54%, 57%, and 64% in the IV, SC, and RP2D groups, respectively. Step-up dosing was conducted to mitigate the risk of severe CRS, and no cases of grade 3 or higher CRS occurred.

The phase 1 study remains ongoing, and a phase 2 expanded study has been initiated, Garfall concluded.

Garfall AL, Usmani SZ, Mateos M-V, et al. Teclistamab, a B-cell maturation antigen (BCMA) X CD3 bispecific antibody, in relapsed and/or refractory multiple myeloma (RRMM): updated phase 1 results. Presented at: 2nd European Myeloma Network Meeting; March 3-6, 2021; virtual.

Investigators reported an objective response rate of 73% for the anti–B-cell maturation antigen teclistamab  in patients with relapsed/ refractory multiple myeloma, according to results from an ongoing study.

Teclistamab Demonstrates High Response Rate and Good Tolerability in Multiple Myeloma

Infection mortality rate were lower in patients with multiple myeloma who were coronavirus disease 2019 (COVID-19) positive and received maintenance lenalidomide (Revlimid) than those who did not receive lenalidomide, according to study results presented during the 2nd European Myeloma Network Meeting held virtually in March.

Further, maintenance treatment with lenalidomide was found to be a safe treatment for patients, supporting use of the immunomodulatory drug (IMiD) in this population.

Data showed that the infection mortality rate was 23.8% in patients who were COVID-19 positive and on maintenance lenalidomide compared with 33.3% for those who had COVID-19 and did not receive lenalidomide. The recovery rates in both arms were 76.2% and 66.7%, respectively.

““Although cytopenias and immunoparesis may develop during continuous maintenance, lenalidomide seems to be safe and has effects in favor of less severe COVID-19 forms and also similar mortality among [patients with multiple myeloma],” said Ekin Kircali, MD, of the Department of Hematology at Ankara University School of Medicine in Turkey, during the virtual presentation. “Based on our experience, we do not recommend discontinuation during this pandemic.”

Lenalidomide maintenance following consolidation therapy with high-dose melphalan is a common approach known to prolong progression-free survival in patients with multiple myeloma, Kircali noted in her presentation.

Lenalidomide also may induce neutropenia and lymphopenia, which in turn exposes patients to infections, including COVID-19.

However, small case series and other reports have suggested that IMiDs could protect patients from severe cases of COVID-19.

In the study, investigators evaluated 60 patients with multiple myeloma between March 2020 and December 2020 and compared outcomes of those who received continuous lenalidomide maintenance (n = 42) vs no lenalidomide (n = 18).

Patients were divided into 3 groups: those who were COVID-19 positive and taking lenalidomide (n = 21), those who were COVID-19 negative and taking lenalidomide (n = 21), and those who were COVID-19 positive and not taking lenalidomide.

In the COVID-19–positive/lenalidomide group, the median age was 61 years (range, 57-70), and 10 patients were women. The number of lenalidomide cycles was 16 (range, 9-99), and 14 patients had a very good partial response (VGPR) or better to therapy. The neutrophil counts and lymphocyte counts were 1.43 (range, 0.74-9.2) and 0.97 (range, 0.01-2.84), respectively. IgG, IgA, and IgM levels were 7.94 mg/dL (range, 3.2-19.1), 0.69 mg/dL (range, 0.1-3.5), and 0.31 g/L (range, 0.1-0.7), respectively.

Also, in this arm, patients had either nonsevere COVID-19 (n = 15) or severe COVID-19 (n = 6), and 5 patients died. The infection fatality rate was 23.8%, and the recovery rate was 76.2%.

In the COVID-19–negative/lenalidomide group, the median age was 63 years (range, 58-71), and 11 patients were women. Sixty-one cycles (range, 10-90) of lenalidomide were given, and 18 patients had a VGPR or better to therapy. The neutrophil count was 1.65 (range, 0.77-4.24), and the lymphocyte count was 1.40 (range, 0.31-2.72). The IgG, IgA, and IgM levels were 9.46 mg/dL (range, 2.8-32.7), 1.73 mg/dL (range, 0.0-206), and 0.24 g/L (range, 0.1-0.9), respectively (

Within this group, 1 patient died, the infection fatality rate was 4.8%, and the recovery rate was not applicable as no patients in the group had COVID-19.

Finally, in the COVID-19–positive group without lenalidomide, the median age was 66 years (range, 46-79) and 12 patients were women. Eight patients had a VGPR or better to therapy. The neutrophil count and lymphocyte count were 3.21 (range, 0.45-67.48) and 1.03 (range, 0.03-3.81), respectively. The IgG, IgA, and IgM levels were 10.25 mg/dL (range, 2.6-113), 0.41 mg/dL (range, 0.0-2.2), and 0.26 g/dL (0.0-1.3), respectively.

In this arm, 11 patients had nonsevere COVID- 19 and 7 patients had a severe case. Six patients died; the infection fatality rate was 33.3% and the recovery rate was 66.7%.

Kircali, E, Seval GC, Toprak SK, et al. Outcome of COVID-19 infection occurring during lenalidomide maintenance. Paper presented at: 2nd European Myeloma Network Meeting; March 3-6, 2021; virtual. Abstract P34.

Infection mortality rate were lower in patients with multiple myeloma who were coronavirus disease 2019 positive and received maintenance lenalidomide than those who did not receive lenalidomide, according to study results presented during the 2nd European Myeloma Network Meeting.








Lenalidomide Reduces Infection Mortality Rates in COVID-19-Positive Patients With Multiple Myeloma

In preclinical models of KRAS-mutant cancer, voruciclib, a CDK9 inhibitor, showed early activity as monotherapy and when used in combination with sotorasib (AMG 510) and adagrasib, according to findings presented during Week 1 of the 2021 AACR Annual Meeting.

The early results showed that voruciclib led to a rapid decrease in the phosphorylation of proteins that promote MYC transcription and quickly decreases phosphorylation of MYC protein on Serine 62 (Ser62), which is a site implicated in stabilizing MYC in 

“Voruciclib demonstrated single-agent efficacy against multiple 

-mutant cancer cell lines and acted synergistically with KRAS G12C inhibitors in both in vitro and in vivo models,” Sandra Wiley, MD, of MEI Pharma, the developer of the CDK9 inhibitor, said in a virtual presentation of the data. “Collectively, these experiments suggest that voruciclib could be an attractive therapeutic option for cancers driven by 

Voruciclib is an oral small molecular inhibitor of CDK 9, 4, 6, and 1 that is currently being evaluated in a phase 1b trial of patients with B-cell malignancies and acute myeloid leukemia. Although the study presented during the 2021 AACR Annual Meeting focused on the activity of the agent in 

-mutant cancers, its effect on MYC regulation is “at the heart of the story,” Wiley said.

CDK9 is an integral part of the PTEFb complex that regulates RNA polymerase II. Upon initiation of transcription, RNA polymerase II is subject to promote proximal pausing. After release from an inhibitory complex, PTEFb interacts with the polymerase II complex and phosphorates proteins that relieve pausing and allow for productive elongation.

In AML models, voruciclib inhibition of CDK9 leads to decreased expression of RNA polymerase II transcriptional targets, including MYC and MCL1. Furthermore, 

 mutations are often complemented by stabilization by the MYC oncoprotein. Signaling through the RAS/RAF/MEK pathway leads to ERK1 phosphorylation of MYC on Ser62. Recent reports have shown that CDK9 can also directly phosphorylate MYC on Ser62 and may regulate MYC protein stability, in addition to MYC transcription.

For this study, investigators sought to determine whether voruciclib could acutely affect proteins that regulate RNA pol II activity in 

-mutant solid tumor models. Through the use of a phosphoproteomics approach, researchers utilized MIA PaCa-2 cells in a pancreatic cancer line with a 

Investigators noted that there was “good coverage and detected hundreds of proteins with a decrease in phosphorylation after voruciclib treatment. Consistent with a role in inhibition of PETfb, after exposure to voruciclib, there was a rapid downregulation of RNA polymerase II–associated proteins that control MYC transcription,” Wiley explained.

Additionally, an immunoblot analysis with a phosphor-specific antibody revealed that voruciclib led to a rapid inhibition of phosphorylation of MYC on Ser62. Here, data showed that there was a 60% decrease of Ser62 phosphorylation at 5 minutes was observed that reached 80% by 60 minutes. However, there was no decrease in total MYC proteins at either time point. However, there was a reduction in total MYC at 60 minutes that reached 50% at 240 minutes.

This is consistent with Ser62 de-phosphorylation promoting MYC protein instability and degradation, Wiley noted.

Furthermore, voruciclib was found to inhibit proliferation of 

-mutant cancer cell lines in vitro and in vivo. Through an in vitro assay tested 22 cancer cell lines harboring multiple 

 mutations—including G12D, G12V, G12C, G12A, G12S, Q61H, G13C—results showed that voruciclib “decreased viability in all cell lines tested with low micromolar IC50s [half maximal inhibitory concentration],” Wiley said.

Additionally, voruciclib was found to inhibit tumor growth in vivo in 

-mutant colorectal cancer and lung cancer xenograft models.

Regarding combination strategies with voruciclib, investigators hypothesized that the CDK9 inhibitor may have synergy with the KRAS G12C inhibitors sotorasib and adagrasib. By measuring growth inhibition in a panel of 

-mutant cell lines treated with voruciclib in combination with each agent, synergy was observed in most of the cell lines harboring 

Stemming from this activity, researchers also examined the synergy of voruciclib with sotorasib in an in vivo MIA PaCA-2 tumor model utilizing Presage CIVO technology, which involved in vivo intratumoral injection of the compound, followed by immunohistochemistry testing. Similar testing was conducted with adagrasib, Wiley noted.

“Collectively, the data reported today offer the opportunity to expand our current development activities with voruciclib and support its potential as a therapeutic option for KRAS mutated cancers in combination with direct inhibitors of KRAS,” Daniel P. Gold, PhD, president and chief executive officer of MEI Pharma, said in a statement. “Beyond these data, we have ongoing efforts to explore other potential synergistic combinations in various 

-mutated cancers as we evaluate opportunities to confirm these findings in a clinical setting.”

1. Wiley S, Su Y, Ge Y. Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models. Presented at: 2021 AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract 1962.

2. MEI Pharma reports preclinical data demonstrating ability of voruciclib to regulate myc and synergize with KRAS inhibitors in KRAS mutant cancers. News release. MEI Pharma. Published April 10, 2021. Accessed April 10, 2021.

In preclinical models of KRAS-mutant cancer, voruciclib, a CDK9 inhibitor, showed early activity as monotherapy and when used in combination with sotorasib and adagrasib, according to findings presented during Week 1 of the 2021 AACR Annual Meeting.

Gina Mauro | Authors

Articles

Study Identifies Ideal Ixazomib Triplet Regimen for Newly Diagnosed Multiple Myeloma

Teclistamab Demonstrates High Response Rate and Good Tolerability in Multiple Myeloma

Lenalidomide Reduces Infection Mortality Rates in COVID-19-Positive Patients With Multiple Myeloma

Voruciclib Demonstrates Preliminary Activity Alone or in Combination with Sotorasib or Adagrasib in KRAS+ Cancers