ASH 2021 Recap: Multiple Myeloma

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Evidence-Based Oncology, January 2022, Volume 28, Issue 1

The 63rd American Society of Hematology (ASH) Annual Meeting and Exposition featured leading experts who discussed research on multiple myeloma.

Sub-Q Isatuximab Combo Offers Safety, Efficacy Profile Comparable With Phase 3 Results in IV Formulation

Results from a phase 1b study of subcutaneous (sub-Q) isatuximab, used along with pomalidomide and dexamethasone, produced safety and efficacy results consistent with those seen in the phase 3 study that led to FDA approval of intravenous (IV) isatuximab with this combination to treat relapsed and refractory multiple myeloma (RRMM) in patients who have received at least 2 prior therapies.1,2

The findings were presented during the 2021 American Society of Hematology Meeting & Exposition, held in Atlanta, Georgia, and online.1

Isatuximab, sold as Sarclisa, was approved in March 2020 to treat certain patients with RRMM based on results of the ICARIA-MM study (NCT02990338), which found that isatuximab added to pomalidomide (Pomalyst) and dexamethasone demonstrated significant progression-free survival (PFS) of 11.53 months compared with 6.47 months with pomalidomide and dexamethasone alone (HR, 0.596; 95% CI, 0.44-0.81; P = .001).2

This triplet combination also demonstrated an improved overall response rate (ORR) compared with pomalidomide and dexamethasone: 60.4% vs 35.3% (P < .0001).

Pharmacists have heralded sub-Q drug delivery in multiple myeloma as more convenient for patients and more efficient for hospital administrators; the arrival of sub-Q delivery for isatuximab gives this anti-CD38 therapy a feature achieved by a competitor, daratumumab (Darzalex).

The multicenter, open-label study presented at ASH 2021 evaluated the safety, pharmacokinetics (PKs), and efficacy of sub-Q vs IV isatuximab and pomalidomide in patients with RRMM who had received at least 2 prior treatments, including lenalidomide and a protease inhibitor.

Patients were randomized 2:1 to receive sub-Q 1000-mg isatuximab or IV 10-mg/kg isatuximab. Following evaluation of the safety, PKs, and CD38-receptor occupancy of isatuximab in the sub-Q formulation, new patients were randomized in 2 new cohorts to receive sub-Q 1400 mg or IV 10 mg/kg. Both formulations were administered once weekly for 4 weeks (cycle 1) and then every 2 weeks in combination with pomalidomide.

Primary end points assessed safety, including dose-limiting toxicity, injection-site reactions, and PK parameters. Secondary end points included ORR, PFS, CD38 receptor occupancy, and patient-reported outcomes.

Of the 34 patients randomized and treated, 12 received IV isatuximab 10 mg/kg with pomalidomide; 12, isatuximab sub-Q 1000 mg with pomalidomide; and 10, isatuximab sub-Q 1400 with pomalidomide. As of March 31, 2021, 7 patients (58%) from the IV group, 14 (33%) from the sub-Q 1000-mg group, and 7 from the sub-Q 1400-mg group remained on treatment.

The median time from the initial multiple myeloma diagnosis to the first study treatment was approximately 5 years; average number of prior lines of therapy was 3.5, with a range of 2 to 7 in the IV cohort, 2 to 6 in the sub-Q 1000-mg cohort, and 1 to 4 in the sub-Q 1400-mg group. When patients entered this study, the International Staging System classified them as 58.4%, 33.3%, and 60.0%, respectively. Due to time of accrual, follow-up was longer with the IV patients.

Safety. Infusion reactions were infrequent, with less than 10% across all groups, and all grade 2 and at the first infusion. Local tolerability of the sub-Q infusion was very good, with a single instance of grade 2 site reaction of erythema and pain. There were similar instances of grade 3 or higher treatment-emergent adverse events and neutropenia across all groups and no treatment-related events that led to death or premature discontinuation. There was 1 case of neutropenia in the sub-Q 1000-mg group and 1 case of pulmonary infection in the sub-Q 1400-mg group. No maximum tolerated dose was identified.

Outcomes. At 8 months, PFS was 73% in the IV and sub-Q 1000-mg groups and 89% in the sub-Q 1400-mg group. ORR, very good partial, and complete response rates were 66.7%, 33%, and 16.7%, respectively, in the IV group; 66.7%, 41.7%, and 25% in the sub-Q 1000-mg group; and 80%, 40%, and 20% in the sub-Q 1400-mg groups.

The authors concluded that sub-Q isatuximab and pomalidomide administration “appears to be a promising and convenient option for patients with RRMM.” 

References

  1. Moreau P, Parmar G, Prince M, et al. A multi-center, phase 1b study to assess the safety, pharmacokinetics, and efficacy of subcutaneous isatuximab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 2744. Accessed December 15, 2021. https://ash.confex.com/ash/2021/webprogram/Paper147136.html
  2. Sanofi: FDA approves Sarclisa (isatixumab-irfc) for patients with relapsed refractory multiple myeloma. News release. Sanofi. March 2, 2020. Accessed December 15, 2021. https://bit.ly/3m6nnZt

Phase 1/2 Trial Results Underscore Teclistamab’s Efficacy in RRMM

Updated results of the MajesTEC-1 phase 1/2 study on teclistamab show that the treatment resulted in an overall response rate (ORR) of 62% (95% CI, 53.7%-69.8%) among patients with relapsed/refractory multiple myeloma (RRMM), suggesting that treatment responses were durable and deepened over time. These additional findings were presented at the 2021 American Society of Hematology Annual Meeting & Exposition.

Teclistamab is a T-cell–redirecting, bispecific immunoglobulin G4 antibody that targets the B-cell maturation antigen (BCMA) and CD3 receptors to induce T-cell–mediated cytotoxicity of BCMA-expressing myeloma cells, researchers explained.

The off-the-shelf therapy is manufactured by Janssen and received a Breakthrough Therapy Designation from the FDA in June 2021. Results of prior preclinical studies revealed that teclistamab killed myeloma cell lines and bone-marrow–derived myeloma cells.

The ORR was reported after a median follow-up of nearly 8 months in 150 patients who received the recommended subcutaneous (SC) phase 2 dose (RP2D) of 1.5 mg/kg across the phase 1 and 2 studies. All participants had received at least 3 prior lines of therapy and were triple-class exposed.

In the phase 1 study, the researchers sought to identify the SC RP2D and to characterize the treatment’s safety and tolerability; phase 2 was carried out to determine efficacy at RP2D.

Among responders, the median time to first confirmed response was 1.2 months (range, 0.2-5.5), while the ORR was consistent independent of cytogenetic risk or extent of prior therapy refractoriness.

However, median duration of response was not reached at the clinical cutoff; at this time, 92 of 93 responders were alive and continuing treatment. Median overall survival was also not reached.

Additional findings include:

  • 58% of patients receiving teclistamab achieved a very good partial response or better
  • 29% achieved a complete response (CR)
    or better
  • 21% achieved a stringent CR
  • By intent to treat, 25% of patients achieved minimal residual disease (MRD) negativity at a threshold of 10–5 (95% CI, 18.0%-32.4%)
  • In patients who achieved a CR or better, the MRD negativity rate was 42%
  • Progression-free survival rate at 9 months was 59% (95% CI, 48.8%-67.0%)

Throughout the course of the trial, no patients required a dose reduction and the most commonly reported adverse events (AEs) were cytokine release syndrome (CRS; 72%), injection-site erythema (26%), and fatigue (25%). One patient discontinued use due to adenoviral pneumonia. All CRS events were low grade, with the exception of one grade 3 event, and all resolved without treatment discontinuation.

Neutropenia, anemia, and thrombocytopenia were the most common hematologic AEs reported, while 5 patients developed immune effector cell–associated neurotoxicity syndrome.

A phase 3 study is currently underway, in part to evaluate the treatment in earlier-line settings and in combination with other agents. Additional data regarding patients with prior BCMA will also be reported. 

Reference

Moreau P, Usmani SZ, Garfall AL, et al. Updated results from MajesTEC-1: phase 1/2 study of teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in relapsed/refractory multiple myeloma. Presented at: 63rd American Society of Hematology Annual Meeting & Exposition; December 13, 2021; Atlanta, GA. Abstract 896. https://ash.confex.com/ash/2021/webprogram/Paper147915.html

iStopMM: Investigators From Iceland Report First Results of Population-Based Screening for Multiple Myeloma

Before the blood cancer multiple myeloma (MM) develops, clinicians can detect precursor conditions, including monoclonal gammopathy of undetermined significance (MGUS), or related lymphoproliferative disorders (LPs). If patients receive a diagnosis at this stage, the chances of survival are greatly improved, but less than 5% of cases are caught at this point.

Five years ago, investigators in Iceland led by Sigurdur Kristinsson, MD, PhD, professor of hematology at the University of Iceland in Reykjavik, sought to evaluate what would happen if screening for MGUS were widely available: Would it lead to an improvement in overall survival?

They launched the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study (NCT03327597), described as “the first population-based screening study for MGUS that includes a randomized clinical trial of follow-up and treatment strategies.”1

Early results from iStopMM were presented in 4 abstracts during the 2021 American Society of Hematology Meeting & Exposition, held in Atlanta, Georgia, and online.

In a video prepared for the International Myeloma Foundation, Kristinsson outlined the scope and mission of the project. “No one has ever done anything like this before—ever,” he said.2 Public support for and participation in the project have been tremendous, according to Kristinsson: “The president of Iceland was the first to give informed consent.”

The project is gathering next-generation sequencing (NGS) data on all those screened, which will be invaluable in researching biomarkers for MM and possibly other blood cancers. Another important aspect of the trial, Kristinsson explained, involves tracking participants’ quality-of-life scores; thus far, it appears that having a positive screen for MGUS does not detract from quality of life.2

Although early results are “encouraging” and show that following patients with detected MGUS closely does yield more positive diagnoses, investigators are cautious. “Until final results of the iStopMM study become available, including data on survival and quality of life, we advise against systematic MGUS screening in healthy individuals,” they wrote.

According to the study authors, iStopMM was open to all Iceland residents born before 1976. Of the 148,708 eligible residents, just over half (54.3%; 80,759) provided consent for screening, and serum samples were collected over a 4-year period through the end of 2020. Investigators collected samples from 75,422 people (93.4%) who provided their initial consent.

Samples were tested for M proteins and free light chains; those with a prior diagnosis of MGUS were excluded. Per protocol and informed consent, those found to have MGUS were randomized to 3 study arms. Arm 1’s 1164 participants were not contacted, arm 2’s 1159 participants were followed based on current guidelines, and arm 3’s 1164 participants will be given intensive diagnostic and monitoring. Those who progress will receive early treatment.

Of the participants screened, 3725 (4.9%) were found to have MGUS over the course of the study. The condition was more likely to be seen as participants grew older: 2.3% among those aged 40 to 59 years; 6.2%, 60 to 79 years; 12.9%, 80 to 103 years. MGUS prevalence was higher in men than women (5.9% vs 4.1%). Most participants were low risk (38%) or low to intermediate risk (36%); 26% had high-intermediate risk, and high-risk MGUS was seen in just 0.2% of cases (9 participants).

After a median follow-up of 3 years, 194 patients received a diagnosis of LP: 9 in arm 1, 92 in arm 2, and 133 in arm 3 (P < .001). In arm 1, 2 patients had smoldering Waldenström macroglobulinemia (SWM), 2 had WM, 1 had chronic lymphocytic leukemia (CLL), and 4 had MM.

Arm 2 included 1 patient with amyloidosis; 18, SWM; 2, WM; 2, CLL; 1, non-Hodgkin lymphoma (NHL); 56, smoldering MM; and 12, MM. Arm 3 had 2 patients with amyloidosis; 22, SWM; 5, CLL; 6, NHL; 82, SMM; and 16, MM.

In a separate abstract, the investigators found that they “did not find MGUS to be associated with SARS-CoV-2 susceptibility or COVID-19 severity. This is contrary to MM, which is preceded by MGUS.” The findings, they wrote, suggest that the immunosuppression in MGUS is different from that in MM, which has important implications for management and treatment.3

References

  1. Screening for monoclonal gammopathy of undetermined significance: a population-based randomized clinical trial. first results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 156. https://ash.confex.com/ash/2021/webprogram/Paper152333.html
  2. iStopMM. International Myeloma Foundation. June 21, 2021. Accessed December 18, 2021. https://www.myeloma.org/black-swan-research-initiative/istopmm
  3. Monoclonal gammopathy of undetermined significance and COVID-19: results from the population-based Iceland Screens, Treats, or Prevents Multiple Myeloma Study (iStopMM). Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Abstract 154. https://ash.confex.com/ash/2021/webprogram/Paper153145.html