Rob Miani joined the MMRF team as Chief Financial Officer in 2016. Most recently he was the Vice President of Finance and Corporate Controller of Aptuit, LLC, a global contract research organization providing integrated early discovery to mid-phase drug development services in the pharmaceutical industry. Rob has over 20 years of leadership experience in the private and public sectors, holding managerial positions in the renewable energy, private equity, Internet and technology industries, including Davenport Newberry, Oak Investment Partners and INT Media Group. He began his career with Arthur Anderson LLP in the Assurance and Business Advisory Services Division. Rob is a CPA and received his BS degree in Accounting from Fairfield University.
MMRF ASH 2021 Blog: ASH Day 1!
Welcome to our 2021 recap of the latest updates on myeloma treatments reported at the American Society of Hematology (ASH) meeting! This year, ASH is being held as a hybrid meeting—offering participants the option of attending scientific sessions in Atlanta or from the comfort (and safety) of home. For many clinicians, this meeting marks one of the first major oncology meetings to be able to gather and collaborate with each other in person in a long time!
Let’s dig into Saturday morning’s myeloma session that focused on updates to ongoing advanced-stage clinical trials.
Transplant-Eligible Newly Diagnosed Patients
We were first introduced to the phase 2, 4-drug combination regimen trial comparing Darzalex-Velcade-Revlimid-dexamethasone (Dara-VRd) to VRd in newly diagnosed, autologous stem cell transplantation (ASCT) eligible patients (the GRIFFIN trial) from earlier ASH meetings. The primary analysis of this trial showed that the Dara-VRd regimen improved the rate of stringent complete responses (sCRs; that is, no detectable M protein in the blood, normal free light chain ratio, and no myeloma cells in the bone marrow) compared to VRd following post-ASCT consolidation therapy. The results of this analysis are published here. At this meeting, Dr. Jacob Laubach from the Dana-Farber Cancer Institute presented results on 207 patients continuing to be followed on the GRIFFIN trial after 2 years of maintenance therapy with Darzalex-Revlimid or Revlimid alone (ABSTRACT 79). His results showed that:
- More patients achieved sCR receiving Darzalex-Revlimid maintenance than Revlimid (66% vs 47.4%)
- More patients achieved minimal residual disease (MRD) negativity who were treated with Dara-VRd than VRd (64.4% vs 30.1%) and that MRD negativity was sustained for more than 1 year in more patients receiving Dara-VRd than VRd (44.2% vs 12.6%)
- MRD negativity rates in patients treated with Dara-VRd were consistent across all subgroups of patients, including those with high-risk features
- There is a trend towards more patients experiencing a longer time until disease progression when treated with Dara-VRd
The investigators conclude that Dara-VRd as induction and consolidation with ASCT followed by Darzalex-Revlimid maintenance demonstrates deep and durable responses. It is possible that this regimen becomes an option for newly diagnosed patients—results from the phase 3 PERSEUS trial (NCT03710603) comparing Dara-VRd followed by Darzalez-Revlimid maintenance vs VRd followed by Revlimid maintenance are eagerly awaited!
Dr. Shaji Kumar presented the final analysis of the BELLINI trial —a large, phase 3 trial testing Venclexta-Velcade-dex vs Velcade-dex for patients with relapsed/refractory myeloma (ABSTRACT 84). Venclexta is a drug that targets a protein called Bcl-2 found in myeloma cells. Initial studies of Venclexta combined with dexamethasone showed encouraging activity in patients who harbored the chromosomal translocation 11;14—t(11;14). The initial analysis of this trial showed that more patient deaths occurred in the Venclexta arm than the control arm (Velcade-dex). Dr. Kumar reported:
- Patients harboring either t(11;14) or myeloma cells expressing high levels of Bcl-2 (specific biomarkers to identify the most appropriate patients for treatment) benefited the most from Venclexta -Velcade-dex.
- Patients with t(11;14) lived significantly longer before disease progression than those treated with Velcade-dex (36.8 months vs 9.3 months)
- Patients with high BCL-2 expression (measurable amounts of the gene that encodes the Bcl-2 protein) lived significantly longer before disease progression than those treated with Velcade-dex (30.1 months vs 9.9 months)
- Common side effects of Venclexta-Velcade-dex included: diarrhea, nausea, and constipation
- Serious side effects include low platelets, low neutrophils, pneumonia, low red cells, and diarrhea
- In the overall trial population, side effects led to 12 patient deaths in the Venclexta arm (with 9 due to serious infection) and 1 death in the control arm
- In patients with t(11;14) or Bcl-2 overexpression, Venclexta may be a suitable option with a favorable benefit-risk profile.
Saturday afternoon’s myeloma sessions provided us with initial reporting from two of the largest screening studies for myeloma precursor conditions, as well as updates on some of the newest agents to be studied in patients with relapsed/refractory myeloma.
Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM)
Patients with multiple myeloma typically have a preceding phase of disease in which there are changes in the bone marrow but no symptoms or organ damage. The diseases that occur in this phase are monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), collectively known as myeloma precursor conditions. Some patients learn that they have MGUS or SMM when M protein is detected in their blood or urine. Because most people are not screened for these precursor conditions (doctors do not routinely order tests to measure M protein) and there are no signs or symptoms associated with either condition, diagnosis of MGUS or SMM usually only happens incidentally—when a doctor investigating another health issue happens to discover M protein in the blood or urine. Many patients who have MGUS or SMM remain undiagnosed for several years.
To identify patients with these precursor conditions, two, large nationwide studies—the iStopMM study in Iceland and the PROMISE study in the US and Canada—aim to define clinical characteristics of MGUS and SMM via screening. Three presentations came from the iStopMM investigators and one from PROMISE study investigators.
Today’s presentation represents the first time the iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma) study investigators shared their findings (ABSTRACT 151). Impressively, 148,704 individuals over 40 years of age and older in Iceland were enrolled and 75,422 were screened for M protein and abnormal free light chain ratio and of these patients, 3,725 were identified as having MGUS (4.9% of individuals [ABSTRACT 156]) and then randomized to one of the three arms of the study: Arm 1, continued care via Icelandic healthcare system; Arm 2, provided care according to current guidelines via study clinic; and Arm 3, same care as Arm 2 but underwent bone marrow testing and imaging. There were 1,279 individuals randomized to Arm 3 and of those who underwent bone marrow testing, 10.8% were found to have SMM, making the prevalence of 0.53% in individuals 40 years of age or older. Based on the 2/20/20 risk stratification model (three risk factors associated with progression to active myeloma: M protein levels, free light chain ratio, and the number of plasma cells in the bone marrow), about one-third of those patients have an intermediate or high-risk of progression to myeloma.
In a separate analysis, iStopMM investigators assessed the association of MGUS and testing positive for SARS-CoV-2 (the virus causing COVID-19 infection) and the association of MGUS and severe COVID-19 (ABSTRACT 154). In the presentation, the investigators surprisingly showed that MGUS was not associated with COVID-19 susceptibility or COVID-19 severity contrary to observations in myeloma patients. These findings suggest that immunosuppression in MGUS is different than in myeloma.
The PROMISE study led by Dr. Irene Ghobrial at the Dana-Farber Cancer Institute screened individuals aged 40 years or older with an additional myeloma risk factor (high risk individuals include Blacks and those with a first-degree relative diagnosed with a hematologic malignancy or a precursor condition to myeloma). Dr. Ghobrial’s team reported on the screening data for the first 2,960 participants on the study (ABSTRACT 152). The results showed that heavy-chain MGUS was detected in 9.6% of patients; the prevalence increased with increasing age (4.9% in ages 40 to 49 and 13% in ages 70 to 79). The results confirm that older adults who are Black or have a first-degree relative with a hematologic malignancy have an increased prevalence for MGUS compared with other racial groups and may benefit from screening to allow for early detection and possible clinical intervention.
To learn more about myeloma precursor conditions, we have recent presentations from myeloma experts, including PROMISE study principal investigator Dr. Irene Ghobrial, on this topic. We also have a High Impact Topic video. Please visit our education resources page for lots more!
Bispecific Antibodies
Bispecific antibodies or bispecific T-cell engagers are a type of T-cell–directed therapy. Unlike chimeric antigen receptor (CAR) T-cell therapy that uses a patient’s own T-cells engineered to attack myeloma cells, bispecific antibodies are made from two different antibodies, or pieces of antibodies, that have been fused together, so that one piece binds to myeloma cells and another piece binds to cells of the immune system. Most bispecific antibodies target BCMA on myeloma cells and bind to a protein called CD3 that is found on T-cells. The T-cell, once attached to the myeloma cell, releases a type of poison that kills the myeloma cell. Additionally, other proteins on myeloma cells other than BCMA are used as targets for some bispecific antibodies as described below.
Cevostamab
The first bispecific antibody presented today is called cevostamab and it binds to a protein called FcRH5 on myeloma cells. FcRH5 is found at a higher level on myeloma cells than normal B cells (the cell that myeloma cells transform from). Dr. Suzanne Trudel from Princess Margaret Cancer Centre in Toronto, Ontario, Canada presented an update from an ongoing phase 1 study of cevostamab in relapsed/refractory patients (ABSTRACT 157). In this trial, 160 patients have been treated and most had been exposed to at least 6 different lines of prior therapies. Many patients were considered to be triple-class refractory—meaning that they no longer respond to the 3 main classes of myeloma drugs: the proteasome inhibitors (such as Velcade, Kyprolis, and Ninlaro), the immunomodulatory drugs (such as Revlimid and Pomalyst), and the anti-CD38 monoclonal antibody Darzalex. Some patients on this trial had even previously received CAR T-cell therapy, other bispecific antibodies, the antibody-drug conjugate belantamab mafodotin. The results showed:
- 80% of patients experienced cytokine release syndrome (CRS) and 13% immune effector cell-associated neurotoxicity (ICANS)
- 56.7% of patients responded to higher doses of cevostamab (132-198 mg) than lower doses (36.1% at 20-90 mg)
Talquetamab
Talquetamab is another bispecific antibody that binds to a different protein than BCMA on myeloma cells—for this antibody, GPRC5D is the myeloma target. Dr. Amrita Krishnan from the City of Hope presented updated and new results from an ongoing phase 1 study of talquetamab at its recommended phase 2 dose (RP2D) in relapsed/refractory patients (ABSTRACT 158). Ninety-five relapsed/refractory patients (most were triple-class refractory) had been treated at one of two RP2Ds of talquetamab injected subcutaneously: (1) 30 patients received 405 μg/kg weekly, and (2) 25 patients received 800 μg/kg biweekly. The results showed:
- For patients treated weekly at 405 μg/kg
- Common side effects included cytokine release syndrome, low white cell counts, skin-related side effects, taste disorder, and infections
- 70% of patients responded
- For patients treated biweekly at 800 μg/kg
- Common side effects included cytokine release syndrome, dry mouth, low white cell counts, skin-related side effects, and infections
- 66.7% of patients responded
Another phase 1 study of talquetamab—this time in combination with Darzalex—was presented by Dr. Ajai Chari from Mount Sinai School of Medicine (ABSTRACT 161). Twenty-nine patients with relapsed/refractory myeloma (exposed to at least 6 prior lines of therapy) were treated with Darzalex (subcutaneously) and differing doses of talquetamab. Results showed:
- Common side effects included taste disorder, low white cell counts, low platelets, low red blood cell counts, cytokine release syndrome, and skin exfoliation
- 17 out of 21 evaluable patients responded to the combination therapy across all dose groups
Further investigation of talquetamab as a single-agent and in combination with other agents is underway.
REGN5458
Results from a phase 1 trial of the BCMA-targeting bispecific antibody REGN5458 was presented by Dr. Jeffrey Zonder at the Karmanos Cancer Institute (ABSTRACT 160). Sixty-eight patients with relapsed/refractory myeloma (exposed to at least 5 prior lines of therapy with over half of the patients being penta-refractory—meaning that they were refractory to the top 5 myeloma agents: Velcade, Kyprolis, Revlimid, Pomalyst, and Darzalex) were treated with REGN5458 at increasing doses. Results showed:
- Common side effects included cytokine release syndrome, nausea, low white cell counts, and fatigue
- 75% of patients responded at the 200 mg to 800 mg doses
The phase 2 portion of this study is currently recruiting patients.
Updates on MORE bispecific antibodies are happening during Monday’s ASH presentations, so be sure to check back in.
For a visual overview of how bispecific antibodies—and other immunotherapies—work, be sure to view our High Impact Topic video here on immunotherapy.
Iberdomide
A new class of drugs called CELMoDs (cereblon E3 ligase modulators) includes agents such as iberdomide. CELMoDs are related to the immunomodulatory drugs (IMiDs) Revlimid (lenalidomide) and Pomalyst (pomalidomide), but they are more potent. Dr. Sagar Lonial from Emory University presented the results of a phase 1/2 study of iberdomide combined with dex in relapsed/refractory patients (ABSTRACT 162). One hundred and seven patients—who had received at least 6 prior lines of therapy (all had received proteasome inhibitors [Velcade, Kyprolis, Ninlaro], IMiDs [Revlimid, Pomalyst] and anti-CD38 antibodies [Darzalex, Sarclisa]) and 97% were triple-class refractory—received treatment with iberdomide-dex. The results showed:
- 26.2% of patients responded with the response lasting a median of 7 months
- Common side effects included low red blood cell counts, low white cell counts, low platelets, and infection
A phase 3 trial comparing iberdomide-Darzalex-dex vs Darzelex-Velcade-dex in patients with relapsed or refractory multiple myeloma is underway (NCT04975997).
The Multiple Myeloma Research Consortium (MMRC), a unique collaboration of cancer centers in the United States and Canada, will be opening clinical trials using cevostamab or iberdomide in the coming months. Check our clinical trial finder here to check out these studies and more!
We’ll be back tomorrow with more myeloma findings from ASH!
