The American Society of Clinical Oncology (ASCO) meeting this year was held virtually. As many of us are so fully aware—this decision was made due to concerns for the safety of the attendees around the current COVID-19 pandemic. ASCO is no different than many other key societies that have made the switch to virtual for their annual meetings that were expected to be held this spring. The silver lining to all of this is that regardless of ASCO being live or virtual this year, it was a great year of multiple myeloma data presentations! Here we summarize the key findings important for you to know.
ASCO organized the main myeloma oral abstract and poster discussion sessions from Friday into key topics including:
For a summary of abstracts presented on Saturday and Sunday click here.
New Class: CELMoDs
The first of the novel therapies discussed include a new class of drugs called CELMoDs which stands for cereblon E3 ligase modulators. This drug class works somewhat similarly to the immunomodulatory drugs (IMiDs) Revlimid (lenalidomide) and Pomalyst (pomalidomide), but they are more potent. Consider that the CELMoDs may be the next generation of IMiDs! You may recall hearing about a CELMoD—iberdomide—which was discussed at last year’s International Myeloma Workshop meeting (key summaries from IMW are posted here).
Another CELMoD—called CC-9480—was tested for the first time in humans and the results of the phase 1 study were the focus of the first presentation by Dr. Paul Richardson at Dana-Farber Cancer Institute (ABSTRACT 8500). Patients in this study had relapsed or refractory myeloma and were very heavily pretreated—many having already been treated by a stem cell transplant and with many of the main drugs used to treat myeloma including: Velcade (bortezomib), Revlimid, Pomalyst, and Darzalex (daratumumab)—also referred to as triple-class refractory. Sixty-six patients received varying doses of CC-9480 plus dexamethasone and treatment resulted in:
- Responses in 21% of patients in all dose groups (responses were independent of refractoriness to previous immunomodulatory drugs)
- Responses in 48% of patients in the groups receiving 1.0 mg per day
- Neutropenia (low neutrophil count) in 53% of patients
Studies are ongoing to further test CC-9480.
XPOVIO in Combination With Velcade-Dexamethasone
The next novel therapy to be discussed was XPOVIO (selinexor)—the first in a new drug class called selective inhibitors of nuclear export (SINE). XPOVIO was approved last year in combination with dexamethasone for the treatment of patients who have relapsed or refractory multiple myeloma, have received at least four prior antimyeloma treatment regimens, and are refractory to at least two proteasome inhibitors (such as Velcade, Kyprolis, and Ninlaro), at least two immunomodulatory drugs (such as Revlimid and Pomalyst), and an anti-CD38 monoclonal antibody (Darzalex). In his presentation, Dr. Meletios Dimopoulos provided the results of the anticipated phase 3 trial called the BOSTON study that evaluated the combination of Velcade plus dexamethasone with or without XPOVIO (ABSTRACT 8501). This study included 402 patients with relapsed myeloma who had received only one to three prior therapies—so these patients were much less heavily pretreated than the patients in the study that led to XPOVIO’s approval. Velcade-dex was administered twice a week and XPOVIO-Velcade-dex was administered once a week. Compared to patients receiving Velcade-dex, XPOVIO-Velcade-dex treatment resulted in:
- More patients responding (76.4% versus 62.3%)
- Longer time until disease progression (median 20.3 versus 12.9 months)
- More patients experiencing low platelet counts, fatigue, and nausea
- Fewer patients experiencing peripheral neuropathy
These data are being used to evaluate whether XPOVIO can be used in patients who have received one to three prior therapies and these data have been submitted to the FDA for review, so we anxiously await the approval of this new combination for relapsed/refractory patients!
Antibody-Drug Conjugate: Belantamab mafodotin (belamaf)
The last of the novel therapies to be presented is belantamab mafodotin, also referred to as belamaf—the antibody-drug conjugate that, earlier this year, was granted a priority review by the FDA. Dr. Ajay Nooka of Emory University presented the results of the DREAMM-6 study evaluating belamaf plus Velcade and dexamethasone or Revlimid and dexamethasone in relapsed/refractory myeloma patients (ABSTRACT 8502). Currenty, most of what we know about belamaf’s activity is as a single agent—as described below in the Renal Insufficiency section. So, this study is the first to evaluate how belamaf works in combination with traditional myeloma therapy. The data presented here at ASCO is solely on the 52 patients treated with the combination of belamaf-Velcade-dex and of those 18 patients received a single dose of belamaf in the combination:
- 78% of patients responded to treatment
- The most common side effects observed were corneal events (changes in the surface of the cornea observed on eye exams, blurred vision, and dry eye) and low platelet counts
CAR T Cell Therapies
Three different chimeric antigen receptor (CAR) T cell constructs were presented, and we are learning the actual drug names on two rather than their numeric designations! This is a good sign as it means these drugs are advancing farther in their clinical development. For a refresher about CAR T cells, check out our blog here.
bb2121 Now Known as Idecabtagene Vicleucel (ide-cel)
First up is idecabtagene vicleucel (formerly known as bb2121)—also referred to as ide-cel. Ide-cel is a CAR T-cell therapy in which the patient’s T cells are engineered to bind to the B-cell maturation antigen (BCMA) protein found on myeloma cells. You can learn more about BCMA as a myeloma target here. Dr. Nikhil Munshi from Dana-Farber Cancer Institute presented data from the KarMMa phase 2 trial which investigated ide-cel at different cell doses in 128 patients with triple-class refractory myeloma (ABSTRACT 8503). Ide-cel treatment resulted in:
- Responses in 73% of patients
- 50% of patients who achieved a very good response or better (VGPR) became minimal residual disease (MRD) negative
- Response lasted a median of 10.7 months
- Low white blood cell counts in 97% of patients
- Cytokine release syndrome in 84% of patients
- Neurotoxicity in 18% of patients
While ide-cel hit a bit of a setback earlier this month with a delay for its FDA review; we anxiously await the review of this new therapy!
JCARH125 Now Known as Orvacabtagene Autoleucel (orva-cel)
The next CAR T cell presentation is on orvacabtagene autoleucel (formerly known as JCARH125)—also known as orva-cel. Investigators at Memorial Sloan Kettering Cancer Center presented the results of the EVOLVE study investigating different cell dose levels of orva-cel in relapsed/refractory myeloma patients (ABSTRACT 8504). Sixty-two patients who were heavily pretreated received orva-cel which resulted in 92% of patients responding to treatment and 84% of patients becoming MRD negative. Low white blood cell counts and cytokine release syndrome were the main side effects experienced by patients.
Finally, Dr. Jesus Berdeja at the Sarah Cannon Cancer Center provided an update on the JNJ-4582 CAR T cell trial called CARTITUDE-1 (ABSTRACT 8505). CARTITUDE-1 is a phase 1/2 trial evaluating JNJ-4582 treatment in relapsed/refractory myeloma patients. Results from this trial were initially presented in December at the American Society of Hematology (ASH) and you can read our blog post here. In his virtual ASCO presentation, Dr. Berdeja provided longer follow up of the 29 patients treated and reported on at ASH (that is, it is now a median of 9 months since the first patient was treated). Key highlights from the presentation included:
- All patients responded to treatment
- Patient who could be evaluated for MRD were MRD negative
- Most patients experienced low neutrophil and platelet counts as well as cytokine release syndrome
Clinical evaluation of JNJ-4582 which received a Breakthrough Therapy Designation from the FDA will continue and clinical trials—including a phase 3 trial—have been initiated.
Newly Diagnosed High-Risk Myeloma
The next three presentations focused on different combination treatment strategies for patients with newly diagnosed multiple myeloma. These studies also included a subset of patients who are considered to have high-risk disease features. Each study revealed how these treatments may be of benefit to these patients who do not enjoy long-term clinical remission. ASCO presentations focused on a large, randomized phase 3 trial of post-transplant strategies and two trials of monoclonal antibody-based quadruplet regimens to improve outcomes for patients with high-risk disease.
Long-Term Update From the STaMINA Trial
The first study to be presented was the STaMINA trial—a phase 3 trial that tested additional treatments after induction and autologous stem cell transplant (ASCT) to improve patient survival. The 758 patients enrolled onto the study all received induction therapy followed by an ASCT and then they received one of the following treatment plans:
- A second ASCT followed by Revlimid maintenance therapy (Auto/Auto group)
- Consolidation therapy with Revlimid-Velcade-dexamethasone followed by Revlimid maintenance (Auto/RVD group)
- Revlimid maintenance (Auto/Rev group)
The initial analysis of this trial has been published here and the analysis presented at ASCO by Dr. Hari from the Medical College of Wisconsin is based on 6 years of follow up for patients on this study (ABSTRACT 8506) comparing the outcome between the three different treatment groups. The results showed:
- There was no difference in overall survival between the three groups
- For patients considered to have high-risk disease, more patients in the Auto/Auto treatment group benefited with longer time until disease progression than in the other two groups
Tandem transplantation (ie, Auto/Auto group) has been considered non-beneficial to patients based on previous studies, but the results presented here at ASCO show that tandem transplants may specifically benefit patients with high-risk myeloma.
4-Drug Combination Therapies With Monoclonal Antibodies for High-Risk Patients
Empliciti (elotuzumab)—the monoclonal antibody that targets SLAMF7 on myeloma cells—is being studied in a phase 2 trial. Currently, Empliciti is only approved for use in patients with relapsed/refractory myeloma. Dr. Saad Usmani from the Levine Cancer Institute investigated whether the combination of Revlimid-Velcade-dex (RVD) followed by RVD maintenance with or without Empliciti would benefit newly diagnosed patients with high-risk disease (ABSTRACT 8507). This is the first randomized study solely in high-risk myeloma patients. Patients considered high risk on this trial were defined as having one of the following:
- Gene-expression profiling high-risk
- Translocation of chromosomes 14 and 16
- Translocation of chromosomes 14 and 20
- Deletion of the short arm of chromosome 17
- Amplification of chromosome 1
- Primary plasma cell leukemia
- Elevated serum lactate dehydrogenase
Dr. Usmani reported no differences in survival or time to progression between the patients receiving RVD and RVD-Elo. Even though no differences were observed, the results serve as an important benchmark for future trials that focus on high-risk myeloma.
Another monoclonal antibody—Sarclisa (isatuximab), a CD38-targeted antibody—was used in combination in patients with high-risk disease. Sarclisa is only approved for use in patients with relapsed/refractory myeloma. Researchers in Germany evaluated Sarclisa combined with Kyprolis (carfilzomib)-Revlimid-dex (Isa-KRD) in 50 patients with newly diagnosed myeloma with high-risk disease (ABSTRACT 8508). High risk was defined as patients having International Staging System II or III disease and one of the following cytogenetic abnormalities:
- Deletion of the short arm of chromosome 17
- Translocation of chromosomes 4 and 14
- Translocation of chromosomes 14 and 16
- Amplification of chromosome 1
All patients responded to Isa-KRD treatment and 60% became MRD negative (those who were assessable). The most common side effect was low white blood cell and platelet counts. These are encouraging results so far as the clinical trial is ongoing and expecting to enroll at least 100 more high-risk patients.
Venclexta (venetoclax) Combinations For Patients With Chromosomal Translocation 11 and 14
The novel combinations to be discussed during this session include the drugs Venclexta (venetoclax) and XPOVIO. The first to be discussed was Venclexta —a bcl-2 inhibitor not approved for patients with myeloma—in a large, randomized phase 3 trial called BELLINI. This trial compared Velcade-dexamethasone with or without Venclexta in relapsed/refractory myeloma. The results were recently presented at last year’s International Myeloma Workshop meeting and updated results were presented here at ASCO by Dr. Shaji Kumar of the Mayo Clinic (ABSTRACT 8509). Results showed:
- In the total population of patients treated, the addition of Venclexta to Velcade-dex lengthens time to disease progression but at the risk of increased mortality compared to Velcade-dex alone
- Venclexta-Velcade-dex treatment benefited patients who have the chromosomal translocation 11 and 14 or who have high expression of the BCL2 gene in which the benefits of Venclexta outweighs the risks associated with its use
Another trial of Venclexta was presented—this time combined with Darzalex-dexamethasone with or without Velcade in relapsed/refractory patients (ABSTRACT 8511). The study, led by Dr. Jonathan Kaufman at Emory University, was conducted in two parts:
- Part 1 (24 patients): patients with t(11;14) were treated with Venclexta-Darzalex-dex
- Part 2 (24 patients): patients—irrespective of having t(11;14) were treated with Venclexta-Darzalex-Velcade-dex
Over 90% of patients responded to treatment in either of the two parts of the study. Most common side effects included fatigue, diarrhea, nausea, insomnia, upper respiratory tract infections, cough, and shortness of breath.
We are hopeful that Venclexta will be a valuable addition to the treatment options for patients who harbor t(11;14).
XPOVIO in Combination With Darzalex-Dexamethasone
XPOVIO treatment was the focus of another study at this year’s ASCO. XPOVIO combined with Darzalex-dexamethasone was evaluated in a phase 1/2 study in patients with relapsed/refractory myeloma who had received 3 or more prior lines of therapy (ABSTRACT 8510). Clinicians from Duke University treated 34 patients with XPOVIO-Darzalex-dex and showed:
- 73% of patients responded to treatment (all patients had not previously received Darzalex as a treatment)
- Common side effects included low white cell, red cell, and platelet counts, fatigue, and nausea
XPOVIO-Darzalex-dex therapy will continue to be investigated based on these results. The investigators of this study suggest that XPOVIO-Darzalex-dex is a novel combination that lacks a proteasome inhibitor (like Velcade) and an immunomodulatory drug (like Revlimid) and may serve as a backbone earlier in treatment.
Achieving a complete response (CR) to treatment does not eliminate all myeloma in the body. Some myeloma cells can remain in the body and this is called minimal residual disease (MRD), and it can cause a relapse. MRD measurement aims to detect any myeloma cells that remain in the body after a CR is achieved. Conventional blood and bone marrow tests are not sensitive enough to detect these remaining cells, but new MRD tests—such as next-generation sequencing—can detect at least 1 myeloma cell in a million healthy cells from a bone marrow sample. Studies have shown that patients who achieve MRD negativity live longer without disease progression than those who remain MRD positive. To get a visual perspective on what MRD is and what it means, please view our High-Impact Topic video listed.
MRD Assessment by Blood and Bone Marrow Samples
Three abstracts presented this year discussed new ways to detect MRD and the clinical implications of losing MRD negativity. In the first presentation, investigators from Spain investigated methods using blood samples in addition to existing tests using bone marrow samples to detect MRD in high-risk smoldering multiple myeloma (SMM) patients who were receiving treatment (that is, SMM patients at the highest risk of progression to active myeloma [existing guidelines do not recommend treatment for SMM patients]) (ABSTRACT 8512). The study revealed that MRD detection was more sensitive when using blood tests in addition to bone marrow tests. The importance of this finding is that perhaps, a more non-invasive testing (i.e., blood samples) can be conducted to detect MRD at earlier time points to then dictate the appropriate timing of a more invasive test using bone marrow samples.
Another study looked to compare assessment of MRD in the blood versus the bone marrow. Investigators at the University of Chicago paired blood and bone marrow samples from newly diagnosed myeloma patients who had received treatment with Kyprolis-Revlimid-dexamethasone followed by an ASCT (ABSTRACT 8513). MRD assessment by the blood test was similar (possibly better) in sensitivity to the bone marrow test. And the blood test showed to be a better predictor of time before tumor progression than the bone marrow test. Also, MRD positivity measured by the blood test predicted the conversion of MRD negativity to positivity by the bone marrow test. A larger, prospective trial comparing these testing modalities should be conducted to confirm these results.
Clinical Significance of Loss of MRD Negativity
The last presentation on MRD assessment focused on what the clinical impact would be for myeloma patients who convert from MRD negative to positive. Clinicians from the University of Arkansas for Medical Sciences identified and followed 606 patients who had achieved MRD negativity following treatment (ABSTRACT 8514). They observed the following:
- 60% of patients had sustained MRD negativity
- 40% of patients converted to MRD positive a median of 5.7 years from ASCT and 6.3 years from diagnosis
- The risk of clinical relapse was higher in patients who converted to MRD positive compared to those who remained negative
- Loss of MRD negativity preceded clinical relapse by a median of 1.1 years; and 27% of patients who lost MRD negativity did not relapse
- Those who converted to MRD positivity did not live as long without disease progression as those who remained MRD negative
- Patient survival was shorter if conversion occurred within 5 years of diagnosis versus more than 5 years after diagnosis; yet this impact on survival was absent if conversion occurred more than 5 years after diagnosis
These results are just the tip of the iceberg in terms of determining the true clinical implications of achieving and maintaining MRD negativity. We look forward to further investigations into this very important research as MRD negativity is used more and more as a clinical endpoint in clinical trials. The MMRF continues our efforts toward validating MRD as a clinical endpoint with the goal of incorporating the measurement of MRD into standard practice in the treatment of MM. A recap of last year’s Advances in MRD Testing in Myeloma Roundtable is here.
More than half of myeloma patients experience a decrease in their kidney (renal) function at some point in the course of the disease. The reason for this is that the accumulation of M protein and calcium (caused by bone destruction) in the blood can overwork the kidneys. The amount of urine produced may decrease, and the kidneys may fail to function normally. Abnormally functioning kidneys is referred to as renal insufficiency or renal impairment.
Typically, patients with renal insufficiency are excluded from clinical trials and therefore the effectiveness of existing treatment regimens is unknown in this group of patients. Luckily, three presentations focused on the use of different treatments in patients with renal insufficiency.
Therapies to be Used in Patients with Renal Insufficiency
The first presentation in this series analyzed the impact of using Revlimid-Velcade-dexamethasone on renal function in transplant-eligible and -ineligible, newly diagnosed patients with renal insufficiency contained within the Connect MM Registry (ABSTRACT 8518). Dr. Sikander Ailawadhi at the Mayo Clinic showed that patients with renal insufficiency who received Revlimid-Velcade-dex saw improvement in renal function within 3 months, regardless of their eligibility for transplant. This result is great news for patients as it provides evidence to support further study of this regimen in patients with moderate to severe renal insufficiency.
The next presentation studied the use of belantamab mafodotin (belamaf) in patients with relapsed/refractory myeloma and renal impairment. Investigators from the MD Anderson Cancer Center looked at the effect of single-agent belamaf from a subset of patients who had mild to moderate renal impairment in the DREAMM-2 study (ABSTRACT 8519). The results of the DREAMM-2 study in all patients was recently published. The results of this subset analysis showed:
- Response rates for patients with mild to moderate renal impairment were similar to those in the overall patient population
- Rates of low red blood cell and platelet counts and fever were more frequent in patients with renal impairment but rates of corneal disease and albumin in the urine were the same in those with and without renal impairment
- Renal function stayed the same or improved while on treatment
Overall, these results show that belamaf is safe and equally effective in patients with renal impairment.
Xgeva as an Alternative to Bisphosphonates in Patients With Renal Insufficiency
The final presentation focused on options for the management of skeletal complications in patients with renal insufficiency. Typically, bisphosphonates like Zometa (zoledronate) are used for this purpose but these drugs can actually cause renal impairment. The drug Xgeva (denosumab) is a monoclonal antibody that is equivalent in efficacy to Zometa as reported here and does not have the same renal toxicity. Dr. Elizabeth O’Donnell at Massachusetts General Hospital evaluated the use of denosumab in 20 newly diagnosed or relapsed/refractory myeloma patients with renal insufficiency (ABSTRACT 8520). The results showed:
- 39% of patients experienced low calcium levels
- Two patients developed osteonecrosis of the jaw
This trial is ongoing to continue monitoring Xgeva’s safety and efficacy regarding the prevention of skeletal-related events.
Saturday & Sunday Abstracts
We wrap up our coverage of the virtual ASCO meeting with two abstracts that were presented in real-time virtually over the weekend. One focused on a new bispecific antibody and the other covered an important head-to-head trial of key triplet regimens for newly diagnosed myeloma patients.
In the first presentation, Dr. Saad Usmani of the Levine Cancer Institute investigated the clinical efficacy of the bispecific called teclistamab in patients with relapsed/refractory myeloma. This antibody has the ability to bind to the B-cell maturation antigen (BCMA) found on myeloma cells and a cell surface protein found on T cells called CD3. You can learn more about bispecific antibodies here and you can also watch our High-Impact Topic video on immunotherapy listed here. Dr. Usmani and his colleagues treated 66 patients—most of whom were triple-class refractory (that is, most patients were refractory to the three main classes of myeloma drugs: proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies)—with teclistamab at different doses (ABSTRACT 100). The results showed:
- 67% of patients responded to treatment at the highest dose
- The most common side effects were cytokine release syndrome, low white blood cell and red blood cell counts
Clinical evaluation of teclistamab will continue and we will continue to update you on its progress.
The last presentation was part of the late-breaking abstract session—this session highlights practice-changing studies. Dr. Shaji Kumar of the Mayo Clinic shared the results of the head-to-head trial that compared the efficacy of Velcade-Revlimid-dexamethasone (VRD) and Kyprolis-Revlimid-dexamethasone (KRD) (ABSTRACT LBA3) in over 1,000 patients with standard/intermediate-risk newly diagnosed myeloma who deferred an immediate autologous stem cell transplant. What is important about this study is (1) it directly compares 2 triplet regimens, and (2) it compares 2 different proteasome inhibitors (Velcade and Kyprolis). The main findings of this study included:
- KRD did not prolong time to disease progression compared to VRD
- No difference in overall survival between both treatment groups
- KRD was associated with a higher rate of cardio-pulmonary side effects and VRD was associated with a higher rate of peripheral neuropathy
Dr. Kumar and the study investigators concluded that VRD should continue being the standard of care as initial therapy for patients. In a follow-up discussion of the results presented by Dr. Jesus Berdeja of the Sarah Cannon Cancer Center, he noted the practice implications are that patient comorbidities and the side effect profile of each triplet should guide the choice between these therapies and that ultimately, VRD is less costly than KRD. VRD remains a key backbone therapy onto which to add additional agents like monoclonal antibodies.