Every other year, renowned myeloma specialists from all over the world gather at the International Myeloma Workshop (IMW) to present and discuss the latest advances in multiple myeloma clinical research. This year in Vienna, Austria attendees met in-person and, as usual, the MMRF was there to share key information with patients and caregivers. Today, we learned a lot about the treatment path for newly diagnosed patients: various induction regimens for those who are not autologous stem cell transplant (ASCT) candidates, maintenance therapy, and strategies for patients with high-risk disease. And for patients who have relapsed from or who have become refractory to their latest treatment, we learned more about a new agent on the horizon: iberdomide.
Treatment for Newly Diagnosed Multiple Myeloma
An ASCT remains the standard of care for newly diagnosed, eligible patients. ASCT—for those who are eligible—offers myeloma patients their best chance at a deep, long-lasting response (periods in which there are no symptoms of myeloma or detectable abnormal plasma cells). However, a variety of factors such as fitness and frailty influence a patient’s eligibility for ASCT. Fortunately, many of the same options used in patients who are eligible for ASCT are used for patients who are ineligible due to their fitness or frailty.
Induction Therapy for Transplant-Ineligible Patients
Darzalex Darzalex is a monoclonal antibody that targets the protein CD38 on myeloma cells. Darzalex is approved for use in newly diagnosed myeloma patients as induction therapy in both transplant-eligible and ineligible patients. Data from two phase 3 trials of patients who are ineligible for ASCT (the MAIA and ALCYONE trials), led to the approval of Darzalex as induction either in combination with Revlimid and dexamethasone (DRd) or with Velcade, melphalan, and dexamethasone (D-VMP). During IMW, data from both trials were reviewed.
In the first presentation, the MAIA trial investigators provided a 5-year update of patients treated on the trial. The results showed:
- Responses to DRd deepened over time with more patients achieving a complete response or better compared with treatment with RD (51% vs 30%)
- Patients receiving DRd experienced a significantly longer time before disease progression (progression-free survival, PFS) compared to Rd (not yet reached vs. 34.4 months)
- Patients in the DRd group had a 32% reduction in the risk of death compared to the Rd group
- No new safety concerns were observed and the most common serious side effect was low neutrophil counts for patients treated with DRd (54.1%) than Rd (37%)
These results show an impressive survival benefit to patients receiving the triplet regimen DRd and the investigators suggest that this regimen is the new standard of care for newly diagnosed patients ineligible for ASCT.
In another presentation, data from a sub-group of patients treated on the MAIA and ALCYONE trials were analyzed. In this analysis, investigators—led by Dr. Andrzej Jakubowiak at the University of Chicago—evaluated the impact of Darzalex-based induction regimens for transplant-ineligible patients with high-risk disease. For more information about high-risk disease, please see the next section. In this analysis, high-risk status was based on cytogenetics such as the presence of deletion of chromosome 17p (del[17p]), translocation of chromosomes 4 and 14 (t[4;14]) or translocation of chromosomes 14 and 16 (t[14;16]). There were 101 high-risk patients who received an induction regimen that included Darzalex and 89 high-risk patients who received a regimen without Darzalex. The results showed:
- Patients receiving a Darzalex regimen had a 41% reduction in the risk of disease progression or death compared to patients who did not receive Darzalex
- More patients receiving a Darzalex regimen did not progress and were alive than patients who did not receive Darzalex (41.3% vs. 19.9%)
- Higher response rates and deeper responses (that is, achieving minimal residual disease [MRD] negativity) occurred in the patients receiving a Darzalex regimen than in patients who did not receive Darzalex
Both of these studies show the value of Darzalex-based regimens as induction treatment for patients are ineligible to receive an ASCT—even in patients with high-risk disease. To learn more about Darzalex, click here.
Sarclisa Sarclisa is another anti-CD38 monoclonal antibody approved for use in combination with Pomalyst-dex or Kyprolis-dex for patients with relapsed or refractory myeloma. International investigators studied the use of Sarclisa in 46 newly diagnosed patients as part of a four-drug induction regimen in combination with Velcade, Revlimid, and dexamethasone (Isa-VRd). In this trial, Sarclisa was administered in a way to reduce the infusion time during treatment cycles. Over half of patients achieved a complete response or a stringent complete response and over half of patients in whom MRD could be measured achieved MRD negativity. The most common side effects experienced by patients were constipation, diarrhea, weakness, peripheral neuropathy, and low white blood cell counts. The Isa-VRd regimen is continuing to be investigated in newly diagnosed patients in phase 3 trials. You can learn more about Sarclisa here.
For a quick video that visually explains all about ASCT and eligibility, please check out our High Impact Topic video here. Also, please be sure to register for our next webinar on ASCT here.
Maintenance Therapy
There is increasing evidence supporting the role of maintenance therapy (that is, to maintain a response to treatment for as long as possible) after the completion of induction therapy or after ASCT. Many trials are investigating the benefit of ASCT as part of initial treatment (early) compared to ASCT following relapse (late) and most patients on these trials also received maintenance therapy with Revlimid. Revlimid is the only drug approved for use as maintenance therapy following ASCT. Additional agents are being investigated for use as maintenance therapy.
Kyprolis In the CARDAMON trial, investigators from the United Kingdom examined the use of Kyprolis as induction, consolidation, and maintenance in newly diagnosed patients. In this trial 218 patients received induction therapy with Kyprolis-Cytoxan-dex and then they were divided into two groups that received either (1) an ASCT followed by Kyprolis maintenance, or (2) Kyprolis-Cytoxan-dex followed by Kyprolis maintenance. The results showed:
- 6-months following maintenance therapy, patients who were MRD negative lived longer without disease progression than patients who were MRD positive
- More patients converted to MRD negativity following ASCT (Group 1) than following Kyprolis-Cytoxan-dex consolidation therapy (Group 2) (39.1% vs 16.1%)
- 23.5% of MRD positive patients converted to MRD negative during maintenance therapy
- More patients withdrew from maintenance therapy who had previously received an ASCT than consolidation with Kyprolis-Cytoxan-dex (9.1% vs 1%)
- There was no evidence that the timing of achievement of MRD negativity impacted progression-free survival
Ultimately, this study showed that Kyprolis maintenance therapy improves MRD negativity rates especially following an ASCT; however, previous ASCT may increase the risk of side effects.
Revlimid In the Myeloma XI trial, investigators from the United Kingdom assessed MRD status at two different time points: prior to and 6 months after maintenance therapy with or without Revlimid. In this study, patients received induction therapy followed by ASCT and then they were split between receiving maintenance therapy with Revlimid or no maintenance therapy. The results showed:
- Over 60% of patients achieved MRD negativity before and after maintenance therapy (with or without Revlimid)
- More patients who were MRD positive after ASCT converted to MRD negative following 6 months of maintenance with Revlimid than patients who did not receive maintenance (30% vs 17%)
- Regardless of MRD status, patients who received Revlimid as maintenance experienced longer time before disease progression and survival compared with patients who did not receive maintenance
In this trial, Revlimid maintenance benefited patients with longer time to disease progression and survival even without achieving MRD negativity. However, patients with high-risk cytogenetics did not reap the same benefits.
Induction and Maintenance Therapy for Transplant-Eligible Patients With High-Risk Disease
Myeloma patients who do not enjoy long-term clinical remission are considered to have high-risk disease. To be high risk means that patients have genetic or clinical features that make their myeloma more aggressive meaning they may relapse quickly after treatment or a shorter time in remission than patients who do not have those genetic or clinical features. Today, a couple of studies evaluated different treatment approaches for patients with high-risk disease.
Investigators from the United Kingdom examined the use of a 5-drug regimen of Darzalex-Cytoxan-Velcade-Revlimid-dex to treat myeloma patients considered to have ultra high-risk disease. Patients considered ultra high risk on this trial, called the OPTIMUM trial, were defined as having one of the following:
- Two or more cytogenetic abnormalities such as
- Translocation of chromosomes 4 and 14
- Translocation of chromosomes 14 and 16
- Translocation of chromosomes 14 and 20
- Gain of the long arm of chromosome 1
- Deletion of the short arm of chromosome 1
- Deletion of the short arm of chromosome 17
- High risk gene expression profiling
- Plasma cell leukemia
107 patients were treated with Darzalex-Cytoxan-Velcade-Revlimid-dex followed by an ASCT, followed by consolidation with Darzalex-Velcade-Revlimid-dex and maintenance therapy with Darzalex-Revlimid. Results showed:
- 94% of patients responded (with 41% achieving MRD negativity) following induction therapy
- 83% of patients responded (with 64% achieving MRD negativity) following ASCT; response rate was lower for patients with plasma cell leukemia
- Common side effects were low white blood cell counts and infection
Another study, called the FORTE trial, was presented by investigators from Italy who studied the use of Kyprolis as a part of an induction and consolidation regimen (following ASCT) and maintenance (combined with Revlimid) for newly diagnosed myeloma patients. They evaluated treatment on its ability to lengthen time until disease progression and 1-year sustained MRD negativity according to patient risk. In this trial, 396 patients were divided into 3 groups and each given a Kyprolis-based regimen as both induction and consolidation:
- Group 1: Kyprolis-Revlimid-dexamethasone (KRd) followed by ASCT and consolidation with KRd
- Group 2: KRd only (that is, no ASCT or consolidation treatment)
- Group 3: Kyprolis-Cytoxan-dexamethasone (KCd) followed by ASCT and consolidation with KCd
Following treatment in each group, patients were then randomized to receive maintenance therapy with either Kyprolis-Revlimid or Revlimid. The results were presented based on whether patients had high-risk cytogenetics (one or more chromosomal abnormalities), double-hit cytogenetics (two or more chromosomal abnormalities), or standard risk cytogenetics (absence of any chromosomal abnormalities) and they showed that:
- All risk subgroups benefited with respect to longer time until disease progression from:
- Treatment with KRd followed by ASCT (Group 1)
- Maintenance therapy with the Kyprolis-Revlimid combination
The results from this study suggest that KRd followed by ASCT and Kyprolis-Revlimid maintenance is effective in most high-risk subgroups (that is, patients with deletion of the short arm of chromosome 17; deletion of the short arm of chromosome 1; translocation of chromosomes 4 and 14; gain of the long arm of chromosome 1)—except for patients with amplification of the long arm of chromosome 1
Treatment for Relapsed/Refractory Multiple Myeloma
Iberdomide
A new class of drugs called CELMoDs (cereblon E3 ligase modulators) includes agents such as iberdomide and CC-9480. Drugs in this class are related to the immunomodulatory drugs (IMiDs) Revlimid (lenalidomide) and Pomalyst (pomalidomide), but they are more potent.
Dr. Sagar Lonial from the Winship Cancer Institute at Emory University presented the results of a phase 1/2 study evaluating the maximum tolerated dose, safety, and efficacy of iberdomide in different treatment combinations. Seventy-seven patients who had previously received one or more regimens that contained Revlimid or Pomalyst and a proteasome inhibitor (such as Velcade, Kyprolis, or Ninlaro) were treated with one of the following combinations:
- Iberdomide-Darzalex-dex (IberDd)
- Iberdomide-Velcade-dex (IberVd)
- Iberdomide-Kyprolis-dex (IberKd)
Most patients responded to each combination with 46% responding to IberDd, 56% to IberVD, and 50% to IberKd. Common side effects included low white blood cell counts and low platelet counts. We look forward to the further clinical development of iberdomide and other CELMoDs!
Be sure to hear what myeloma experts Dr. Melissa Alsina and Dr. Shaji Kumar have to say about the day’s presentations here.
Stay tuned for more updates from IMW 2021!…
