CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Nurses: 1.00 Nursing contact hour
Released: April 26, 2023
Expiration: April 25, 2024
Disease and Patient Factors Influence Treatment Choices in Relapsed/Refractory Myeloma
Unfortunately, despite these advances in therapy, patients do continue to relapse. An increasing portfolio of drugs is becoming available for patients with relapsed disease.
With the number of treatment options that have become available for management of relapsed disease, multiple variables need to be considered when selecting a regimen. The presence of randomized phase III trials showing benefit is important. In addition, we need to consider patient characteristics such as age, performance status, comorbidities, and disease-related status. We also have to consider what drugs they have previously received and whether the patient is refractory to drugs in the same class. The risk assessment is important to consider as well, particularly the characterization of patients who have functionally high-risk disease. Of course, patient preference is equally important.
Randomized Studies in R/R Myeloma With Lenalidomide/Dexamethasone Control Arms
With the increasing use of lenalidomide-based maintenance therapy, many patients tend to be refractory to lenalidomide at the time of first relapse. When patients who are not refractory to lenalidomide experience disease progression, we can take data from several phase III trials that used Rd as a backbone and added either ixazomib, elotuzumab, carfilzomib, or daratumumab. All these trials have shown improved PFS as well as a trend towards improved OS. Both carfilzomib and daratumumab in combination with Rd appear to be very effective regimens in this relapsed patient population.68-71
Randomized Studies in R/R Myeloma With Bortezomib/Dex Control Arms (Including Lenalidomide Refractory)
There are several options available for patients who are refractory to lenalidomide and for whom a regimen without it would be preferred. We can use a PI backbone, such as Kd, and add a second generation IMiD like pomalidomide, an anti-CD38 mAb like daratumumab, or combine newer therapies like venetoclax or selinexor.
Addition or either venetoclax or selinexor to the bortezomib/dexamethasone backbone have been shown to provide deep responses in patients with relapsed MM.72-77
Pomalidomide-Based Salvage Therapy for R/R Myeloma
Particularly relevant in the context of patients who prefer oral therapy, there are several pomalidomide-based regimens that have been explored and include other oral agents like ixazomib or cyclophosphamide. In addition, anti-CD38 mAbs, including isatuximab and daratumumab; PIs, like carfilzomib; and other mAbs, like elotuzumab have been explored in combination with pomalidomide. These triplet regimens have been highly effective in controlling disease, particularly in earlier lines of therapy when patients are going through their first to third relapse.72,78-83
Phase III APOLLO: Responses and PFS With SC Daratumumab + Pd vs Pd in R/R Myeloma
It is important to highlight a few regimens that are more commonly used. One is the combination of daratumumab with pomalidomide/dexamethasone (dara-Pd). This was studied in the APOLLO trial, which showed that dara-Pd is associated with improved PFS and also, a trend towards improved OS.84,85
Phase III CANDOR: Responses and PFS With Dara-Kd vs Kd in R/R MM
Similarly, daratumumab has been combined with carfilzomib/dexamethasone (dara-Kd) in the CANDOR trial, which showed a significantly improved PFS over 2 years (28.6 months) with dara-Kd, almost double the PFS with Kd alone (15.2 months).86,87
Phase III ICARIA-MM: Responses and OS With Isa-Pd vs Pd in R/R MM
The phase III ICARIA-MM trial evaluated the addition of isatuximab to Pd and showed similar benefit to what was seen with the combination of dara-Pd in the APOLLO trial. In the ICARIA-MM trial, there was a significant improvement in OS with dara-Pd (24.57 months) compared with Kd alone (17.71 months; HR: 0.776; P = .0319).42,88
Phase III IKEMA: Responses and PFS With Isa-Kd vs Kd in R/R MM
Finally, the IKEMA trial compared isatuximab plus Kd vd Kd alone and showed almost a 3 year PFS with the addition of isatuximab to Kd (35.7 months vs 19.2 months with Kd alone).89,90
IKEMA: Toxicity Profile of Isatuximab, Carfilzomib, and Dexamethasone vs Kd in R/R Myeloma
These regimens play an important role in the management of patients with early relapses, particularly during the first 3 relapses or the second to fourth line of therapy. These regimens are reasonably well tolerated as well.49
Phase II ELOQUENT-3: Elotuzumab + Pd vs Pd in R/R MM
In addition, data from the ELOQUENT 3, which evaluated the benefit of adding elotuzumab to Pd, demonstrated a significant improvement in PFS and OS. So, this remains yet another triplet combination of choice.69,91
Anti-CD38 Antibody Toxicity Considerations
When we use an anti CD38 mAb, there are certain toxicities that need to be considered. The use of an anti CD38 mAb has been associated with an increased risk of infection.92,93 This risk may be partially related to hypogammaglobulinemia, so, patients with profound hypogammaglobulinemia should be considered for IVIG replacement.94 These antibodies can be associated with infusion related reactions and this needs to be considered as well.95 Clearly, daratumumab has the advantage that it can be administered subcutaneously, which makes it easier for patients.92 Ongoing clinical trials are examining subcutaneous forms of isatuximab as well (NCT05704049, NCT05405166).
STORM: Phase II Trial of Selinexor and Dexamethasone in Triple-Class Refractory Myeloma
It becomes challenging to manage relapsed MM once patients become triple-class refractory: refractory to the IMiDs, PIs, and anti CD38 mAbs. In that context, several drugs have been explored.
Selinexor is a nuclear transport protein inhibitor that has been evaluated in the phase II STORM trial in combination with dexamethasone. The primary endpoint was ORR, which was 26.2% with selinexor + dexamethasone.96,97
Phase III BOSTON: Selinexor + VD in R/R MM
The phase III BOSTON trial evaluated the combination of selinexor and Vd. The results showed an improved PFS compared to Vd, making this combination another therapy option. There are also phase II data evaluating the combination of selinexor with an anti CD38 mAb or carfilzomib,98,99 creating additional options for the triple-class refractory patient population.76,100
Selinexor: Toxicity Considerations
Unique toxicities are associated with selinexor, particularly significant hematological toxicity and nausea and gastrointestinal issues. Patients should be on prophylactic therapy for nausea and very carefully managed in terms of both the dose of selinexor and supportive care management.101,102
Targeting BCL2 With Venetoclax in Myeloma: Responses in Patients With t(11;14)
Venetoclax is a BCL2 inhibitor that has been shown to have significant activity in patients with t(11;14). This occurs in about 15% to 20% of patients. In the relapsed setting, venetoclax in combination with dexamethasone,103,104 Vd,105 Kd,106 or daratumumab107 has been associated with significant efficacy.
BELLINI: Venetoclax, Bortezomib, and Dexamethasone vs Vd in R/R Myeloma
The phase III BELLINI trial evaluated the addition of venetoclax to bortezomib and dexamethasone (Vd) in patients with R/R myeloma after 1-3 prior lines of therapy and who were not refractory to PI therapy. The primary endpoint was PFS and key secondary endpoints were ORR, VGPR or better, OS, and QoL/patient reported outcomes (PRO) parameters.77,105
BELLINI Final Survival Analysis: PFS and OS in Key Patient Subgroups
The BELLINI trial demonstrated that the benefit of adding venetoclax to bortezomib/dexamethasone was isolated to patients with high BCL2 expression or t(11;14). The remaining patients showed no benefit, and in fact, this combination may be detrimental to their outcomes.108
Management Considerations With Venetoclax
When using venetoclax off label, these findings need to be considered. Infection prophylaxis is important. Tumor lysis is extremely uncommon but should be considered as well. Infections, blood counts, tumor lysis syndrome, and toxicities should be monitored.105,109
Venetoclax/Dara/Dex vs Bortezomib/Dara/Dex in t(11;14) R/R MM: Part 3 Study Design
Clinical trials are currently ongoing to investigate the combination of venetoclax with other drugs, such as daratumumab.107
Key Points for Clinical Practice: Treatment of R/R MM
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