Managing relapsed and refractory multiple myeloma in heavily pretreated patients: does less sometimes equal more?

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Today we have more treatment options for multiple myeloma (MM) than ever before and patients can now survive for over a decade, where historically, the expected survival was only ~3 years from diagnosis.1 However, for most patients, a relapse is still inevitable.2 Three-drug (triplet) regimens are the current standard-of-care for patients with MM, and as multiple lines of therapy are often required throughout the course of treatment, the disease can become refractory to more than one drug. Patients who have received a wide range of drug combinations in multiple lines of therapy are more likely to have poorer responses than patients who are just beginning their course of treatment.3 Treating relapsed and refractory MM (RRMM) while maintaining a focus on patients’ quality of life is a key challenge for clinicians today.

 RRMM is heterogeneous and no single treatment is effective for all patients, but a regimen containing lenalidomide is a common choice for first line of therapy.2 Subsequently at later lines of treatment, lenalidomide-free options are required as the disease becomes refractory to this drug.4 Proteasome inhibitors (PIs) such as bortezomib and carfilzomib in lenalidomide-free regimens have demonstrated efficacy benefits in RRMM patients,4 but these drugs are administered parenterally in the hospital or clinic, which increases the treatment burden for an already heavily pretreated patient. These patients usually have residual comorbidities or impairments from previous myeloma treatment and, as they have aged since treatment onset, are likely to be frailer and less tolerant to the toxicity that standard triplet regimens bring.3 Therefore, there is a need for more convenient regimens, such as all-oral, two-drug regimens (doublets), that are active, have manageable toxicity, and do not adversely impact patients’ quality of life.

 Pomalidomide-dexamethasone is one such oral doublet approved for use in these patients, but it is associated with hematological toxicities and infections.5 Additionally, patients may have been previously exposed and/or become refractory to pomalidomide in a triplet regimen, so alternative options are required. Ixazomib, the first oral PI, is approved in the United States and European Union in combination with lenalidomide-dexamethasone for patients with MM who have received at least one prior line of therapy,6,7 and is a well-tolerated long-term therapy, with predictable and manageable toxicities.8 We tested it in a phase 2 trial in combination with dexamethasone, versus pomalidomide-dexamethasone, among adult patients who had previously received treatment with a PI, and whose disease was refractory to lenalidomide.

 We found that progression-free survival (PFS) was comparable with ixazomib-dexamethasone and pomalidomide-dexamethasone with medians of 7.1 and 4.8 months, respectively, with no statistically significant difference between arms. However, when conducting a subgroup analysis, we found that PFS outcomes appeared better in patients with at least three prior lines of therapy and in patients with renal impairment (creatinine clearance of <60 mL/min) compared to the total patient population.

 After a median follow-up of 15.3 and 17.3 months, median overall survival (OS) was 18.8 months with the ixazomib doublet and was not reached in the pomalidomide doublet. OS data were not mature at data cutoff, with only 36% of patients having died, and the study was not powered for OS comparisons. Nevertheless, preliminary outcomes exceeded expectations for this patient population in both arms, as previous studies in heavily pretreated RRMM patients report medians of 4–5 months and ~12–15 months for PFS and OS, respectively.9-11

 We found ixazomib-dexamethasone and pomalidomide-dexamethasone to be similarly tolerable for patients. Notably, ixazomib was sufficiently well tolerated at a starting dose of 4 mg, which enabled 64% of patients to escalate to a 5.5 mg dose. This dose escalation of ixazomib was based on a previous phase 2 study where greater efficacy was seen with an ixazomib dose of 5.5 mg versus the standard 4 mg.12 However, we found that the median duration of treatment with ixazomib 5.5 mg was approximately 2 cycles, suggesting a challenging dose for patients. Subsequent dose reductions were required for patients to continue ixazomib treatment. Nonetheless, the rate of patients who discontinued the study due to adverse events was similar to that of patients receiving pomalidomide-dexamethasone. Thus, ixazomib-dexamethasone appears tolerable in this treatment setting.

 There were no consistent differences between the two regimens in terms of their overall safety profiles. We did see differential rates of specific adverse events that are more commonly associated with ixazomib or pomalidomide, such as diarrhea and thrombocytopenia with ixazomib, and anemia and pneumonia with pomalidomide.9,10,13 Of note, the overall rate of peripheral neuropathy, which is an adverse event of clinical importance with bortezomib-based treatment,14 was 29% with the ixazomib doublet and only 6% with the pomalidomide doublet. However, this rate for ixazomib is consistent with that reported for ixazomib 4 mg in combination with lenalidomide-dexamethasone in the phase 3 TOURMALINE-MM1 trial (27%),8 despite the higher ixazomib dose of 5.5 mg that some patients received in our study. Rates of cardiovascular and renal toxicities, which can be associated with carfilzomib-based treatment,15 were notably low with ixazomib-dexamethasone, suggesting that this PI-based doublet regimen may be preferred for patients at risk of those toxicities.

 The tolerable safety profiles of ixazomib-dexamethasone and pomalidomide-dexamethasone were reflected in the quality of life and healthcare resource utilization data collected from patients receiving each doublet. The data were generally similar throughout the trial, indicating that there was no relative adverse impact on patient quality of life with one regimen versus the other.

 Our results suggest that ixazomib in combination with dexamethasone can be effective in heavily pretreated, lenalidomide-refractory, PI-exposed RRMM patients, which is a population with considerable unmet medical needs. The doublet was tolerable, with patients reporting a comparable quality of life to those receiving pomalidomide-dexamethasone. As mentioned, RRMM is a heterogeneous disease, and no single treatment benefits all patients; however, ixazomib-dexamethasone is an appropriate option for patients who cannot tolerate triplet combinations, patients who would prefer to receive oral versus parenteral treatment administration, or patients who require a non-immunomodulatory drug-based treatment approach, such as those with lenalidomide-refractory disease.

 References

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MELETIOS DIMOPOULOS

PROFESSOR, NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS