Ixazomib, thalidomide, and dexamethasone for relapsed/refractory multiple myeloma

Ixazomib is a novel, oral proteasome inhibitor (PI) which has a favorable toxicity profile with a fixed dose administration. Based on this, the use of ixazomib over other PIs, such as carfilzomib and bortezomib, may increase patient quality of life (QoL). The combination of ixazomib, lenalidomide, and dexamethasone (IRd) has shown promising efficacy as an induction therapy for patients with relapsed/refractory (R/R) multiple myeloma (MM, RRMM) when compared to lenalidomide and dexamethasone (Rd) alone in the TOURMALINE-MM1 trial.¹ Additionally, the TOURMALINE-MM4 study, comparing ixazomib maintenance to placebo in patients with transplant-ineligible, newly-diagnosed multiple myeloma, recently met its primary endpoint of prolonging progression-free survival (PFS).² These results indicate ixazomib may be efficacious in MM and fit into the treatment pathway in both the frontline and R/R setting.  

Based on the promising results above, the all-oral combination of ixazomib, thalidomide, and dexamethasone (ITd), followed by maintenance with ixazomib, was evaluated in patients with RRMM (NCT02410694).³ The results of this study were recently published in the British Journal of Cancer⁴, with a subgroup analysis of patient QoL published in Leukemia and Lymphoma.⁵

Study design and patient characteristics⁴

The study recruited 90 patients with RRMM who had received one or more prior lines of therapy, with 73.3% having received 1–2 prior lines. The median patient age was 67.3 years (range: 44–84) and there was a relatively equal distribution of international staging system (ISS) stage disease (I vs II vs III: 37 vs 30 vs 23). 94.4% of patients had previously been exposed to a PI, with 15.6% being refractory to lenalidomide.⁴

Cytogenetic analysis was conducted, with high-risk defined as the presence of one or more of the following: t(4;14), t(14;16), and/or del(17p). Gain 1q21 was analyzed as an additional prognostic factor. Of the 61 evaluable patients, 29.5% (18/61) had high-risk cytogenetics, with 52.5% (32/61) having gain 1q21.⁴

The primary endpoint of the study was PFS, with secondary objectives including overall response rate (ORR), overall survival (OS), impact of cytogenetic risk, effect of renal impairment on efficacy, safety, myeloma frailty status, and QoL.⁴

Dosing schedule⁴:

Eight 28-day cycles followed by ixazomib maintenance for one year.

• Induction therapy:
  • Ixazomib: 4mg on Days 1, 8, and 15
  • Thalidomide: 100mg daily
    • Dose adjustment (patients ≥75 years old): 50mg daily
  • Dexamethasone: 40mg weekly
    • Dose adjustment (patients ≥75 years old): 20mg weekly
• Maintenance therapy:
  • Ixazomib: 4mg on Days 1, 8, and 15 of a 28-day cycle for one year
    • Dose adjustment (patients ≥75 years old): 3mg

Efficacy⁴

Efficacy results are shown in Table 1 at a median follow-up of 19.1 months.

Table 1. Efficacy results of ITd in the total cohort, and per protocol population*

Of the 43 patients who enrolled in the maintenance phase, five achieved a higher response category within 1–9 months after initiation of maintenance.

Subgroup analysis⁴

Response rates

• Cytogenetics: no difference in responses between standard- and high-risk patients, between patients with or without gain 1q21, or between patients with high-risk cytogenetics and gain 1q21 or no gain 1q21

 PFS

• PFS was similar within the following subgroups: ISS stage disease, prior lines of treatment, patient age, frailty status, glomerular filtration rate (GFR), cytogenetic risk, prior IMiD exposure, and presence of gain 1q21
• However, PFS was significantly different (p= 0.044) when patients with gain 1q21 (PFS: 6.2 months), were compared to patients with:
  • High-risk cytogenetics: 10.3 months
  • None of these features: 10.8 months

 OS

• The following factors were significantly associated with OS (p values <0.2):
  • Longer OS with ISS stage I and II disease: p< 0.0001
  • Longer OS with only one prior therapy: HR= 0.39 (95% CI, 0.14–1.07), p= 0.064
  • Shorter OS with GFR <60ml/min: HR= 2.09 (95% CI, 0.81–5.43), p= 0.0409,
  • Shorter OS with gain 1q21: HR= 0.07 (95% CI, 0.01–0.55), p= 0.0009
• Similar to PFS, a significant difference was noted (p= 0.001) when comparing OS for patients with gain 1q21 alone (15.6 months), high-risk cytogenetics, or none of these features (both NR)

Multivariate regression analysis⁴

• The above factors associated with OS were tested in Cox multivariate regression analysis
• Most significant factors associated with shortened OS:
  • Gain 1q21: HR= 14.29 (95% CI, 1.69–100), p= 0.014
  • Low hemoglobin (<100g/l): HR= 5 (95% CI, 1.11–25), p= 0.034

Safety⁴

• Most common Grade III/IV adverse events (AEs) were hematological
  • Anemia: 17.8%
  • Leukopenia: 5.6%
  • Neutropenia: 2.2%
  • Thrombocytopenia: 7.8%
• Most frequent non-hematological AEs were infections:
  • Grade I/II infection: 61.1%
  • Grade III/IV infection: 18.9%
• During maintenance, most AEs were Grade I or II and were rare

QoL analysis⁵

Analysis design

• QoL was evaluated using the European Organization of Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire and the myeloma QLQ-MY20 module
  • Comorbidity was assessed using activities of daily living (ADL), the instrumental ADL scale, and the Charlson comorbidity index
• Patients completed questionnaires at baseline, on Day 1 of each cycle, at the end of induction, at the start of maintenance, and monthly during maintenance
  • This continued until the end of Month 12 or treatment discontinuation/progression
• The nine pre-selected QoL domains for evaluation were:
  • Functional: health-related QoL (HRQoL), physical, cognitive, and social functioning
  • Symptom: fatigue, pain, neuropathy, disease symptoms, and side effects of treatment
  • Results were standardized to a 0–100 final scale score
    • Higher functional scores indicate better QoL
    • Lower symptom scores indicate a better QoL
    • A difference of ten or more points was considered the minimal important difference and suggested the results were clinically relevant
• This was an exploratory analysis as a secondary objective of the study
• Data cutoff: 31^st March 2019
• Compliance was consistently >95% of patients still on therapy at the various timepoints

QoL results

Table 2 shows QoL domains that were significantly different between patients and the general population. There were no significant differences in relation to nausea/vomiting, insomnia, and financial burden. Differences were noted in other factors but did not reach the threshold for clinical relevance. These included global health status, emotional, cognitive function, dyspnea, appetite loss, constipation, and diarrhea.

Table 2. QoL domains with significant differences between patients and the general population

QoL during induction therapy

• Of the 47 patients who discontinued induction treatment, 33 discontinued due to PD, five due to investigator decision, three had unacceptable AEs, and six stopped due to death, patient decision, or insufficient response
• The most relevant dimensions in QoL remained stable (such as global health-status, physical, cognitive, and social function, and fatigue)
• There was a clinically relevant reduction in pain in Cycles 5–8 and at the end of induction
• However, polyneuropathy (PNP) worsened to a clinically significant level in Cycles 4, 5, 7, 8, and the end of induction

QoL during the maintenance phase

• Of the 76 eligible patients, 43 started maintenance with 13 completing all 12 cycles
• Discontinuations during the maintenance stage were due to PD in 26, PNP in one, and patient decision in three
• Patients who discontinued induction therapy early typically had lower QoL scores when last assessed compared to patients who started maintenance
• Clinically relevant differences were observed with patients on maintenance reporting less fatigue (p= 0.021) but more neuropathy (p= 0.19)
• Predominantly, scores improved for most QoL dimensions during maintenance
• On the symptom scale, most remained stable aside from fatigue, which improved

QoL associations with PFS and OS

• HRQoL score: PFS and OS were significantly longer in patients with a HRQoL score of ≥66.7 (the median value at baseline):
• PFS (HRQoL ≥66.7 vs <66.7): 10.2 vs 6.6 months, p= 0.019
• OS (HRQoL ≥66.7 vs <66.7): NR vs 22.9 months, p= 0.005
• Physical functioning: using a median cut-off of 77.3:
• OS was longer in patients with higher scores (≥77.3 vs <77.3): NR vs 22.9 months, p= 0.005
• No difference in PFS was observed by physical functioning score

Limitations

This trial had a short screening period of seven days, meaning patient selection may have been less stringent than in other clinical trials. However, this also may indicate a patient population more relatable to the real-world experience. Other limitations of the study include the lack of a randomized control arm and a lack of cytogenetic data in 32% of patients.⁴ For the QoL analysis, the limitations include the fact patients could not complete assessments following discontinuation, the open-label design of the trial, and the small number of patients available for analysis following maintenance therapy.⁵

Conclusion

The authors concluded that ITd was active in patients with RRMM and well-tolerated, irrespective of cytogenetic risk. They also noted that gain 1q21, with or without other high-risk features, led to a shorter OS with the ITd regimen. This is inline with the TOURMALINE-MM1 results of IRd in RRMM, where gain 1q21 also led to a shorter median PFS.⁶ In this analysis, gain 1q21 was the most significant prognostic parameter for OS. The authors recommend gain 1q21 be considered as part of the high-risk definition in future.⁴

In this study, clinically relevant differences were observed when comparing patient QoL to the general population and it was noted that physicians should not underestimate the severity of symptom burden in myeloma treatment. The authors agreed that patient reported outcomes and QoL data should be utilized by regulatory authorities to effectively guide clinical practice when combined with clinical observations.⁵

The authors added that since access to lenalidomide is limited in many parts of the world, the ability to use thalidomide in combination with ixazomib and dexamethasone likely represents a valuable option for treating patients with RRMM.⁴