The safety and efficacy of a reduced toxicity regimen in frail patients with NDMM

Frail patients diagnosed with multiple myeloma (MM) are not transplant eligible; thus, the recommended frontline treatment consists of a combination of the anti-CD38 antibody, daratumumab, with either lenalidomide and low-dose dexamethasone, or low-dose bortezomib-based combinations. Such regimens appear to be safe and effective for newly diagnosed MM, however, clinical trials have historically included patients of various baseline performance statuses. Therefore, it has been difficult to gauge the precise safety and tolerability in the frail population, which has been reported to achieve shorter survival and higher discontinuation rates.¹

Stege et al. recently performed a prospective study; HOVON-143, which explored the efficacy and safety data on a reduced toxicity regimen; ixazomib-daratumumab-low-dose-dexamethasone (Ixa-Dara-dex). This study has been long awaited for being the first to include only frail patients characterized by age or comorbidities. Find below further details on the recently published analysis in the Journal of Clinical Oncology.¹ We have previously provided a summary of this and other studies with similar approaches in elderly patients.

Study design

This was a prospective, multicenter phase II trial conducted at 39 hospitals throughout the Netherlands and Belgium. The study design is summarized in Figure 1.

IV, intravenous.
*Adapted from Stege et al.^1
ⴕ Each induction cycle (Cycles 1–9) lasted 28 days.
^‡Maintenance was performed until progression for a maximum of 2 years.

Eligibility criteria

• Previously untreated symptomatic MM
• Frail patients, according to the IMWG-frailty index
• Absolute neutrophil count ≥1.0 × 10⁹/L; platelet count ≥75 x 10⁹/L
• Must not have severe organ dysfunction (New York Heart Association Class III and IV)
• Creatinine clearance ≥20 mL/min
• Patients with neuropathy Grade ≥1 with pain or Grade ≥2 and active or uncontrolled infections were excluded

Results

Patient characteristics are summarized in Table 1.

Table 1. Patient characteristics*

IMWG, International Myeloma Working Group; R-ISS, Revised International Staging System. *Adapted from Stege et al.1 †IMWG score for frail status is ≥2
Characteristic	N = 65
Median age, years (range)	81 (70–92)
Frailty status, %
Based on age alone	20
Based on other parameters	49
Based on both age and other frailty parameters	31
IMWG frailty score, %†
2	49
3	29
4	20
5	2
R-ISS disease stage, %
I	15
II	38
III	18
Unknown	18
Median creatinine clearance (mL/min, range)	56 (20–90)

Efficacy

The overall response rate was 78% (95% confidence interval, 0.73–0.82), 8% of whom had a stringent complete response, 28% who had a very good partial response, and 43% who had a partial response. The median time to first response was 1 month (range, 1–6 months) and the median duration of response was 11 months (range, 1–26 months). Survival outcomes after a median follow-up of 22.9 months are summarized in Table 2.

Table 2. Survival outcomes after a median follow-up of 22.9 months*

CI, confidence interval; OS, overall survival; PFS, progression-free survival. *Adapted from Stege et al.1
Outcome	N = 65	95% CI
Median PFS, months	13.8
Frail based on age alone	21.6	9.2–not reached
Frail based on other parameters	13.8	7.8–not reached
Both age >80 years and other parameters	10.1	3.3–21.4
Mortality, %	38	—
12-month OS, %	78	66–87
Frail based on age alone	92	57–99
Frail based on other parameters	78	59–89
Both age >80 years and other parameters	70	44–85

A total of 13 patients died while on the treatment protocol, of which three cases were attributed to disease progression. For the other ten patients, causes of non-relapse mortality included infection (40%), organ dysfunction (30%), sudden death (20%), and bleeding because of thrombocytopenia (10%).

Safety

A total of 33 (65%) patients discontinued treatment during induction, with the most common reasons summarized in Table 3.

Table 3. Reasons for discontinuing the ixazomib-daratumumab-low-dose-dexamethasone regimen*

*Adapted from Stege et al.1
Reason for discontinuation, %	N = 65
Progression	19
Intercurrent death	9
Toxicity	9
Noncompliance to treatment	6
Other reasons	8
Infection	6

The discontinuation rate was greater in patients aged >80 years with or without frail comorbidities compared with younger patients (30% and 38% vs 13%, respectively).

A total of 32 (49%) patients started maintenance therapy, of whom 47% discontinued after a median follow-up of 13.6 months, mainly because of disease progression.

The incidence of hematologic and non-hematologic Grade ≥3 adverse events and serious adverse events were comparable between the three frail subgroups. The most common events after a median follow-up of 22.9 months are summarized in Table 4.

Table 4. Incidence of Grade ≥3 or serious AEs*

AE, adverse event; GI, gastrointestinal. *Adapted from Stege et al.1
AE, %	N = 65
Grade ≥3 hematologic	31
Anemia	3
Thrombocytopenia	23
Neutropenia	9
Grade ≥3 non-hematologic	74
Infections	25
GI	13
Cardiac	11
Peripheral neuropathy	6
Serious AEs	81.5

Finally, all patients completed a health-related quality of life questionnaire at baseline, after three induction cycles (96.6% compliance), and after nine cycles (92.7% compliance). The investigators observed a statistically significant improvement in global health score or quality of life score from baseline to after three cycles, which further improved by cycle nine (54.1, 65.8, and 71.5, respectively; p < 0.001).

Conclusion

Overall, this study demonstrated that a non-toxic regimen could produce effective responses in frail patients. However, patients on this protocol experienced a high rate of Grade ≥3 and serious adverse events, and as such, a relatively high early mortality rate, discontinuation rate, and reduced long-term compliance. Such observations were found both in frail patients characterized by age and by comorbidities. Besides the need to explore alternative regimens with reduced toxicity in this vulnerable population, more trials are necessary with a larger sample size to allow for multivariate analyses and to accurately identify prognostic factors associated with adverse clinical outcomes.