Efficacy and feasibility of dose/schedule-adjusted Rd-R in elderly, intermediate-fit patients

Combination treatments such as lenalidomide + dexamethasone (Rd) and bortezomib + melphalan + prednisone (VMP) were considered until recently the standard treatment options for elderly patients not eligible for autologous stem cell transplantation. Today, both regimens are preferably administered in combination with daratumumab, an anti-CD38 antibody.

Continuous Rd demonstrated to be effective and safe in elderly patients with newly diagnosed multiple myeloma (NDMM); however, the evidence on its safety in patients aged >75 years is limited. Older patients are more susceptible to adverse events (AEs) due to prolonged use of steroids, the presence of comorbidities, and functional impairment. Several trials have shown that patients either discontinued continuous Rd or had their doses reduced. Continuous Rd led to AEs and affected the quality of life of patients with MM; therefore, an adapted treatment strategy is required for such patients.

In a randomized controlled trial published in Blood, Larocca and colleagues¹ investigated the efficacy and feasibility of reduced dose Rd + lenalidomide (Rd-R) in patients with NDMM, and their findings are summarized here.

Study design

This was a phase III randomized controlled multicenter trial (NCT02215980), which included patients aged >65 years and ≤80 years who were ineligible for autologous stem cell transplantation and classified as intermediate-fit as defined by the International Myeloma Working Group (IMWG) frailty score.

• The primary endpoint was event-free survival (EFS), defined as discontinuation of lenalidomide, disease progression, death, or the occurrence of Grade 4 hematologic AEs or Grade 3–4 non-hematologic AEs, including second primary malignancy.
• Secondary endpoints included progression-free survival (PFS), overall survival (OS), response rate, and incidence of dose reductions and drug discontinuation.

Patients randomized to continuous Rd or Rd-R received nine 28-day induction cycles of lenalidomide (25 mg per day for 21 days) + dexamethasone (20 mg on Days 1, 8, 15, and 22) followed by lenalidomide maintenance (10 mg per day for 21 days). Patients allocated to continuous Rd received 28-day cycles of lenalidomide (25 mg per day for 21 days) + dexamethasone (20 mg on Days 1, 8, 15, and 22).

Results

Baseline characteristics

The median age was 75 years, 23% of all patients had an International Staging System score of III, and 21% had high-risk chromosomal abnormalities. The baseline characteristics were well balanced between the two groups (Table 1).

Table 1. Baseline characteristics*

ADL, activity of daily living; CCI, Charlson Comorbidity Index; ECOG PS, European Eastern Cooperative Group Performance Status; IADL, instrumental ADL; ISS, International Staging System; Rd, continuous lenalidomide + dexamethasone; Rd-R, lenalidomide + dexamethasone followed by lenalidomide maintenance. *Adapted from Larocca et al.1 †At least one among del17, or t(14;16) or t(4;14).
Characteristic, %	Rd-R (n = 101)	Rd (n = 98)
Median age, years (range)               70–80 years	75 (73–77) 48	76 (74–79) 57
Male	52	50
ECOG-PS               0               1               2	37 52 11	37 53 10
Creatinine clearance ≤60 mL/min	36	49
ISS score               I               II               III	32 47 21	38 37 25
High-risk cytogenetics†	19	23
Intermediate-fit               For age               For geriatric impairment                             CCI ≥2                             ADL ≤4                             IADL ≤5	48 23 9 21	57 18 12 13

Efficacy

• The median EFS was 10.4 months and 6.9 months in the Rd-R and Rd arms, respectively (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51–0.95; p = 0.02). EFS was maintained in the Rd-R arm beyond Cycle 9; the median EFS in the Rd‑R and Rd arms was 19.8 months and 10.6 months, respectively (HR, 0.55; 95% CI, 0.32–0.93; p = 0.03).
• No difference was observed for EFS in patients considered intermediate-fit for age compared with intermediate-fit for comorbidities or functional impairments (median EFS, 8.1 months vs 7.6 months; HR, 0.93; 95% CI, 0.68–1.28; p = 0.67).
• The median PFS was 20.2 months in the Rd-R arm compared with 18.3 months in the Rd arm (HR, 0.78; 95% CI, 0.55–1.1; p = 0.16).
• Median OS was not reached, and the 3-year OS was 74% in the Rd-R arm and 63% in the Rd arm (HR, 0.62; 95% CI, 0.37–1.03; p = 0.06).
• Best response was similar across both groups, with an overall response rate of 78% in the Rd-R arm compared with 68% in the Rd arm (p = 0.15) (Table 2).
• A PFS benefit favoring Rd-R was observed in standard-risk patients (HR, 0.62; 95% CI. 0.39–1.00), but not in high-risk patients (HR, 1.10; 95% CI, 0.47–2.55).

Table 2. Best response rates for patients in the Rd-R and Rd arms*

CR, complete response; nCR, near complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; Rd, continuous lenalidomide + dexamethasone; Rd-R, lenalidomide + dexamethasone followed by lenalidomide maintenance; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response. *Adapted from Larocca et al.1 †Immunofixation negative, bone marrow examination not performed.
Best response, %	Rd-R (n = 101)	Rd (n = 98)
ORR               sCR               CR               nCR†               VGPR               PR	78 4 1 19 28 27	68 1 15 22 30 39
≥VGPR	51	39
SD	12	17
PD	0	6
Not evaluable	10	8

Safety

After a median duration of lenalidomide treatment of 17.3 months with Rd-R (interquartile range [IQR], 7.2–34.7) and 12.8 months with continuous Rd (IQR, 4.5–30.3 months), the median accumulated dose administered of lenalidomide was higher in the Rd-R arm compared with the Rd arm (5,798 mg vs 5,408 mg).

As presented in Table 3, no statistically significant differences were reported between arms in terms of safety:

• In total, 26% of patients in the Rd-R arm and 20% in the Rd arm reported Grade ≥3 hematologic AEs (p = 0.40), with the most common AE being neutropenia.
• In addition, 33% of patients in the Rd-R arm and 43% in the Rd arm reported Grade ≥3 non‑hematologic AEs (p = 0.15), and the most common AEs were infections, constitutional, dermatologic, and central nervous system toxicities.
• After nine cycles, the 2-year cumulative incidence of Grade ≥3 hematologic AEs was 16% in the Rd-R arm compared with 13% in the Rd arm, and 10% vs 17% for non-hematologic AEs, respectively.

However, the rate of patients needing a dose reduction or drug discontinuation was higher in the Rd arm for both lenalidomide and dexamethasone. Hence, patients could experience AEs requiring dose adjustments even after nine cycles of treatment.

Table 3. Grade ≥3 AEs, drug discontinuation, and dose reduction in the Rd-R and Rd arms*

AE, adverse event; Rd, continuous lenalidomide + dexamethasone; Rd-R, lenalidomide + dexamethasone followed by lenalidomide maintenance; SPM, second primary malignancy. *Adapted from Larocca et al.1
Incident, %	Rd-R (n = 101)	Rd (n = 98)
Grade ≥3 AEs
Hematologic               ≥1 event               Neutropenia               Anemia               Thrombocytopenia	26 21 9 4	20 18 3 2
Non-hematologic               ≥1 event               Infection               Constitutional               Dermatologic               Gastrointestinal               Nervous               Vascular               Cardiologic               SPM	33 10 3 7 5 2 2 2 2	43 12 12 3 5 6 4 2 2
Drug discontinuation and dose reduction
≥1 lenalidomide dose reduction	45	62
Lenalidomide discontinuation for AEs	24	30
Dexamethasone dose reduction	17	31
Dexamethasone discontinuation for AEs	14	34

Conclusion

The study demonstrated the efficacy and feasibility of switching to reduced lenalidomide maintenance without dexamethasone after nine cycles of Rd, providing similar outcomes to standard treatment. The findings from this study may help to improve and optimize the treatment of elderly patients who may be at a greater risk of treatment toxicity and poor survival due to their age or comorbidities.

This approach for the treatment of NDMM should be evaluated further with newer combinations including CD38 antibodies, along with frailty-adjusted strategies in ongoing and future clinical trials.