Real-life experience of elotuzumab, lenalidomide, and dexamethasone as treatment for patients with relapsed or refractory multiple myeloma

Monoclonal antibodies (mAbs) targeting plasma cell antigens have demonstrated significant clinical efficacy in the treatment of multiple myeloma (MM). Two mAbs targeting SLAMF7/CS1 or CD38 have become key agents in the relapsed/refractory (RR) MM (RRMM) setting. One of these is elotuzumab (Elo), which targets the glycoprotein receptor SLAMF7 and leads to the activation of natural killer cells and antibody-dependent cellular cytotoxicity (ADCC), causing death of myeloma cells. However, as a single-agent, Elo failed to show significant anti-tumor activity. This led to investigators refining its anti-myeloma role, testing Elo in combination with immunomodulatory drugs (IMiDs®) such as lenalidomide (R).

Elo plus R and dexamethasone (d; EloRd) has previously demonstrated significant efficacy in patients with RRMM in the ELOQUENT-2 trial, leading to a longer progression-free survival (PFS) compared to Rd alone. Longer follow-ups of 3, 4, and 5 years demonstrated that EloRd provided greater overall response rate (ORR) and significantly prolonged overall survival (OS) compared to Rd alone. To investigate the real-life experience of EloRd therapy in Italian patients with RRMM, Massimo Gentile and colleagues conducted a study, the results of which were recently published in Haematologica.¹

Patient characteristics and study design

A total of 300 patients with RRMM, treated with EloRd between April 2017 and April 2019 at 40 Italian centers, were included (Table 1). All patients were treated with EloRd according to the marketing approval guidelines.

• Dosing schedule
  • Intravenous Elo 10 mg/kg on Days 1, 8, 15, and 22 during the first two cycles and then on Days 1 and 15 of each subsequent cycle
  • R 25 mg was administered on Days 1–21 of each cycle
    • Patients with mild renal impairment (n = 30): 10 mg
    • Patients with severe renal impairment (n = 24): 15 mg every other day
  • d 40 mg was administered on the days of the week when Elo was not given, and 36 mg on the day when Elo was given
    • Patients > 75 years (n = 123): 20 mg weekly
  • The median number of treatment administrations was 12 (range, 1–43) at the time of last follow-up

Table 1.  Baseline characteristics¹

auto-SCT, autologous stem cell transplant; ISS, International Staging System; Elo, Elotuzumab; R, Lenalidomide; d, dexamethasone * Patients harboring a t(4;14), t(14;16), or del(17p) aberrations were classified as having high-risk disease; all other cases were classified as standard risk.
	Number of patients (%)
Age (years)
< 75	177 (59)
≥ 75	123 (41)
Creatinine clearance (mL/min)
≥ 60	214 (71.3)
< 60	86 (28.7)
ISS stage (%; n = 238)
I	91 (38.3)
II	95 (39.9)
III	52 (21.8)
Number of previous lines of therapy
1	186 (62.0)
2	70 (23.3)
3	20 (6.7)
≥ 4	24 (8.0)
Previous auto-SCT
No	185 (61.7)
Yes	115 (38.3)
Previous treatment with lenalidomide	78 (26)
Cytogenetic profile
Standard risk	49 (16.3)
High risk*	10 (3.3)
Not evaluated	241 (80.4)
Disease status
Biochemical relapse	56 (18.7)
Symptomatic relapse	171 (57.0)
Refractory to last treatment	73 (24.3)
Time from diagnosis to EloRd treatment (years)
≥ 3.5	154 (51.3)
< 3.5	146 (48.7)

Safety

A total of 188 patients (62.7%) had discontinued EloRd by the cut-off date, median follow-up, 19 months (range, 1–36), due to

• disease progression, n = 151
• toxicity, n = 13
• therapy-unrelated deaths, n = 22
• autologous stem cell transplantation, n = 2

Infusion-related reactions occurred in 6.3% of patients and all were Grade 1–2 events that were resolved without discontinuing therapy.

Major hematological Grade 3/4 adverse events (AEs) were neutropenia (19%), anemia (15.7%), lymphocytopenia (12.7%), and thrombocytopenia (10%). Non-hematological Grade 3/4 AEs were infections (34.3%), fatigue (20.7%), pneumonia (16.7%), and diarrhea (7.3%).

Age (< 75 years vs ≥ 75) did not significantly impact the incidence of AEs.

Results

• Overall response rate (ORR): 77%
• Complete remission (CR): 7.6% (n = 23)
• Very good partial remission (VGPR): 29.3% (n = 88)
• Median progression-free survival (PFS): 17.6 months (95% CI, 14.1–21.0); 1-year PFS rate: 59.1%
• Patients who achieved VGPR or better were more likely to achieve better PFS rates compared to patients who achieved partial response (PR) or less (Table 2)

Table 2. PFS by response to EloRd¹

HR, hazard ratio; PFS, progression-free survival; PR, partial remission; VGPR, very good partial remission
Response group	Number of events	PFS rate (%)	Median PFS (months)	HR (95% CI)	p
≥ VGPR	43	80.1	30.5	1 (reference.)	–
PR	69	59	15.7	2.15 (1.46–3.16)	< 0.0001
< PR	58	23.8	4.2	6.74 (4.47–10.15)	< 0.0001

• Patients with high-risk cytogenetics had a shorter median PFS of 6.3 months vs6 months in patients with standard-risk (HR 3.58; 95% CI, 1.56–8.22; p = 0.003)
  • The cytogenetic profile was not available for 80.4% of patients, therefore, conclusions are limited
• Patients with asymptomatic biochemical relapse did not show improved PFS with EloRd treatment, indicating only patients with symptomatic disease recurrence should start treatment
• Median time to next treatment (TTNT): 25.3 months (95% CI, 22.1–28.3)
• Median overall survival (OS): not reached; 1-year OS: 65.5%
• Median time to first response: 1.7 months
• Median time to best response: 3.5 months
  • Approximately 73% and 91% of patients achieved best response at 6 and 12 months, respectively
• Out of the 300 patients, 173 experienced disease progression or died (n = 94) during the follow-up period

The worst responses to treatment were among patients with refractory disease at the start of EloRd treatment and those with prior lenalidomide exposure. Multivariate ordinal regression analysis showed prior lenalidomide treatment had an adverse and independent correlation with the best response (OR 2.04; 95%CI, 1.2–3.3; p = 0.005).

Factors associated with a significantly higher risk of disease progression or death (in univariate Cox analyses) were

• refractory disease status at the start of the EloRd treatment vs non-refractory disease (HR 1.572; 95% CI, 1.054–2.345; p = 0.027)
• a shorter time period from the time of diagnosis to EloRd treatment (< 3.5 vs ≥ 3.5 years; [HR 1.505; 95% CI, 1.036–2.187; p = 0.032])
• > 2 lines of previous therapy vs < 2 lines of previous therapy (HR 1.777; 95% CI, 1.227–2.572; p = 0.002)
• serum albumin level (< 35 g/L vs > 35 g/L; [HR 1.849; 95% CI, 1.241–2.757; p = 0.003])

Factors that had an independent prognostic impact on PFS (multivariate Cox model)

• Serum albumin level (< 35 g/L vs > 35 g/L [HR 1.721; 95% CI, 1.147–2.581; p = 0.009])
• A shorter time period from the time of diagnosis to EloRd treatment (< 3.5 vs ≥ 3.5 years; [HR 1.811; 95% CI, 1.179–2.781; p = 0.007])
• > 2 previous lines of therapy vs < 2 lines of previous therapy (HR 2.116; 95% CI, 1.39–3.22; p < 0.0001)

Conclusion

In summary, the data from this study show the EloRd regimen was well tolerated and effective for patients with RRMM, confirming the results reported in the ELOQUENT-2 clinical trial. Both trials support EloRd as a first salvage regimen in patients who have not been exposed to lenalidomide and in patients with longer disease duration.

To read more about the ELOQUENT-2 overall survival results with 5-year follow-up,  click here.

Future direction

The EloRd combination is also being investigated in patients with transplant-ineligible newly diagnosed MM in the ELOQUENT-1 trial (NCT01335399). It was recently announced, however, that EloRd failed to provide a statistically significant improvement in PFS compared to Rd alone. Read more here.