TOURMALINE-MM2 trial: Ixazomib with Rd versus Rd in newly diagnosed patients with MM

Transplant ineligible patients who are diagnosed with multiple myeloma (MM) are a diverse group; some are fit while some are very frail, which means one treatment does not fit all. In particular, a patient’s ability to travel frequently to the clinic for treatment is variable. In this scenario, an oral proteasome inhibitor like ixazomib could reduce the treatment burden and improve therapy tolerance.

 At the Eighth Annual Meeting of the Society of Hematologic Oncology (SOHO) and the 6th World Congress on Controversies in Multiple Myeloma (COMy), Thierry Facon presented the results of the phase III TOURMALINE-MM2 trial (NCT01850524) that tested the oral triplet combination of ixazomib (ixa), lenalidomide (R, len), and dexamethasone (d, dex).^1,2

Study design

The study included 705 patients with newly diagnosed (ND)MM.

Inclusion criteria:

• Adult patients with measurable NDMM diagnosed according to the International Myeloma Working Group criteria
• Transplant-ineligible but suitable for treatment with len and dex
• Eastern Cooperative Oncology Group performance score 0−2
• Sufficient hepatic, hematological, and renal function (creatinine clearance ≥ 30 ml/min)

Exclusion criteria:

• Previously treated for MM
• Unmanaged cardiovascular condition
• Unable to tolerate/receive prophylactic treatment for thromboembolisms
• Any major surgery, severe infection, or localized radiation treatment 2 weeks prior to randomization
• Peripheral neuropathy Grade ≥ 2 or Grade 1 with pain

Patients were randomized 1:1 to receive Rd with a placebo or with ixa as shown in Figure 1.

R, lenalidomide, PD, disease progression, MM multiple myeloma.
*10 mg in patients with renal impairment.
^&Patients ≥ 75 years. 

Patient characteristics were similar between the two treatment arms, with over 40% of patients being 75 years or older (Table 1). Almost 40% of patients had high-risk cytogenetics, and 58% had creatinine clearance greater than 60 ml/min.

Table 1. Patient baseline characteristics¹

CrCl, creatinine clearance; d, dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance score; ISS, International Staging System; Ixa, ixazomib; R, lenalidomide. *t(4;14), t(14;16), del(17p), amp(1q21).
Characteristic		Ixa-Rd (n = 351)	Placebo-Rd (n = 354)
Median age (range), years		73 (48−90)	74 (48−88)
Age ≥ 75 years, %		43	44
ECOG PS %	0	31	30
1	52	56
2	17	14
ISS stage at entry, %	I	49	43
II	35	40
III	16	17
Expanded high-risk cytogenetics*, %		38	41
CrCl > 60 ml/min, %		58	58

The primary endpoint was progression-free survival (PFS). 

Time to progression (TTP) was also assessed and differs from PFS in that it only counts as disease progression, death was not counted as an event.

The secondary endpoints were:

• Overall survival (OS)
• Complete response (CR) rate

Key findings

• The median follow-up for PFS was 53.3 months for the ixa-Rd arm compared with 55.8 months for the control arm. In both groups, only 54% of patients entered Cycle 19.
• There was a significantly increased TTP in the ixa-Rd arm compared with the placebo arm, 45.8 months compared with 26.8 months, respectively (HR 0.738 [95% CI, 0.589−0.925]; p = 0.008).
• Median PFS for ixa-Rd was 35.3 months vs 21.8 for the placebo (HR 0.830 [95% CI, 0.676−1.018]; p = 0.073). The study did not meet its primary endpoint of PFS. However, there was a positive trend in the ixa arm in PFS. When the overall group was split into certain subgroups, as shown in Table 2, a PFS benefit was seen vs Rd.

Table 2. PFS in specific subgroups of note¹

d, dexamethasone; ixa, ixazomib; ISS, International Staging System; PFS, progression-free survival; R, lenalidomide.
Subgroup	Event n/N		Median PFS, months		HR	95% CI
	Ixa-Rd	Placebo-Rd	Ixa-Rd	Placebo-Rd
≥ 75 years (n=308)	94/198	117/199	27.9	20.5	0.871	0.640−1.186
ISS stage III at screening (n = 123)	33/59	47/64	27.9	16.1	0.736	0.466−1.163
Expanded high-risk cytogenetics (n=280)	80/134	104/146	23.8	18.0	0.690	0.506−0.941
≤ 60 ml/min (n = 298)	65/148	100/150	40.0	19.4	0.625	0.450−0.869

A CR was seen in 26% of patients in the ixa-Rd group, with an overall response rate (ORR) of 82.1% (Figure 2). In the placebo arm, a CR of 14% (p < 0.001) and an ORR of 79.7% were reached, which was not significantly different from the ixa-Rd arm. The difference in the percentage of very good partial responses achieved between groups was significant (p < 0.001).

The median follow-up for OS was similar in the two treatment arms, 57.8 months compared with 58.6 months for the ixa-Rd group vs the placebo group. In both treatment arms, the median OS was not reached but to date, both curves practically overlap (HR 0.998 [95% CI, 0.790−1.261]; p = 0.988).

Safety

Treatment-emergent adverse events (TEAEs).

In the study, all patients had a TEAE, with 88.1% of ixa-Rd patients experiencing Grade ≥ 3 compared with 81.4% in the placebo arm, as shown in Figure 3.

The most frequent TEAEs were diarrhea 61.0% vs 46.1%, rash 56.2% vs 37.2%, and peripheral edema 48.6% vs 33.5% for the ixa-Rd group compared with the placebo cohort, respectively. In terms of Grade ≥ 3 TEAEs, neutropenia, anemia, and thrombocytopenia were the most common. Of note, peripheral neuropathy was reported in 33.9% of patients with ixa-Rd (vs 27.5 with Rd), but the vast majority were considered of Grade 1–2.

Conclusions

While the study did not meet its primary endpoint, positive results were seen in the percentage of patients achieving CR and the time to progression in the ixa-Rd arm. The safety profile was consistent with previous reports and was generally tolerated in this elderly patient population. This oral treatment combination could reduce the treatment burden for transplant-ineligible patients with NDMM.