Isatuximab with RVd in patients with newly diagnosed MM

For patients with newly diagnosed multiple myeloma (NDMM) the recommended first-line treatment is combination treatment with lenalidomide, bortezomib, and dexamethasone (RVd). Anti-CD38 monoclonal antibodies appear to increase the efficacy of treatment; therefore, isatuximab (Isa) was assessed in combination with this triplet standard of care.

Hartmut Goldschmidt¹ presented a talk at the 63rd American Society of Hematology Annual Meeting & Exposition on the primary endpoint results of the GMMG-HD7 trial (NCT03617731) in which this quadruplet therapy was tested.

Study design

In total, 662 patients with NDMM eligible for transplant were enrolled in this phase III trial. The study design is shown in Figure 1.

ASCT, autologous stem cell transplantation; Bor, bortezomib; D, day(s); Dex, dexamethasone; HDT, high dose therapy; i.v., intravenous; Isa, isatuximab; Len, lenalidomide; MRD, measurable residual disease; NDMM, newly diagnosed multiple myeloma; p.o., orally; PD, progressive disease; RVd, lenalidomide, bortezomib, and dexamethasone; s.c. subcutaneous.
*Adapted from Goldschmidt.¹

The primary endpoint for this trial was reaching measurable residual disease (MRD) negativity at the end of induction treatment. For this trial MRD was measured by next-generation flow with a sensitivity limit of 10⁻⁵.

The secondary endpoints were:

• Complete response (CR) after induction
• Safety profile

Results

Patient characteristics

As shown in Table 1, patient characteristics were comparable between the two cohorts, though the Isa-RVd cohort had a slightly higher number of patients with elevated lactate dehydrogenase (19%) than the RVd group (13.1%). There was also slight imbalance between the number of patients with revised International Staging System (R-ISS) Stage I and II between the arms. Most patients in this study were classified as R-ISS Stage I and II. There were fewer patients who discontinued treatment in the Isa-RVd arm (5.4%) compared with the RVd arm (10.6%).

Table 1. Baseline patient characteristics*

Isa, isatuximab; LDH, lactate dehydrogenase; R-ISS, revised International Staging System; RVd, lenalidomide, bortezomib, and dexamethasone; WHO, World Health Organization. *Adapted from Goldschmidt.1
Characteristic, % (unless otherwise stated)	Isa-RVd (n = 331)	RVd (n = 329)
Median age at randomization (range), years	59 (37−70)	60 (26−70)
Male	61.6	62.6
WHO performance score
0	47.7	51.1
1	41.4	39.5
>1	10.6	9.1
Heavy chain type
IgG	58.6	58.4
IgA	20.5	21.0
Light-chain only	17.8	18.5
Renal impairment
No	94.3	93.3
Yes	5.7	6.7
ISS stage
I	37.5	45.3
II	38.4	34.7
III	24.2	20.1
High-risk cytogenetics
No	76.7	71.4
Yes	17.5	20.1
Unknown	5.7	8.5
Elevated LDH
No	81.0	86.9
Yes	19.0	13.1
R-ISS stage
I	23.3	30.1
II	65.9	56.2
III	8.5	7.9
Not classified	2.4	5.8

Primary endpoint

This trial met its primary endpoint of MRD negativity at the end of induction, with the Isa-RVd group exhibiting significantly more MRD-negative patients compared with RVd-only group (odds ratio, 1.83; 95% confidence interval, 1.34−2.51; p < 0.001; Figure 2). The MRD negativity benefit of Isa-RVd was consistent across different subgroups, including age, sex, WHO performance status, renal impairment, ISS/R-ISS stage, high-risk cytogenetics, and elevated lactate dehydrogenase.

Isa, isatuximab; MRD, measurable residual disease; RVd, lenalidomide, bortezomib and dexamethasone.
*Adapted from Goldschmidt.¹

Response rate

Isa-RVd treatment did not result in a significant difference in CR and ≥ near CR rates when compared with RVd treatment. There was a significant difference between ≥ very good partial response and ≥ partial response rates between the two groups (p < 0.001 and p = 0.02, respectively; Figure 3). Hartmut stated that the reason for this difference may be because of the length of the half-life of the Isa monoclonal antibody, which is long and therefore does not fully disappear from the urine/serum prior to response analysis (which uses the International Myeloma Working Group criteria²).

CR, complete response; Isa, isatuximab; nCR, near complete response; PR, partial response; RVd, lenalidomide, bortezomib, and dexamethasone; VGPR, very good partial response.
*Adapted from Goldschmidt.¹

Safety

A similar number of patients discontinued therapy because of adverse events (AEs) in both groups (RVd, 2.4% vs Isa-RVd, 2.1%).

The safety profile of the treatments is shown in Table 2. The overall number of patients experiencing AEs was similar between groups. In total, there were four deaths in the Isa-RVd group and eight in the RVd group.

There were a few differences in AEs between the two groups. Blood and lymphatic disorders were higher in the Isa-RVd group compared with the RVd group (25.8% vs 16.8%, respectively). Leukocytopenia/neutropenia was recorded in 26.4% of the Isa-RVd group and 9.1% of the RVd group. No infusion-related reactions were recorded in the RVd group, whereas four occurred with Isa-RVd.

Table 2. Safety profile*

AE, adverse event; CTCAE, common terminology criteria for adverse events; Isa, isatuximab; NA, not applicable; RVd, lenalidomide, bortezomib, and dexamethasone; SOC, system organ class. *Adapted from Goldschmidt.1 †SOC considered as investigations, as defined by the CTCAE.
AEs CTCAE Grade ≥3, %	Isa-RVd (n = 330)	RVd (n = 328)
Any AE	63.6	61.3
Any serious AE (any grade)	34.8	36.3
Deaths	1.2	2.4
Investigations	23.9	23.5
Blood and lymphatic system disorders (SOC)†	25.8	16.8
Infections and infestations (SOC)†	13.0	10.4
Nervous system disorder (SOC)†	8.5	10.1
Gastrointestinal disorders (SOC)†	8.2	9.5
Metabolism and nutrition disorders (SOC)†	3.6	7.9
Specific hematologic AE
Leukocytopenia/neutropenia	26.4	9.1
Lymphopenia	14.5	19.8
Anemia	3.9	6.1
Thrombocytopenia	6.4	4.6
Specific non-hematologic AE
Peripheral neuropathy	7.6	6.7
Thromboembolic events	1.5	2.7
Infusion-related reactions	1.2	NA

Dose intensity of RVd was not impacted by the addition of Isa.

Conclusion

The GMMG-HD7 trial met its primary endpoint of MRD negativity by the end of induction in patients with NDMM eligible for transplant. The safety profile of RVd was not significantly impacted by the addition of Isa. This trial is currently still ongoing after the second randomization for maintenance.