Facing lenalidomide-refractory myeloma

In this issue of Blood, Mikhael et al report the results of a phase 1b study of isatuximab combined with standard-dose pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) who had received ≥2 prior lines of treatment that included lenalidomide and a proteasome inhibitor (PI).¹ 

Over the past few years, therapeutic advances in MM have been remarkable. Nevertheless, most patients eventually relapse and, unfortunately, some are refractory to their therapy. Multiple factors have an impact on the selection of salvage therapy, including the relapsed or refractory status of the disease, the biochemical or clinical pattern of relapse, and patient- and disease-related characteristics. The prior treatment history is also critical, including such factors as continuous or fixed (ie, for a definite time period) exposure to different classes of agents, number of lines of therapy, and depth and duration of response to each of the regimens, in particular to the last line preceding progression. Therefore, the choice of retreatment using the same classes of drugs vs switching from first- to next-generation agents belonging to the same class vs switching to different classes of agent is important to effectively manage RRMM. One of the most challenging areas in the evolving treatment landscape for this disease is identifying the most appropriate option for patients refractory to lenalidomide and/or PIs such as bortezomib, a growing population of individuals with a dismal prognosis.² 

Isatuximab is a chimeric immunoglobulin G1-κ (IgG1-κ) monoclonal antibody (mAb) that binds selectively to a unique epitope on the cell surface antigen CD38 and targets tumor cells via different mechanisms, including Fc-dependent immune-effector mechanisms and immunomodulatory effects.³  However, preclinical studies suggested that the antitumor activity of isatuximab is primarily dependent on antibody-dependent cellular-mediated cytotoxicity. Data from several phase 1 and 2 studies provided evidence of the efficacy of isatuximab monotherapy at doses ≥10 mg/kg in patients with advanced RRMM, with an overall response rate (ORR) ranging from 24% to 29% and median progression-free survival (PFS) of 3.7 months.⁴  Additional studies also showed that the activity of isatuximab was enhanced by lenalidomide and dexamethasone, with an ORR of 56% (52% in the lenalidomide-refractory subgroup) and a median PFS of 8.5 months.

On the basis of preclinical data showing that isatuximab combined with pomalidomide results in increased direct toxicity and lysis of CD38⁺ plasma cells compared with isatuximab alone, Mikhael et al designed a phase 1b dose-escalation study to assess the safety and efficacy of isatuximab (5, 10, or 20 mg/kg intravenously for 4 weekly doses, then every 2 weeks thereafter) plus standard-dose pomalidomide and dexamethasone (Pd) for RRMM.¹  Forty-five patients with a median of 3 prior lines of therapy were enrolled; of these, 91% were refractory to their last line of treatment, 82% were lenalidomide-refractory, 84% were bortezomib- or carfilzomib-refractory, and 71% were double-refractory to PIs and immunomodulatory agents (IMiDs). Overall, 22 patients were treated in the dose-expansion phase of the study with 10 mg/kg doses of isatuximab, which was selected for future combination studies. Despite the fact that the addition of isatuximab to Pd resulted in a higher rate of grade ≥3 neutropenia (84%) compared with that reported with Pd in the MM-003 study, rates of grade ≥3 infections (24.5%) and grade 4 neutropenic infection (2%) were comparable with the safety profile for Pd. These data are consistent with those from a phase 1b study of daratumumab combined with standard-dose Pd (grade ≥3 neutropenia, 77%; grade ≥3 infection, 32%) in heavily pretreated patients with RRMM, 71% of whom were double-refractory.⁵  In another randomized phase 2 study of elotuzumab plus standard-dose Pd for RRMM patients with a median of 3 prior lines of therapy (90% were lenalidomide-refractory, 78% were PI-refractory, 68% were double-refractory), the rate of grade ≥3 neutropenia was 18% and the rate of grade ≥3 infection was 13%.⁶ 

Isatuximab-related infusion reactions were reported in 42% of patients, similar to the rate observed with daratumumab-Pd (50%)⁵  and were mostly grade 1 to 2. Median infusion times at isatuximab 10 mg/kg were shorter compared with intravenous daratumumab (first infusion, 3.3 vs 7 hours; second infusion, 2.9 vs 4.2 hours; subsequent infusions, 2.9 vs 3.4 hours). The ORR in the population treated with isatuximab-Pd was 62%, including 27% of patients with a very good partial response or higher. These values, although possibly underestimated because of interference by isatuximab (with IgG monoclonal protein assessment by serum immunofixation electrophoresis), are twofold to fourfold higher than expected with Pd. Importantly, the efficacy of isatuximab-Pd in terms of ORR was retained across all subgroups of patients with prior refractoriness to different classes of novel agents, including IMiDs (57%), PIs (63%), IMiDs plus PIs (59%), and both bortezomib and lenalidomide (65%). At a median follow-up of 8.6 months, a median PFS of 17.6 months was reported in all treated patients and in the 10-mg/kg dose subgroup, whereas the 1-year estimated overall survival was 89%. These data, albeit promising, should be cautiously interpreted because of the small sample size and the short follow-up. Results of the global phase 3 ICARIA-MM study comparing isatuximab-Pd with Pd for patients with RRMM after ≥2 prior lines of therapy are eagerly awaited.

Despite the current availability of many classes of novel agents and new-generation drugs within the same class, each with distinct mechanisms of action and safety profile, the best treatment option for MM patients who are refractory to a PI and/or lenalidomide remains a challenge. These patients represent a difficult-to-treat subset of individuals who have been largely excluded from or included only in limited numbers in recent phase 3 studies aimed at establishing new standard-of-care regimens incorporating lenalidomide, bortezomib,⁷  or carfilzomib⁸  in early RRMM patients after a median of 1 to 2 prior lines of therapy. More recently, several studies have been designed to specifically address this patient population. Preliminary results from some of these studies in RRMM are summarized in the table.^5,6,9,10 

Taken together, these data suggest that Pd or carfilzomib-dexamethasone (Kd) represent the backbone for developing safe and effective triplets for the treatment of lenalidomide- or double- refractory MM through the addition of a third agent, such as bortezomib or mAbs targeting CD38 or SLAMF7 antigens. Promising results from these pilot studies have provided a compelling rationale for further investigation of these 3-drug regimens in the ongoing ICARIA-MM, APOLLO (daratumumab-Pd vs Pd), CANDOR (daratumumab-Kd vs Kd), and IKEMA (isatuximab-Kd vs Kd) large phase 3 clinical trials.