With the MDS-004 trial,1  we finally have a randomized, double-blind, phase 3 study supporting the use of lenalidomide in lower-risk myelodysplastic syndrome (MDS) patients with the del(5q) cytogenetic abnormality—proof of principle that phase 3 studies can be performed in patients with rare diseases. But crossover from placebo to active drug, while ethically prudent, eliminates any chance of determining if lenalidomide prolongs survival or accelerates leukemia progression.

The immunomodulatory drug lenalidomide was approved by the US Food and Drug Administration in 2005 specifically for the treatment of lower-risk, transfusion-dependent MDS patients with the del(5q) cytogenetic abnormality. Whether the drug truly works by modulating the immune system or by selectively suppressing the clone through inhibition of haplodeficient cell-cycle regulatory targets coded within the 5q31 commonly deleted region (CDR)2,3  or a combination is debatable.

Table 1

Comparison of MDS-003 and MDS-004 trials

TrialLenalidomide dose (28-day cycle)Median age, y (range)Isolated 5q deletionMedian time since diagnosis, yErythroid response*Any cytogenetic response
MDS-003 10 mg daily × 21-28 days 71 (37-95) 74% 2.7 76% 73% 
MDS-004 10 mg daily × 21 days or 5 mg daily × 28 days 69 (36-86) 76% 2.5 56% 50% (10 mg arm) 25% (5 mg arm) 
TrialLenalidomide dose (28-day cycle)Median age, y (range)Isolated 5q deletionMedian time since diagnosis, yErythroid response*Any cytogenetic response
MDS-003 10 mg daily × 21-28 days 71 (37-95) 74% 2.7 76% 73% 
MDS-004 10 mg daily × 21 days or 5 mg daily × 28 days 69 (36-86) 76% 2.5 56% 50% (10 mg arm) 25% (5 mg arm) 
*

Erythroid response as defined by 2000 International Working Group Criteria.8 

Lenalidomide's development within lower-risk MDS patients has been relatively rapid. The first dedicated MDS study, MDS-001, was an open-label, phase 1/2 clinical trial of 43 patients, 74% of whom were transfusion-dependent at study initiation, and 12 of whom had the del(5q) abnormality.4  Patients received lenalidomide at 10 mg daily, 25 mg daily, or 10 mg daily for 21 days of a 28-day cycle, and 49% had a major erythroid response, 83% of those with del(5q). This prompted 2 concurrent, single-arm phase 2 studies, both for transfusion-dependent, lower-risk MDS patients with (MDS-003, the registration trial) or without (MDS-002) the del(5q) lesion. In MDS-003, 148 patients with the del(5q) abnormality were treated with lenalidomide 10 mg daily for 21 or 28 days of a 28-day cycle.5  Most (73%) had failed prior erythropoiesis stimulating agents (ESAs), and 74% had no additional cytogenetic abnormalities. Sixty-seven percent of patients achieved transfusion independence, with a median duration of response of > 2 years. Karyotype phenotype, when it included the del(5q) lesion, had no significant effect on the rate of transfusion-independence (72%, 48%, and 67% for patients with 0, 1, or ≥ 2 additional abnormalities, respectively). A complete cytogenetic response was achieved by 45% of evaluable patients. In the MDS-002 study,6  26% of patients became transfusion-independent—a much lower proportion than that observed in the 5q(del) population in the MDS-003 study. The median duration of response was also lower, at 41 weeks, supporting a specific effect of the drug on the del(5q) clone.

In this issue of Blood, Fenaux and colleagues report the results of the MDS-004 study, a phase 3, double-blind study in which 205 transfusion-dependent, lower-risk del(5q) MDS patients (139 in the modified intention-to-treat (mITT) analysis) were randomized 1:1:1 to lenalidomide 10 mg/d on days 1-21, lenalidomide 5 mg/d on days 1-28, or placebo on days 1-28 of 28-day cycles. Those without an erythroid response by week 16 were discontinued from the double-blind phase, unblinded, and eligible for open-label treatment. Approximately half (52%) had been exposed to ESA therapy previously. The authors report that significantly more patients in the mITT population achieved the primary end point (red blood cell transfusion independence for ≥ 26 weeks) with lenalidomide 10 mg (56.1%) and 5 mg (42.6%) versus placebo (5.9%; P < .001 for lenalidomide vs placebo). Response duration was at least a median of 82.9 weeks with lenalidomide 10 mg and 41.3 weeks with lenalidomide 5 mg, with complete cytogenetic response rates of 29.4% and 15.6%, respectively (P = .29). With a median follow-up of 31-36 months, 52 patients (25.4%) progressed to AML. This included 4 of 11 patients (36.4%) just receiving placebo; 17 of 56 patients (30.4%) who initially received placebo and then crossed over to lenalidomide 5 mg; 16 of 69 patients (23.2%) in the lenalidomide 5 mg group; and 15 of 69 patients (21.7%) in the lenalidomide 10 mg group. One analysis of 381 untreated del(5q) MDS patients, with a median follow-up of ∼ 4 years, showed a rate of AML evolution of 17% at 5 years, though it is challenging to say that these populations are comparable.7  There were no apparent survival differences among groups, although crossover from placebo to lenalidomide confounded the ability to assess the effect of the drug on this or on leukemia transformation. Erythroid and cytogenetic responses appeared lower than those seen in the MDS-003 trial despite similar baseline characteristics, as might be expected when moving from the phase 2 to the phase 3 setting, but are still substantial8  (see table).

So, is this fourth study of lenalidomide in MDS truly “the charm?” To answer, we turn to the etymology of the phrase, “Third time's the charm.” A popular interpretation from the 19th century refers to an English law freeing a condemned man after 3 failed attempts at hanging him. Yet, the approximate phrase appears earlier, in Shakespeare's The Merry Wives of Windsor, as stated by the character Falstaff: “Pr'ythee, no more prattling—go. I will hold: this is the third time; I hope good luck lies in odd numbers.… They say there is divinity in odd numbers, either in nativity, chance, or death” (Act V, scene 1, lines 1-5). Perhaps for lenalidomide, and more importantly for MDS patients, there is good luck in even numbers, with excellent response rates and hopefully, less chance of death by disease or leukemia, although this remains to be seen.

Conflict-of-interest disclosure: The author has served on an advisory board for Celgene. ■

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