French researchers earlier this week published updated results of a small Phase 2 clinical trial testing the combination of Revlimid, Velcade, and dexa­metha­sone (RVD) in newly diagnosed multiple myeloma pa­tients.

The researchers found that RVD, when given before and after stem cell trans­plan­ta­tion – and when followed by maintenance therapy with Rev­limid – led to very deep treatment responses and significant survival rates.

The 31 newly diagnosed patients in the French trial initially were treated with three cycles of RVD therapy.  Next, the trial participants underwent autologous (own) stem cell transplants, followed by two cycles of RVD consolidation therapy, and concluding with a year of Revlimid maintenance therapy.

All patients in the study achieved at least a partial response to this treatment regimen.  Almost 60 percent achieved a complete response or stringent complete response.  And a full two thirds of the patients achieved so-called minimal residual disease (MRD)-negative status, meaning that sensitive testing could not find any sign of myeloma in their bodies.

Perhaps the most noteworthy outcome of the trial, however, is how many patients survived a full three years from the time of their diagnosis: 100 percent.

Equally important, however, is the trial’s finding that, among the patients who achieved MRD-negative status, the three-year progression-free survival rate was also 100 percent.  In contrast, the three-year progression-free survival rate was just 23 percent for trial participants who did not achieve MRD-negative status.

These results, the authors write, “strongly suggest that MRD negativity must be the goal of treatment for every front-line transplantation-eligible patient with multiple myeloma.”

The French researchers also believe the treatment regimen tested during the trial showed “favorable toler­abil­ity.” There were, for example, no cases of severe peripheral neuropathy (pain, tingling, or numbness in the extremities) observed during the trial.

Some patients, however, struggled with the Revlimid maintenance regimen. Almost two thirds of the patients dropped their Revlimid dose below the target dose, and a fifth of the patients halted the Revlimid maintenance therapy altogether.

In addition, among the 31 patients who participated in the trial, there were three cases of secondary cancer – two cases in one patient, and one in another. None of the secondary cancers, though, were blood cancers such as leukemia or myelodysplastic syndromes.

The Broader Significance Of The Trial

Overall, the results of the French study are likely to attract attention for reasons that go beyond its noteworthy response and survival rates.

In particular, the outcomes of the current trial may provide a preview of the yet-to-be-announced results of an important U.S.-French clinical trial.  The large two-country Phase 3 trial is investigating a key question in myeloma therapy: Is it beneficial to have newly diagnosed myeloma patients undergo a stem cell transplant within a year of their diagnosis, or is it better to wait and carry out a stem cell transplant after a patient ex­per­i­ences their first relapse?

The U.S.-French Phase 3 trial, known as the IFM/DFCI 2009 study, involves two groups of patients: one that is receiving early stem cell transplants, and a second that is not.

The patients in the early stem cell transplant group in the IFM/DFCI trial, it turns out, are receiving a treatment regimen that is almost exactly the same as the one tested in the current (smaller) French Phase 2 study.

Initial results of the IFM/DFCI trial are not expected until later this year, at the earliest. Until then, the results of the current study are the best indication of the outcomes to be expected from the early-transplant arm of the larger trial.

That, in turn, suggests that the bar has been set rather high for the outcomes of the delayed-transplantation arm of the trial.

Study Design

The Phase 2 trial included 31 newly diagnosed myeloma patients under the age of 65 who were eligible for stem cell transplantation. The patients were recruited at ten treatment centers across France between Sep­tember and December 2009.

The median patient age was 58 years old.

Overall, 27 percent of patients were classified as having high-risk chromosomal abnormalities based on their having either a del(17p) or t(4;14) abnormality, determined by fluorescence in situ hybridization (FISH).

Patients received three 21-day treatment cycles of 25 mg of Revlimid ^[1](lenalidomide) per day on days 1 to 14, along with 1.3 mg/m² of Velcade ^[2] (bortezomib) administered by infusion (not subcutaneously) on days 1, 4, 8 and 11, and 40 mg of oral dexamethasone ^[3] (Decadron) on days 1, 8, and 15.

All patients proceeded to transplantation using 200 mg/ m² of melphalan ^[4] (Alkeran) as conditioning treat­ment.

Two months after recovery of blood counts, patients who had not progressed received consolidation therapy consisting of two cycles of RVD at the same schedule as during induction therapy and at the last tolerated dose.

Patients then received maintenance therapy with continuous Revlimid for one year. The starting dose was 10 mg per day, which was escalated to 15 mg per day after three months according to blood cell counts and side effects.

The median follow-time was 39 months.

Study Results

Overall, 93 percent of patients responded to the initial three cycles of RVD therapy, with 10 percent reaching a stringent complete response, 13 percent a complete response, 35 percent a very good partial response, and 35 percent a partial response; 16 percent of patients were MRD-negative after induction therapy.

Responses deepened significantly after transplantation and consolidation therapy, with 40 percent reaching a stringent complete response, 10 percent a complete response, 37 percent a very good partial response, and 10 percent a partial response; 58 percent of patients were MRD-negative after consolidation therapy.

Responses also improved further for some patients during maintenance therapy.

After all treatment sequences, 68 percent of patients had achieved MRD negativity.

The three-year progression-free survival rate was 77 percent. This rate was significantly lower in patients who had never reached MRD negativity (23 percent). In contrast, none of the patients who had reached MRD negativity relapsed within three years of diagnosis.

In addition, all patients were alive at three years after diagnosis.

The researchers note that survival outcomes for patients with high-risk chromosomal abnormalities were similar to those of the entire group. The three-year progression-free survival for high-risk patients, for example, was 86 percent.

The French researchers described the side effects associated with treatment during the trial as predictable and in line with those seen in previous studies.

The most common severe side effects during RVD induction and consolidation therapy were low white blood cell counts (35 percent) and low platelet counts (13 percent).

Approximately half the patients (55 percent) experienced mild to moderate peripheral neuropathy, but there were no severe cases of the condition.

Overall, 39 percent of patients required dose modifications during induction and consolidation therapy.

The most common side effect during Revlimid maintenance therapy was low blood cell counts. In particular, 60 percent of patients experienced severe low white blood cell counts during Revlimid maintenance. Overall, only 37 percent of the patients were able to stay at the planned Revlimid maintenance dose.  One fifth of the patients halted maintenance therapy early due to its side effects.

There were three cases of secondary cancer observed among the 31 trial participants: two cases of basal cell carcinoma, a form of skin cancer, in one female patient, and one case of breast cancer in another female patient.

For more information, please see the study by Roussel, M. et al., “Front-Line Transplantation Program With Lenalidomide, Bortezomib, and Dexamethasone Combination As Induction and Consolidation Followed by Lenalidomide Maintenance in Patients With Multiple Myeloma: A Phase II Study by the Intergroupe Franco­phone du Myélome,” Journal of Clinical Oncology, July 14, 2014 (published online) (abstract ^[5]).