The introduction of bortezomib and immunomodulatory drugs and their judicious combination with old drugs in carefully designed clinical trials has led to a paradigm shift in the treatment of myeloma. These trials showed a high efficacy when any of these drugs were combined with corticosteroids and/or alkylating agents or when they were combined together. The high response rates, especially CR rates, seen in these studies highlight the prospect of obtaining profound reductions in tumor load, potentially translating into improved long-term outcomes. This study is the first to evaluate cyclophosphamide in combination with bortezomib, dexamethasone and lenalidomide in patients with newly diagnosed MM. In the phase 1 study, we determined that cyclophosphamide at a dose of 500 mg/m2 can be safely combined with VDR, resulting in a very high response rate and rate of CRs.
The results of the phase 1 portion of this study indicate that combining two novel agents, bortezomib and lenalidomide, with the standard anti-myeloma agents dexamethasone and cyclophosphamide is a feasible, well-tolerated frontline treatment approach. The most common treatment-emergent hematological and non-hematological AEs were consistent with those seen in previous studies evaluating combinations of bortezomib and/or lenalidomide with cyclophosphamide and/or dexamethasone.5,8,10,12–14
Thrombosis events that have been seen with thalidomide and lenalidomide did not occur in the current study.21
This is despite 18/25 patients receiving aspirin alone as thromboprophylaxis, consistent with other studies of bortezomib in combination with immunomodulatory drugs.10,22
The most common grade 3/4 non-hematological AE was Peripheral Neuropathy (in four patients), a toxicity that is manageable and reversible in the majority of patients. With single-agent bortezomib in previously untreated MM patients, 85% of patients showed improvement or resolution of treatment-related sensory Peripheral Neuropathy in a median of 98 days,23
while in patients with relapsed MM, 64% of patients with grade ≥ 2 Peripheral Neuropathy showed improvement or resolution in a median of 110 days.24
Similar findings have been reported in combination studies in previously untreated patients.25,26
The majority of patients in the present study experienced thrombocytopenia, neutropenia and/or anemia, but these were mild or moderate in severity and manageable. Most importantly, there was no evidence of cumulative hematological toxicity as shown by the lack of any downward trend in the platelet or neutrophil count with increasing duration of therapy (). Nevertheless, grade 3/4 myelosuppression appeared to be somewhat more frequent with VDCR than reported for the two- and three-agent combinations.5,8,10,12
The most common treatment-emergent serious adverse event was febrile neutropenia (three patients). It is important to note that 7 (28%) patients in the current study were aged ≥ 65 years, including 2 who were aged at least 75 years, and the tolerability of the regimen was favorable in this patient group as well.
High response rates were achieved in this phase 1 study; the ORR was 96%, with 40% CR/nCR, including 20% sCR. These response rates appeared to be comparable to or somewhat higher than those reported in recent studies of the three-drug combinations VDR (ORR 100%),10
lenalidomide, cyclophosphamide and dexamethasone (RCd, ORR: 83%),13
VDC (ORR 84–88%),12,14
and VDC (three cycles) followed by bortezomib, thalidomide and dexamethasone (VTD; three cycles) (ORR 95%) in newly diagnosed MM patients.27
Stringent CR rates and durability data have not yet been reported for all these studies.
In addition to the three-drug regimens noted above, other three- and four-drug combinations that include bortezomib and/or lenalidomide or thalidomide are also being evaluated and are proving to be highly active and generally well-tolerated induction therapies in this setting. This plethora of studies suggests a shift in the treatment paradigm for newly diagnosed MM toward the use of such multiagent combinations, both as induction therapy before HDT-ASCT and as frontline treatment for non-transplant patients. However, longer-term follow-up as well as head-to-head comparisons of efficacy and toxicity are required for these combinations to determine whether the high response rates translate into improved survival, and to determine the most efficacious combination in these patient populations.
In addition to the high overall response rates, ongoing trials of combination regimens are targeting the depth of response as indicated by the ability to achieve an sCR or minimal residual disease (MRD) negative status. In many hematological malignancies, assessment of minimal residual disease (MRD) following treatment is standard practice, but this is still under investigation in MM, given the lack of treatments with high CR rates until now.28
Recent data suggest that minimal residual disease (MRD)-negative status, as assessed by immunophenotyping through multiparameter flow cytometry, is a better predictor of survival than CR as evaluated by immunofixation.29
In the current study, baseline bone marrow samples were collected and successfully analyzed using flow cytometry for the majority of patients (23/25; 92%). This information will provide a better estimate of the efficacy of this regimen as additional data are collected in the phase 2 portion of the trial.