VCD Induction Induces High Response Rates in Myeloma

Hermann Einsele, MD

Induction therapy with bortezomib (Velcade), cyclophosphamide, and dexamethasone (VCD) induced strong response rates in treatment-naïve patients with multiple myeloma, according to phase II results from the DSMM XI trial published in the British Journal of Haematology.

A total of 414 patients received three 21-day cycles of VCD prior to autologous stem cell transplantation (ASCT). The overall response rate (ORR) by investigator-based assessment was 85.4%. Investigators observed no clinically relevant differences between patients with or without high-risk cytogenetic abnormalities in ORR post-induction (86.2% vs 84.3%). Fifteen patients (4.5%) had a complete response (CR) and 14 more (4.2%) had an unconfirmed CR.

“The results of this study confirm the utility of VCD induction for previously untreated [multiple myeloma], including patients with poor-risk cytogenetic abnormalities,” first author Hermann Einsele, MD, University Hospital Würzburg, Germany and coinvestigators wrote.

“Furthermore, it is associated with an acceptable tolerability profile, including low mortality, low risk of infection and low incidence of severe and acceptable rates of mild/moderate treatment-emergent polyneuropathy, and is feasible in an outpatient setting. It is possible that subcutaneous bortezomib could even lower the rate of VCD-associated neuropathy,” added Einsele et al.

From March 2006 to June 2009, researchers at 41 centers in Germany enrolled 414 patients into this open-label, prospective, multicenter, nonrandomized, phase II trial. A total of 391 patients received at least 1 dose of bortezomib. Four patients from the first part of the study were not included in the present analysis because they received >1350 mg/m2 of cyclophosphamide (>150% of the maximum-tolerated dose), leaving 395 patients in the safety population.

Patients were assigned to three 21-day cycles of 1.3 mg/m2 of bortezomib (IV) on days 1, 4, 8, and 11; 900 mg/m2 IV cyclophosphamide on day 1; and 40 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12.

After 3 cycles of VCD induction, investigators offered patients stem-cell collection and high-dose melphalan in combination with ASCT.

Patients in this study were eligible to join DSMM XIb (MMY3012/MMY3013), a randomized treatment study of bortezomib as consolidation therapy following HDT/SCT. Only those who enrolled in the MMY3012/MMY3013 consolidation trial were prospectively monitored and externally audited after ASCT and analyzed for ORR, long-term progression-free survival (PFS) and overall survival (OS). Patients who received VCD induction but did not enroll in MMY3012/MMY3013 were not included in this analysis.

Best response for 106 patients (31.7%) was very good partial response (VGPR) and partial response for 153 (45.8%) others.

A total of 291 patients underwent successful molecular cytogenetic analysis with FISH. Of those, 189 had cytogenetic abnormalities compared with 102 who did not. There were 112 patients with del(13q), 38 patients with t(4;14), and 31 with del(17p). There were 104 patients with other chromosomal abnormalities.

Investigators observed no clinically relevant differences in ORR between patients with cytogenetic abnormalities (86.2%) and those without (84.3%). In a subgroup analysis of the response-evaluable population, ORR was highest in patients with del(13q), at 90.2%, and lowest in those with del(17p), at 74.2%. Investigators noted that a high proportion of patients (89.5%) with t(4;14) responded to VCD induction.

Of patients who underwent VCD induction, 113 (27.3%) successfully completed subsequent stem cell collection, were free from progressive disease after high-dose melphalan/ASCT, and enrolled into MMY3012 (DSMM XIb).

Among 112 response-evaluable patients, post-HDT/ASCT ORR, assessed prior to any consolidation therapy, was 95.5%. The CR rate was 30.4% CR, with a ≥VGPR rate of 67.0%. At a median follow-up of 55.5 months (range, 2.6—75.7), median PFS was 35.3 months (95% CI, 27.8-45.9). Median OS was not yet reached.

A total of 353 patients (89.4%) completed 3 cycles of VCD induction. Twenty-four patients discontinued due to adverse events (AEs), 4 discontinued for progression, and 2 patients died.

Nearly all patients (99.2%) experienced treatment-emergent AEs. More than half of patients (n = 214; 54.2%) experienced grade ≥3 AEs.

One hundred-three patients (26.1%) experienced treatment-emergent serious AEs (SAEs). Pneumonia (3.8%) was the most common SAE, followed by pyrexia (3.5%), and leucopenia (2.8%). The vast majority of all SAEs (88.6%) resulted in hospitalization or prolonged hospitalization. Twenty-one patients discontinued treatment due to SAEs including pneumonia (n = 3), and 2 each for herpes zoster, sepsis, leucopenia, neutropenia, vomiting, and cardiac failure.

Muhamed Baljevic, MD, assistant professor, division of Hematology/Medical Oncology, University of Nebraska Medical Center, reviewed the data for OncLive. While the VCD regimen is common in Europe and standard frontline treatment in Germany, he said these findings are unlikely to change clinical practice in the United States.

“Some regional differences between Europe and North America still exist when it comes to standard of care frontline treatments for multiple myeloma, as the European Medicines Agency has not yet approved the triplet of bortezomib, lenalidomide, and dexamethasone (VRD). Here, we certainly consider the combination of proteasome inhibitor (PI) and immunomodulatory (IMiD) drugs to be the standard-of-care because of the plethora of evidence that suggests deeper responses and better overall outcomes for patients with this type of frontline treatment. Compared to VCD combination, which no doubt can be very useful in certain situations, VRD, carries a category 1 recommendation in the major national guidelines.

“The authors say, ‘High response rates have been reported with VTD. However, it is unknown whether such response rates translate into improved long-term outcomes following HDT/ASCT.’ “Though we lack the exact data with the VTD combination, recent studies which evaluated minimal residual disease (MRD) provide the body of evidence which suggests that the combination of frontline PIs and IMiDs leads to very high rates of MRD negative status, which in turn ultimately translates into improved patient outcomes. The achievement of MRD negative status is becoming more important in the myeloma field, the value of which is highlighted by the FDA’s favorable opinion of it being considered a valid regulatory endpoint in future myeloma studies.

“The study is a fantastic effort by the colleagues in Europe, though I don’t believe it is going to lead to notable changes in practice patterns across the United States. The authors refer to the recently published paper where VCD as a combination, though delivered in a slightly different way, was compared head-to-head with VTD, Velcade-thalidomide-dexamethasone, a PI and an IMiD combination. In that study, VGPR rates as well as overall response rates on average were 10% higher [with VTD]. This and the recently published SWOG S0777 study provide further evidence that the combination of PIs and IMiDs, indeed, is the better choice for all fit newly diagnosed patients irrespective of their transplant candidacy.”

Baljevic went on to say that the paper makes an important point about long-term outcomes of patients with high-risk cytogenetics and those with standard-risk cytogenetics.

“There is a clear difference in the progression-free survival and overall survival, which is much more inferior in patients with high-risk cytogenetics who have received this regimen,” he said. “It is important to note that even thalidomide, and certainly Cytoxan included, doesn’t abrogate the effects of the high-risk cytogenetics, while bortezomib as well as Revlimid, partially do on an individual basis, and even more so in a combination regimens. If anything, I believe this paper highlights the importance of the combination of PI and IMiD agents upfront for newly diagnosed patients, especially those who present with high-risk disease.”

Einsele H, Engelhardt M, Tapprich C, et al. Phase II study of bortezomib, cyclophosphamide and dexamethasone as induction therapy in multiple myeloma: DSMM XI trial [published online September 29, 2017]. Br J Haematol. doi: 10.1111/bjh.14920.