Prashant Kapoor, MD: Thanks to significant strides in research over the past decade, there are a variety of therapeutic options available for the treatment of patients with newly diagnosed MM. While the wide array of options to choose from can flummox us as clinicians, it’s a good problem to have. Once we distill the available data, even in the absence of head-to head comparisons, only a handful of regimens pass muster in the frontline setting.
Selecting a frontline regimen for our patients involves considering disease factors, as well as patient factors, such as comorbidity burden, transplant eligibility, and ability to tolerate high-dose melphalan and individual drugs within a regimen.
In the U.S., the triplet regimen of bortezomib, lenalidomide, and low-dose dexamethasone (VRd) is commonly used across all risk groups, largely based on the results of the SWOG S0777 study, which compared VRd with lenalidomide and dexamethasone (Rd) alone in newly diagnosed patients for whom immediate autologous hematopoietic cell transplantation (AHCT) was not planned.1 The triplet regimen had a median progression-free survival (PFS) benefit of approximately 13 months and an 11-month improvement in median overall survival (OS).
In SWOG S0777, bortezomib was administered in the old-fashioned, intravenous way. For the past few years, we’ve been using bortezomib subcutaneously, an approach that is much less neurotoxic. And nowadays, once-a-week dosing is preferred over the twice-weekly dosing in most circumstances.
Even though bortezomib, thalidomide, and dexamethasone (VTD) – the other combination of proteasome inhibitor (PI) plus immunomodulatory drug (IMiD) – has been well-studied, primarily in Europe, it is associated with more treatment-emergent adverse events (AEs), including a greater risk of developing peripheral neuropathy because this regimen combines two neurotoxic agents (bortezomib and thalidomide).
The VRd regimen has been widely adopted in the U.S., not only because of its tolerability, but also because of its efficacy. To date, there have been no randomized controlled trials (RCTs) directly comparing VRd with VTD, but at the 2018 American Society of Hematology (ASH) Annual Meeting an integrated analysis of the PETHEMA/GEM studies demonstrated a significant improvement in rates of very good partial response (VGPR) or better after induction with VRd compared with VTD (66% vs. 51%; p=0.00281).2
Michaela Liedtke, MD: VRd has definitely become a standard regimen for newly diagnosed myeloma and is commonly used in both transplant-eligible and transplant-ineligible patients. However, approximately one-third of patients diagnosed with myeloma are older than 75 years and many have pre-existing comorbidities. In the SWOG S0777 study, the rate of grade ≥3 AEs was 82% in the VRd arm, and the triplet was discontinued due to AEs in almost one-quarter of patients, compared with 10% of patients receiving Rd. Grade ≥3 neurologic AEs were observed in one-third of patients receiving VRd and, even if bortezomib is given subcutaneously and on a reduced schedule, a significant proportion of patients will develop neuropathy, thrombocytopenia, or gastrointestinal distress related to bortezomib.
Some patients, therefore, will be unable to tolerate VRd. A very reasonable alternative in that situation is daratumumab in combination with lenalidomide and dexamethasone (DRd). In the phase III MAIA trial, DRd reduced the risk of progression or death by 44% compared with Rd in patients with newly diagnosed, transplant-ineligible myeloma. While the OS data are not yet mature, the triplet combination was well tolerated and is a good option for patients who are not able to receive a PI, for example because of pre-existing neuropathy.3
Dr. Kapoor: A modified “VRd lite†approach also has been adopted, primarily for older patients who are ineligible for transplant. This regimen involves a modified bortezomib and lenalidomide schedule to balance VRd’s survival benefit with the risk for long-term toxicities and the risk of discontinuation as a result of those toxicities.4
Bortezomib is effective in patients with certain high-risk features, and there are more data emerging that lenalidomide, particularly in combination with a PI, is valuable in this difficult-to-manage patient population. Although there are caveats associated with cross-trial comparisons, the results of DRd in the high-risk patient population in MAIA were not particularly encouraging, so a clinician cannot afford to omit a PI altogether, particularly in this subset of patients. The MAIA trial had its own limitations, particularly the hardwired bias in its design, using PFS as the primary endpoint, and using Rd as the control arm, which is no longer considered standard of care.5
Dr. Liedtke: Right, but I’ll point out that, in the SWOG S0777 study, even though the PFS numbers were higher for high-risk patients receiving VRd compared with Rd, the difference was not statistically significant, suggesting that VRd is not “the last word†when it comes to improving outcomes for patients with high-risk disease. However, I agree that the DRd regimen should be preferentially used in standard-risk patients, because there didn’t appear to be a benefit of DRd over Rd for high-risk patients.
Of note, one patient subgroup that was excluded from the SWOG S0777 study were patients with renal insufficiency, who are at higher risk for developing cytopenias related to lenalidomide. In addition, patients at very high risk for thromboembolic events may be unable to safely receive an IMiD. Under these circumstances, VRd is not the best choice, and we should develop other standards of care. A commonly used regimen in this situation is the combination of cyclophosphamide, a PI, and dexamethasone.
Dr. Kapoor: Generally, yes. However, there are already some data showing improvement in response rates with a PI and IMiD–based regimen, such as VTD, compared with cyclophosphamide, bortezomib, and dexamethasone (VCd) induction.6
In patients with light chain cast nephropathy, VCd is our go-to regimen, at least until their renal function improves and we can transition to a regimen such as VRd.
Dr. Liedtke: I agree with that approach. A European trial showed that VCd was associated with a lower VGPR rate compared with VTD, so I reserve VCd for patients with renal insufficiency or a high risk of thromboembolic disease.7
In patients who can tolerate a combination of lenalidomide, PI, and dexamethasone, an intriguing strategy is to replace the PI in VRd with carfilzomib and switch the regimen to carfilzomib, lenalidomide, and dexamethasone (KRd). Phase II data have shown that, across the board, the response rates with KRd are very high, with two-thirds of patients achieving a complete response (CR).8 The rate of minimal residual disease (MRD)–negativity also is much higher than what’s observed with VRd.
Dr. Kapoor: I agree, but that comparison is across trials and is based on phase II data, so we should take it with a grain of salt. Ideally, we would like to see these regimens being compared in head-to-head trials. The ongoing phase III ENDURANCE trial (E1A11) is comparing VRd with KRd in standard-risk patients and in patients with t(4;14).9 It has recently completed accrual, and we are eagerly awaiting the initial results, as these regimens reflect the current standard of practice in the U.S.