More Options, More Questions: Debating the Optimal Frontline Regimen for Multiple Myeloma

As part of the 2019 ASH Meeting on Hematologic Malignancies held September 6-7 in Chicago, experts were invited to discuss challenging patient care questions, showcasing their respective evidence-based treatment approaches in “How I Treat”–style presentations. Here, Prashant Kapoor, MD, and Michaela Liedtke, MD, revisit their debate about the best initial therapy for patients with newly diagnosed multiple myeloma (MM), discussing several of the approved triplet regimens, as well as quadruplet regimens under investigation.

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.

Dr. Kapoor: Certainly. In the high-risk patient population, achieving as deep a response as possible should be the initial goal, because we know that the depth of response is important. More critical, however, is maintaining that deep response, because it correlates with survival outcomes. The KRd regimen has shown exceedingly high response rates and MRD-negativity rates, particularly when used in conjunction with AHCT and as post-transplant consolidation and maintenance. If ENDURANCE shows that KRd is superior in the standard-risk patient population, then that finding would be practice-changing, particularly in the U.S., where clinicians have easy access to both KRd and VRd.

Dr. Liedtke: Yes, it’s important to give more intensive therapy for patients who are young, are transplant-eligible, and have high-risk MM to control their disease as quickly and as deeply as possible. I would consider using the triplet of KRd followed by AHCT, given the apparent trend toward much higher MRD and response rates in phase II trials. In this regard it will be interesting to follow the results of the FORTE trial, which is evaluating three combinations: KRd with transplant followed by KRd consolidation; KRd without transplant; and carfilzomib, cyclophosphamide, dexamethasone (KCd) with transplant followed by KCd consolidation.

Dr. Kapoor: The preliminary results of the FORTE trial that were presented at the 2018 ASH annual meeting and the 2019 American Society of Clinical Oncology annual meeting were indeed quite enlightening.¹⁰ First, the KRd regimen was superior to KCd as induction therapy. Second, AHCT remains the cornerstone of the initial approach in the transplant-eligible patient population, even in this era. Third, substituting AHCT with an additional four cycles of KRd is not adequate, because patients with high-risk disease initially assigned to the KRd non-AHCT arm exhibited an increased risk of early relapse despite comparable response rates and depths of response.

We can’t forget that a clinician’s approach also varies by geographic location. In Europe, patients older than 65 or 70 years at the time of diagnosis are considered transplant-ineligible; in the U.S., we consider the patient’s comorbidities plus the physiological age, rather than the chronological age, unless the patient is in his or her late 70s or older. It is crucial to remember that the older population also benefits from AHCT.

We always recommend that hematologists/oncologists refer patients for consideration of AHCT early during the disease course, even if they are unsure about the transplant eligibility because seemingly ineligible patients could become transplant eligible once their performance status improves with induction therapy. By contrast, patients who are eligible at diagnosis may become ineligible at relapse; delaying transplant may not be an advisable strategy to pursue.

While we haven’t seen an OS benefit with early versus delayed transplant, my approach is to typically take patients through transplant early, after three to four cycles of induction. This approach has been associated with a PFS benefit and, moreover, as I said before, the patient’s transplant eligibility status may reverse over time.

For patients who are considered transplant-eligible, our next step is guided by the patient’s myeloma risk status. If a patient has standard-risk disease, outside of a clinical trial, induction with three or four cycles of VRd is a commonly used option. After this, the patient could undergo stem cell mobilization. Once an adequate number of stem cells have been collected, we proceed with AHCT early on, unless the patient prefers to delay it. Typically, we follow this approach in standard-risk patients, with lenalidomide maintenance until disease progression or intolerable side effects of lenalidomide.

However, if a patient has high-risk disease features – such as del17p, t(14;16) or t(14;20), double- or triple-hit MM, or other high-risk genetic abnormalities – I would use KRd induction followed by AHCT and a PI-based consolidation and maintenance.

Dr. Liedtke: Quadruplet regimens also are being explored in frontline treatment, particularly in younger patients. For example, the CASSIOPEIA trial compared VTD with or without daratumumab (DVTD) in 1,085 transplant-eligible patients. Following induction, patients proceeded to AHCT, followed by two cycles of consolidation with either VTD or DVTD, and either observation or maintenance with daratumumab.¹¹

In the preliminary analysis, the data were in favor of the quadruplet regimen, with patients in the DVTD arm experiencing a stringent CR rate of 29%, compared with 20% in the control arm (p=0.001). Among patients who were MRD-negative, the CR rate was higher: 34% in the quadruplet versus about 20% with the triplet.

Although it’s early, and this regimen has not yet been approved for newly diagnosed transplant-eligible patients, we have already seen a PFS difference. At 18 months, 93% of DVTD-treated patients were alive and progression-free, versus 85% with VTD.

GRIFFIN is another study that looks at a daratumumab-based quadruplet regimen, combining daratumumab with VRd, our standard regimen in the U.S.¹² So far, only preliminary results from the safety run-in phase have been presented, but at the end of induction therapy, 94% of the 16 patients enrolled responded to treatment, with 56% of patients achieving at least a VGPR.

Dr. Kapoor: There are other ongoing trials with quadruplet regimens, including one evaluating the oral PI ixazomib plus Rd plus intravenous daratumumab, followed by ixazomib plus daratumumab maintenance.¹³ In the phase II part of S1211, elotuzumab plus VRd (Elo-VRd) is being compared with VRd in high-risk myeloma and the results are awaited.¹⁴ Another open-label, single arm, phase IIa study using Elo-VRd quadruplet in patients with newly diagnosed myeloma dampened enthusiasm when it reported deaths due to sepsis and respiratory failure.¹⁵

Dr. Liedtke: Another quadruplet regimen – daratumumab plus bortezomib, melphalan, and prednisone (VMP) – has been evaluated in the ALCYONE trial, which randomized more than 700 patients.¹³ Compared with the VMP group, the response rates, MRD-negativity rates, and 18-month PFS rates were higher in the quadruplet group. This is not a commonly used regimen because it contains melphalan, but it’s a good example of a quadruplet regimen that appears to be quite tolerable and is resulting in better outcomes.

Dr. Kapoor: I agree; in the U.S., melphalan is not commonly used in the frontline setting because it’s a stem cell toxic agent. Besides, there are more tolerable nonchemotherapy–based options incorporating a PI and an IMiD or a monoclonal antibody and an IMiD. The ALCYONE regimen was built upon the VMP backbone, which has been predominantly used in certain parts of Europe, and, despite the positive trial results, it hasn’t caught on in the U.S.

References

1. Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389:519-27.
2. Dachs LR, Hebraud B, Oriol A, et al. Integrated analysis of randomized controlled trials evaluating bortezomib + lenalidomide + dexamethasone or bortezomib + thalidomide + dexamethasone induction in transplant-eligible newly diagnosed multiple myeloma. Blood. 2018;132:3245.
3. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-31.
4. O’Donnell EK, Laubach JP, Yee AJ, et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol. 2018;182:222-30.
5. Kapoor P, Rajkumar SV. MAIA under the microscope – bringing trial design into focus. Nat Rev Clin Oncol. 2019;16:339-40.
6. Jimenez-Zepeda V, Bahlis NJ, Duggan P, et al. Cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared to bortezomib, thalidomide and dexamethasone (VTD) as induction therapy for the treatment of transplant eligible multiple myeloma. Blood. 2016;128:4505.
7. Moreau P, Hulin C, Macro M, et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016;127:2569-74.
8. Roussel M, Lauwers-Cances V, Robillard N, et al. Frontline therapy with carfilzomib, lenalidomide, and dexamethasone (KRd) induction followed by autologous stem cell transplantation, Krd consolidation and lenalidomide maintenance in newly diagnosed multiple myeloma (NDMM) patients: primary results of the Intergroupe Francophone Du MyéLome (IFM) Krd phase II study. Blood. 2016;128:1142.
9. ClinicalTrials.gov. Bortezomib or carfilzomib with lenalidomide and dexamethasone in treating patients with newly diagnosed multiple myeloma. NCT01863550. Accessed August 29, 2019, from https://clinicaltrials.gov/ct2/show/NCT01863550.
10. Gay F, Cerrato C, Petrucci MT, et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial. Abstract #8002. Presented at the 2019 ASCO Annual Meeting, June 2, 2019; Chicago, IL.
11. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394:29-38.
12. Vorhees PM, Rodriguez C, Reeves B, et al. Efficacy and updated safety analysis of a safety run-in cohort from Griffin, a phase 2 randomized study of daratumumab (Dara), bortezomib (V), lenalidomide (R), and dexamethasone (D; Dara-Vrd) vs. Vrd in patients (Pts) with newly diagnosed (ND) multiple myeloma (MM) eligible for high-dose therapy (HDT) and autologous stem cell transplantation (ASCT). Blood. 2018;132:151.
13. Kumar SK, Berdeja JG, Niesvizky R, et al. Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including ixazomib maintenance. Leukemia. 2019;33:1736-46.
14. Usmani SZ, Sexton R, Ailawadhi S, et al. Phase I safety data of lenalidomide, bortezomib, dexamethasone, and elotuzumab as induction therapy for newly diagnosed symptomatic multiple myeloma: SWOG S1211. Blood Cancer J. 2015;5:e334.
15. Laubach J, Nooka AK, Cole C, et al. An open-label, single arm, phase IIa study of bortezomib, lenalidomide, dexamethasone, and elotuzumab in newly diagnosed multiple myeloma. J Clin Oncol. 2017;35(suppl 15):8002.