Over the last decade, the evolution of myeloma therapy has led to the triplet being the preferred choice in many clinical settings. This has been most prevalent in the induction setting for transplant-eligible patients as well as the relapsed and refractory settings. Although this triumvirate comes in many forms; the combination of a steroid, an immunomodulatory drug, and a proteasome inhibitor (PI) is one of the mainstay industry standards. In November 2015, the US Food and Drug Administration approved 2 monoclonal antibodies (mAbs) for the treatment of multiple myeloma (MM): daratumumab (Dara) and Elotuzumab (Elo).1,2 As has become standard of care in other diseases such as lymphomas, the next logical step was to combine mAbs with the current standards. In turn, the myeloma landscape is now seeing triplets being promoted to quadruplets with the addition of Elo and Dara to the standard regimens. From an efficacy, toxicity, and cost standpoint, are 4-drug regimens here to stay?
Choice of induction therapy for MM (at the time of this publication) still remains intertwined with the notion of transplant-eligible patients versus transplant-ineligible patients, with the former currently more associated with triplet regimens and the latter frequently consisting of doublets.
The chart below details the key phase III randomized trials for newly diagnosed MM. Although there is a general trend toward improved overall response rate (ORR) as we evolve toward more triplets and even quadruplets, what is perhaps more notable is the depth of responses. We see a general increase in very good partial response (VGPR) and complete response (CR). The ability to achieve deeper remissions is what is likely yielding improvements in progression-free survival (PFS) and ultimately overall survival (OS). With the incorporation of novel therapies (with an emphasis on the mAbs), we can now combine 3- and 4-drug combinations and achieve deep and durable responses without adding significant toxicities3–11 (Table 1).
TRIPLET INDUCTION REGIMENS
The general gestalt for induction therapy for transplant-eligible patients in the modern day has been a triplet regimen. The more common therapeutic choices in the United States are bortezomib/cyclophosphamide/dexamethasone (CyBorD), bortezomib/lenalidomide/dexamethasone (VRd), and carfilzomib/lenalidomide/dexamethasone (KRd). These regimens have been associated with high ORR as well as manageable toxicities.
Bortezomib/cyclophosphamide/dexamethasone has been widely used as an induction regimen given the ability for urgent administration as well as ease of dosing in patients with renal impairment. The regimen is associated with high rates of response (ORR; 90%) as well as deep remissions with VGPR rates of 67% and near CR/CR rates of 41%.12 Ultimately, however, the combination of a PI (plus a steroid) appears to be superior when combined with an immunomodulatory drug as opposed to an alkylator. The IFM 2013-04 trial compared CyBorD with bortezomib/thalidomide/dexamethasone (VTD). The ORR was significantly higher in the VTD arm (92.3% vs. 83.4% in the CyBorD arm; P = 0.01); 66.3% of the patients in the VTD arm achieved at least a VGPR versus 56.2% in the CyBorD arm (P = 0.05). Hematologic toxicity was higher with CyBorD, with significantly increased rates of grades 3 and 4 anemia, thrombocytopenia, and neutropenia. However, the rate of peripheral neuropathy was significantly higher in the VTD arm.13
The Southwest Oncology Group 0777 trial evaluated the VRd regimen as compared with RD alone in the induction setting.10 The ORR was 82% (176/216) in the VRd group and 72% (153/214) in the lenalidomide, dexamethasone (Rd) group. The CR rate in the VRd group was 16% (34/216) and 8% (18/214) in the Rd cohort. Adverse events of grade 3 or higher were reported in 198 (82%) of 241 patients in the VRd group and 169 (75%) of 226 patients in the Rd group. Ultimately, 55 (23%) in the VRd group and 22 (10%) in the Rd group discontinued treatment because of adverse events (AEs).
With the advent of the next generation of PIs came the substitution of carfilzomib for bortezomib in the induction setting. Carfilzomib/lenalidomide/dexamethasone in a phase I/II study shows extreme promise and has been adopted by some as the induction regimen of choice. The ORR was 100%, and the PFS rates were 97% at 12 months and 92% at 24 months. The AE profile was manageable, and most patients did not require dose adjustment.14
Although ORR in the varied triplet induction regimens ranging from 90% to 100%, along with generally tolerable adverse effect profiles, the question of a need for a fourth drug arose. Would it deepen remissions and yield improvements in PFS/OS, and could it be done without significantly altering toxicity rates?
In a phase Ib/II trial, 64 transplant-eligible patients received a combination of carfilzomib/cyclophosphamide/thalidomide/dexamethasone.15 The maximum tolerated dose of carfilzomib in this protocol was achieved at the 20/36 mg/m2 level. The ORR was 91% with PFS and OS rates at 24 months of 76% and 96%, respectively. Adverse event rates were within acceptable parameters. Grade 3 or higher neutropenia and anemia rates were 23% and 20%. All peripheral neuropathy was grade 1, seen in 31% of patients, and attributed to thalidomide. All patients who attempted stem cell collection were successful. This regimen represents a highly efficacious approach with manageable AEs and given the pharmacokinetics and pharmacodynamics of the drug combination and represents an option for newly diagnosed MM patients with marrow and renal impairment.
The EVOLUTION trial sought to elucidate the risks and benefits of 3- and 4-drug combinations with lenalidomide (R), bortezomib (V), cyclophosphamide (C), and dexamethasone (D)16 (Table 2).
Although the study did not have the power for a robust comparison of the 4 different regimens, the data showed similar efficacies among the combinations. Notably, the VDCR regimen was associated with an increased rate of toxicity, specifically hematologic AEs. Rates of febrile neutropenia were low in all arms. Overall, the study did not show an advantage of a 4-drug regimen over its 3-drug counterpart. This may stem from the class of drugs available for combination at the time of the trial. The next path would look toward incorporation of mAbs into the induction paradigm.
Elotuzumab has been utilized in the relapsed and refractory setting of myeloma in combination with lenalidomide and dexamethasone.17 In an open-label phase IIa study, Laubach18 evaluated the combination of Elo plus bortezomib, lenalidomide, and dexamethasone (Elo-RVD) in newly diagnosed MM patients. Patients received 4 cycles of Elo-RVD and then underwent stem cell mobilization. Following this, they could either proceed with autologous stem cell transplant (ASCT) or defer transplant and receive 4 more cycles of induction therapy. Following either ASCT or 8 cycles of induction chemotherapy, patients transitioned to risk-adapted maintenance with Elo-Rd or Elo-RVD (high-risk cytogenetics, International Staging System stage II or III). The ORR after 4 cycles was 100%, with 24% achieving a CR, 47% achieving a VGPR, and 29% achieving a partial response (PR). Seventy-one percent of patients achieved a VGPR or better.
The regimen was associated with an acceptable toxicity profile, and stem cell collection was successful with an average collection of 10.3 × 106 CD34 cells/kg. Further follow-up time is needed to appropriately assess the PFS and OS rates. Ultimately, further studies are needed to elucidate the role of Elo in the upfront setting.
The addition of Dara to the KRd regimen was recently evaluated in the newly diagnosed setting.19 The dosing incorporated Dara at 16 mg/kg weekly for cycles 1 and 2, every 2 weeks on cycles 3 to 6, and every 4 weeks thereafter. The carfilzomib was dosed in a similar way as the A.R.R.O.W. trial20 at 20 mg/m2 on day 1 and then increasing to 70 mg/m2 on days 8 and 15 with subsequent cycles utilizing the 70-mg/m2 dose on days 1, 8, and 15. The ORR was 100% with 43% stringent CR, 14% CR, 33% VGPR, and 10% PR. Responses were noted to deepen over time/therapy. Left ventricular ejection fraction was monitored throughout the study without significant changes throughout therapy, except for 1 patient with a transient drop in left ventricular ejection fraction, who ultimately resumed therapy at a reduced dose of carfilzomib. The most common grade 3/4 treatment-emergent AEs included lymphopenia (14 [64%]), neutropenia (4 [18%]), diarrhea (4 [18%]), and pulmonary embolism (3 [14%]).
The trial yielded excellent responses with an acceptable AE profile. Head-to-head trials are needed to better evaluate the role of regimens, such as these, as compared with their non-mAb triplet counterparts. Minimal residual disease (MRD) analysis will be key in future studies as the benefit of the 4-drug approach may not be seen in significant improvements in ORR but in rates of MRD negativity.
UK NCRI MYELOMA XI TRIAL
The UK NCRI Myeloma XI trial is a large, phase III study comparing the induction quadruplet carfilzomib/cyclophosphamide/lenalidomide/dexamethasone to the triplet combinations: cytoxan/lenalidomide/dexamethasone or cytoxan/thalidomide/dexamethasone. There was additional pretransplant consolidation with PI triplet therapy for those with a suboptimal response. The patients in the triplet arms were then randomized to receive additional treatment based on initial response. Patients achieving an minor response or PR were randomized to receive CyBorD or nothing. Patients with stable disease or progressive disease all received sequential therapy with CyBorD. All patients receiving the quadruplet as well as the triplet patients who achieved a VGPR or better proceeded directly to transplant. The quadruplet was associated with a slightly higher rate of hematologic AEs; however, responses to treatment in this arm were both faster and deeper, with 92% of patients achieving a VGPR or better.21 Furthermore, there were no differences seen in mean CD34 selected stem cell harvests.
UPFRONT THERAPY FOR THE TRANSPLANT INELIGIBLE PATIENT
The transplant-ineligible population has, interestingly enough, had a fuller evaluation of the 3- versus 4-drug approach. The combination of bortezomib/melphalan/prednisone (VMP) was found to be superior to MP alone, in a large randomized study, in rates of CR, time to progression, and OS at 3 years.22 In a subsequent study, thalidomide was added to VMP and administered as the quadruplet of VMPT followed by velcade and thalidomide maintenance compared with VMP alone.
The 3-year PFS rate was 56% with VMPT compared with 41% with VMP. However, patients in the VMPT arm received maintenance therapy with bortezomib and thalidomide, whereas patients in the VMP arm did not receive any additional therapy beyond 9 months. Sensory neuropathy rates were not statistically different between the groups with rates of 8% and 5% in the VMPT and VMP arms, respectively. Of note, the CR rates were higher in the quadruplet at 38% compared with 24% in the triplet. This did not result in an improvement in 3-year OS rates. At the 3-year time mark, there was no difference seen in OS with rates of 89% with VMPT and 87% with VMP, respectively.
More recently, the standard VMP induction regimen was compared with Dara-VMP in the ALCYONE trial. The 18-month PFS rate was 71.6% in the Dara group and 50.2% in the control. The ORR was 90.9% in the quadruplet, as compared with 73.9% in the triplet. Daratumumab-VMP was also associated with a CR (or better) rate of 42.6% versus 24.4% with VMP. Furthermore, 22.3% of the patients in the Dara-VMP arm achieved MRD negativity. Hematologic AEs were comparable; however, the quadruplet was associated with higher rates of grade 3/4 infections, 23.1% versus 14.7%. Ultimately, because of the superiority of the quadruplet, Dara-VMP was approved by the US Food and Drug Administration on May 7, 2018.23
RELAPSED AND REFRACTORY MYELOMA
Although the necessity for a 4-drug regimen is debatable in the upfront setting, there are patients with such aggressive and refractory disease in the relapsed setting who all but require this approach for disease control. Histone deacetylase inhibitors are not widely used in day-to-day myeloma therapy, and although they have not demonstrated single-agent activity, they have been studied in 4-drug combinations in refractory patients.
In a phase I study, the QUAD regimen (carfilzomib/vorinostat/lenalidomide/dexamethasone) was studied in a dose-escalated fashion in relapsed and refractory MM. No dose limiting toxicities were observed, and the maximum tolerated dose was not reached. The maximum administered dose was carfilzomib 20/27 mg/m2, lenalidomide 25 mg, vorinostat 400 mg, and dexamethasone 40 mg. The ORR was 53%, with 12% of patients achieving a VGPR and 41% of patients achieving a PR. At the time of publication, the median follow-up was 10 months with a median PFS of 12 months and median OS of no response.24
The VERUMM study evaluated that the combination of vorinostat/bortezomib/doxorubicin/dexamethasone was admitted to elderly patients with relapsed disease. The ORR and clinical benefit rate amounted to 67% and 94%, respectively. At a median follow-up of 30.8 months, the median PFS and OS were 9.6 and 33.8 months. There were no nonhematologic grade 4 toxicities, and the remaining grade 3/4 toxicities were low in number and manageable.
Small case report studies have evaluated a number of quadruplet regimens in the relapsed setting including carfilzomib/pomalidomide/cyclophosphamide/dexamethasone25 and bortezomib/venetoclax/Dara/dexamethasone.26 Additional anecdotal data of single-patient (off study) outcomes on 4-drug combinations exist throughout the myeloma community. This information is hard to integrate into clinical practice, given the small numbers and retrospective nature of the data sets.
Below is a list of more than 20 trials currently listed on clinicaltrials.gov, all of which incorporate a quadruplet regimen either in the upfront or the relapsed/refractory setting. Whether 4-drug regimens are here to stay, there is certainly a desire to study them.
The relapsed setting has a strong argument for the utility of quadruplet regimens. In a landscape where the current dogma is that of an incurable disease with limited therapeutic options, drugs that synergize (and/or resensitize) with regimens that a patient may already be refractory to may offer a new chance of remission. Utilizing drugs such as histone deacetylase inhibitors (vorinostat and panobinostat) as well as nelfinavir in this setting may be able to extend duration of remissions in regimens where the tide is shifting.
From a transplant-ineligible standpoint, Dara-VMP clearly shows benefit and is being utilized as an induction regimen outside the United States. Within the United States, doublet regimens are far more common as induction therapy for this older and frailer group of patients.
Regarding the role of quadruplet induction in transplant-eligible patients, the jury is still out. Triplet-based induction regimens are associated with extremely high ORR, some approaching 100%. What has become clear is the importance of depth of response, especially in the upfront setting. There is evidence from the IFM2009 trial that patients achieving MRD negativity following induction therapy had similar outcomes whether they went on to receive ASCT.27 What follows from this is the potential for quadruplet regimens in the upfront settings to improve PFS and potentially OS via achieving deeper remissions without significant changes in ORR. Ultimately, this needs to be balanced by patient heterogeneity, tumor heterogeneity, toxicity profile, and cost.
Novel recombinations of previously refractory drugs also lend itself to the formation of quadruplet regimens in the refractory setting. The notion of combining drug A and drug B when the patient is already refractory to the individual drugs has become commonplace in the clinic. This was evaluated in the combination of Dara and pomalidomide in patients naive to both refractory to one (or the other) and refractory to both during disparate prior regimens. The ORRs were 89%, 49.9%, and 33.3%, respectively.28 We can both combine previously used therapies in novel ways with or without the addition of a fourth drug. This approach is already used at the bedside but requires prospective analysis to better elucidate the true risk/benefit profile (Table 3).
As our ability to better understand the heterogeneity of myeloma improves, so will our knowledge of who needs a doublet, who needs a triplet, and who needs a quadruplet. As to whether 4-drug regimens are here to stay in myeloma, it appears so.
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