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Triplet or Quad Therapy for MM?
Triplets and Quadruple Combination Therapy in Multiple Myeloma: When, Why, and How?

Released: May 16, 2017

Expiration: May 15, 2018

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With multiple recent approvals of new agents for myeloma, we now have many options for treating our patients with newly diagnosed and relapsed/refractory myeloma. Despite this range of choices, the use of triplet regimens beginning with newly diagnosed disease means that many classes of agents are being used early and most patients will continue to relapse, requiring subsequent treatment. Although using triplet combinations has extended the time to next relapse, patients are also quickly running through their list of potential treatment options.

How First-line Treatment Affects Subsequent Therapy
Combination therapy with bortezomib/lenalidomide/dexamethasone (VRd) has increasingly become the preferred initial therapy for newly diagnosed myeloma based on the randomized phase III SWOG S0777 trial that clearly demonstrated an OS improvement when using a triplet regimen (VRd) vs a doublet regimen (lenalidomide/dexamethasone Rd). In addition to VRd, Zimmerman and colleagues presented phase II data at ASH 2016 showing that carfilzomib/lenalidomide/dexamethasone (KRd) plus autologous stem cell transplantation in 76 newly diagnosed patients produced a 3‑year OS rate of 95% and a 3‑year PFS rate of 86%. These survival findings are unprecedented but need to be validated in phase III randomized trials. Nevertheless, these data are compelling and support the use of potent triplet combinations like KRd or VRd in the frontline setting.

However, once a patient relapses after one of these powerful triplet combinations, there is a lower chance of bringing that patient into another deep and sustained remission with just a doublet or, in some cases, even another triplet, and the question becomes whether there is benefit when these agents are reused in the relapsed setting. One concept in younger, fit, and heavily pretreated patients with multiple relapses is the use of a quadruple combination of multiple drugs at lower doses to attenuate the potential adverse events while remaining very effective and overcoming drug resistance.

Combination Approaches With New Agents in Myeloma 
Daratumumab is an ideal partner to add to an existing combination after resistance develops due to its proven efficacy and tolerable adverse event profile. The combinations of daratumumab with bortezomib/dexamethasone (Vd) in the CASTOR trial and with Rd in the POLLUX trial produced excellent efficacy and safety profiles. In both cases, the addition of daratumumab improved the response rate and increased the median PFS and OS by approximately two thirds vs doublet therapy. Similarly, results with daratumumab plus pomalidomide/dexamethasone were excellent in this population, and all of these trials showed improvement in response rates in favor of daratumumab with only minor added toxicity.

In these trials, approximately 45% to 50% of patients experienced infusion-related reactions (mostly grade 1/2), and grade 3/4 neutropenia occurred more frequently with patients receiving daratumumab vs the control arms (13% vs 4% with Vd and 52% vs 37% with Rd). Otherwise daratumumab was relatively well tolerated, even in older patients, and the potential adverse events can be managed. The neutropenia associated with daratumumab is relatively short lived, and most often seen when daratumumab is used in combinations that include an immunomodulatory drug (IMiD). If neutropenia does occur in my patients, IMiD treatment should be held and growth factor support should be started. Once the neutropenia resolves, the IMiD can be restarted at a lower dose and is usually much better tolerated.

Infusion reactions relating to daratumumab can be successfully managed with early interventions such as decreasing the rate of infusion or interrupting the infusion, along with the use of the preinfusion and postinfusion steroids and preinfusion antihistamine and acetaminophen. Currently, daratumumab is given IV, resulting in the relatively high rate of infusion-related reactions, but the phase Ib PAVO study is evaluating 2 doses of SC daratumumab—1200 mg vs 1800 mg—in patients with relapsed/refractory myeloma. Interim results show a reduction in the rate of infusion‑related reactions, from nearly 50% with IV daratumumab to 24% at the 1800-mg SC dose. Another advantage of SC daratumumab is the dramatically shortened infusion time, as the first IV infusion takes 7 hours, but with SC daratumumab, the infusion time could drop to 2-3 hours.

Likewise, combination of the PO second-generation boronic acid–based proteasome inhibitor ixazomib with Rd (IRd) has shown an impressive efficacy advantage compared with Rd alone in the phase III TOURMALINE-MM1 trial, which showed a 35% improvement in PFS vs Rd alone. However, no patients in this trial were refractory to lenalidomide or a proteasome inhibitor at enrollment. In the phase III ELOQUENT-2 trial, in patients with relatively indolent disease at relapse after 1-3 previous lines of therapy, the combination of elotuzumab plus Rd was found to be superior to Rd alone, with a relative improvement in PFS of 44% by Year 3.

For patients who have limited options—meaning they have exhausted or are not responsive to combination treatments with standard IMiD/proteasome inhibitor combinations—quadruple combination approaches with multiple agents might provide a chance for another remission. In these patients, combining our best available drugs, like pomalidomide, ixazomib or carfilzomib, dexamethasone, and daratumumab, may induce another remission. In the future, daratumumab may also potentially be combined with drugs in other classes, such as the BCL2 inhibitor venetoclax.

Currently, there are no later-phase clinical data using these quadruple combination approaches, but some of these combinations are already being tested in patients with myeloma. The phase III Cassiopeia trial in France, for example, is evaluating the addition of daratumumab to bortezomib/thalidomide/dexamethasone in transplantation-eligible patients with newly diagnosed myeloma. Additional phase II trials are exploring daratumumab with VRd, daratumumab with IRd, and elotuzumab with VRd in newly diagnosed myeloma, and elotuzumab with pomalidomide/bortezomib/dexamethasone in relapsed/refractory myeloma. A phase I trial of elotuzumab with VRd showed the feasibility of this approach from a safety perspective, with no new additive adverse events beyond what is already expected with VRd.

How I Use Quadruple Combinations in Clinical Practice
In the past, I have used quad combinations to treat relapsed myeloma, especially in younger, fit patients who are not eligible for available clinical trials. A valid option for them is to give previously used therapies in combination at lower doses to avoid severe toxicity. Surprisingly, even in patients who are refractory to pomalidomide, another remission could be obtained by combining a lower dose of pomalidomide with ixazomib and daratumumab. In my opinion, the antimyeloma effect does not only depend on drug dosage but is also the result of a synergistic combination of agents and the targeting of multiple recurring clones.

I would not, however, give a quadruple combination to someone who is older than 80 years of age or in a frail condition. These regimens should be reserved for patients with a good performance status who have exhausted the existing treatment options.

To help you select optimal treatment for your patients with myeloma, my colleagues (Kenneth Anderson, MD; Carol Ann Huff, MD; Shaji Kumar, MD; and Sagar Lonial, MD) and I have created an interactive treatment decision aid, available here. This tool is designed to help you rapidly select individualized treatment options based on your patient’s specific disease characteristics and overall fitness by offering recommendations from each of the experienced faculty listed above specifically for the case you enter into the tool. If we enter the information for a fit patient who is refractory to the standard therapies of lenalidomide, bortezomib, and carfilzomib into this tool, expert recommendations for next treatment vary but include the option of quadruple therapy with daratumumab plus IRd (Figure).


Figure. Expert Recommendations for a Patient With R/R MM Who is Refractory to Lenalidomide, Bortezomib, and Carfilzomib

Although multiple treatment approaches are reasonable options, consideration of quadruple therapy for specific patients who have relapsed on multiple therapies and require rapid disease control is a reasonable approach, particularly as clinical trials exploring these treatment modalities mature.

In the comment section below, let me know how you are currently managing your patients with myeloma who have progressed and are refractory to multiple available therapies.

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Would you consider using a quadruple regimen in a young, fit patient who had relapsed on multiple therapies to gain disease control?
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