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Division of Cancer Medicine
Department of Lymphoma/Myeloma
The University of Texas MD Anderson Cancer Center
Elisabet E. Manasanch, MD, has disclosed that she has received consulting fees from Celgene, Janssen, and Sanofi and funds for research support from Merck, Quest Diagnostics and Sanofi.
Treatment options for patients with multiple myeloma (MM) continue to expand at a rapid pace. In this commentary, I share insights on important new findings from recent clinical trials in newly diagnosed MM, how we might interpret these data for clinical practice, and provide some insight into what the future may hold.
My Management Approach for Initial Therapy: ASCT Eligible Patients
Standard induction therapy for most patients with newly diagnosed myeloma consists of a proteasome inhibitor, either bortezomib or carfilzomib, combined with the immunomodulatory drug (IMiD) lenalidomide and dexamethasone (Rd). In my clinical practice, I most often use carfilzomib plus Rd (KRd), in part for the goal of measurable residual disease (MRD) negativity but also because this regimen has a lower risk of neuropathy than bortezomib plus Rd (VRd), which is very important for patients and allows a longer duration of treatment. Recently, there have been a few studies that may give some insight into the future of the treatment of newly diagnosed MM. I believe that we are moving toward using quadruplet treatment regimens, based on data from the CASSIOPEIA trial and other smaller studies with an IMiD, a proteasome inhibitor, a steroid, and an antibody that have shown deep levels of remission in most patients.
I continue to recommend transplant upfront for most patients with newly diagnosed MM, an approach confirmed by the phase II FORTE study, in which KRd as both induction (before autologous stem cell transplant [ASCT]) and consolidation (after ASCT) provided higher persistent MRD negativity rates compared with 12 cycles of KRd without ASCT.
Results From FORTE: KRd as Induction Therapy
The phase II FORTE trial demonstrates the effectiveness of KRd as an induction regimen: response rates after induction therapy showed 73% of patients achieved ≥ VGPR with 4 cycles of KRd (vs 57% with carfilzomib/cyclophosphamide/dexamethasone [KCd]). Recently presented data also showed that premaintenance response rates to KRd with or without ASCT were very similar in the overall population (≥ VGPR: 89% vs 87%, respectively) whereas KCd followed by ASCT had a lower response rate (≥ VGPR: 76%). This was true regardless of risk status; the response rates and depth of response remained comparable between the treatment arms. However, if we look at the 1-year MRD negativity rate, persistent MRD negativity may be more likely with KRd followed by ASCT compared with KRd and no ASCT, particularly in the patients with revised International Staging System (R-ISS) stage II/III disease (90% with KRd and ASCT vs 72% with KRd and no ASCT).
Results From CASSIOPEIA: Quad Induction With D-VTd
As mentioned, the ongoing phase III CASSIOPEIA trial in France is exploring the efficacy of a quadruplet combination of a proteasome inhibitor (bortezomib), an IMiD (thalidomide), a steroid (dexamethasone), and an antibody (daratumumab; anti-CD38) (D-VTd) with ASCT vs standard VTd triplet consolidation therapy in newly diagnosed patients with MM. Results from CASSIOPEIA showed that adding daratumumab to VTd as both induction (before ASCT) and consolidation (after ASCT) significantly improves PFS and the depth of response. The ORR with D-VTd was 93% vs 90% with VTd, and the rate of ≥ VGPR was 84% vs 78%, respectively. The rate of MRD negativity was 64% in patients who received D-VTd vs 44% with VTd alone.
An MRD negativity rate > 60% is excellent in MM, and as demonstrated in CASSIOPEIA, adding daratumumab to VTd provides a meaningful MRD benefit for patients with newly diagnosed MM. Furthermore, the high rate of persistent 1-year MRD negativity reported in FORTE highlights the effectiveness of KRd as induction therapy, with or without ASCT, for patients as well.
ASCT: When Is the Right Time?
For eligible patients, the question is usually when—not if—a patient with MM should undergo ASCT. I recommend that all eligible patients be evaluated by a transplantation specialist and have stem cells collected upfront regardless of when ASCT is planned. Multiple studies have shown that upfront ASCT can delay remission, particularly when newer agents are added to induction and consolidation as we saw in both the FORTE and CASSIOPEIA trials.
A typical newly diagnosed patient with MM considering transplantation has no high‑risk FISH abnormalities, has approximately 60% plasma cell involvement, and is stage I. For these lower-risk patients, newer agents are generating responses that may be similar to bortezomib/lenalidomide/dexamethasone plus upfront ASCT, but it is still important to explain to these patients why the need to collect stem cells remains: MM changes over time, and so although their disease may be low risk currently, the disease can change and may not be low risk a few years from now. It is important to harvest stem cells early to retain the option of a later transplantation.
In my clinic, I typically recommend that newly diagnosed patients with MM receive ASCT because it can increase the time to first relapse, which is very important. For patients that decline ASCT, I will give initial therapy for 8-10 cycles instead of the standard 4-6 cycles before beginning maintenance therapy. For patients with high‑risk MM who do not choose transplantation, I continue treatment as long as possible because they will likely relapse very soon without ongoing treatment. That said, most patients with high-risk features do want an ASCT with a goal of a long first remission.
Managing ASCT-Ineligible Patients: Triple Therapy With Daratumumab
Older patients who are diagnosed with MM often have multiple comorbidities, are more at risk of toxicities from MM therapy, may not be able to tolerate agents like high-dose melphalan for ASCT, and may not be candidates for ASCT. Fortunately, we now have options for transplant-ineligible patients. For example, daratumumab plus Rd (DRd) was recently approved in this setting based on the phase III MAIA study, which compared DRd with Rd alone in ASCT-ineligible patients with newly diagnosed MM. Results demonstrated that triplet therapy substantially reduced the risk of progression by 44%. In addition, combining daratumumab with Rd improved the depth of response: The MRD-negative rate was 24% with DRd vs 7% with Rd. In patients younger than 75 years of age the MRD-negative rate with DRd was 27.9% vs 19.4% in older patients, whereas in both age groups, the MRD-negative rate with Rd was approximately 7.5%.
Many of these patients may also be able to tolerate regimens like KRd without ASCT, and we should not discount the use of proteasome inhibitors for these patients as they remain a key backbone in MM treatment. In my clinical practice, I continue to use KRd for my older patients who can tolerate this therapy and rely on DRd for those who cannot tolerate a proteasome inhibitor, since adverse events tend to be more tolerable with the antibody.
For a standard-risk or low-risk patient who is eligible for ASCT, I usually give 6 cycles of KRd followed by ASCT in an effort to achieve MRD negativity before stem cell collection. Because KRd is not associated with major neuropathy, most patients can be treated for an extended period of 6 or even 8 cycles of KRd in this setting. After ASCT, if the patient is not high risk, I will recommend lenalidomide as maintenance therapy.
For patients with high-risk disease, I recommend 6-8 cycles of KRd followed by ASCT and then continuing KRd as maintenance for as long as feasible. After progression, a daratumumab-containing regimen is an option (eg, daratumumab/pomalidomide/
dexamethasone) followed by a second transplant.
For patients who are ineligible for ASCT, I recommend continuous treatment with KRd for those who can tolerate this therapy or consider other regimens, such as VRd or DRd, based on the patient’s comorbidities and adverse events concerns.
What are your biggest challenges regarding choosing frontline therapy for MM in your practice? Please share your thoughts in the comments box below.