Case-based roundtable on treatment approach for young, fit, newly diagnosed multiple myeloma patients

Mrs. K has active myeloma and meets the serum light chain or imaging abnormalities–hypercalcemia renal failure anemia bone lesions (SLiM-CRAB) criteria,²  but even if she were totally asymptomatic, she would still require therapy based on the new algorithm of definitions of active myeloma, since she has an abnormal involved-to-uninvolved serum free light chain ratio. Mrs. K has had an appropriate workup so far. She has had a comprehensive history and physical, along with basic laboratory tests, including a comprehensive myeloma panel, which would include immunoglobulin levels, serum protein electrophoresis, immune fixation, and urine light chains; and she has also had what we would call a basic radiologic evaluation with a skeletal bone survey, which remains the standard of care for now. New criteria from the International Myeloma Working Group will support using whole-body magnetic resonance imaging, positron emission tomography (PET) computed tomography (CT), or low-dose whole-body CT as alternative and likely recommended imaging strategies (Table 2).^3,4 

During the history and physical of a patient with newly diagnosed myeloma, there are some items that should be specifically addressed, as they impact our decision on how we treat Mrs. K. First, knowing whether there is a history of bleeding and clotting disorders is essential, because many of the medications we give for induction therapy of myeloma increase the risk of deep venous thrombosis and therefore require some form of anticoagulation, which may increase the risk of a bleeding complication. It is essential to know the status of different comorbidities (particularly cardiac, renal, and metabolic), which may affect the decision of what the optimal induction therapy is. Of particular note is a history of diabetes (particularly diabetes with nephropathy or neuropathy), prior stents, or cerebral vascular accident. A history of other malignancies that need to be dealt with during the treatment of myeloma is also essential, as well as signs of dysautonomia or signs of skin plaques, which may suggest the presence of concurrent amyloidosis on physical examination. Since most patients with myeloma will require extensive bisphosphonate, a history of dental extractions and a careful dental examination is also important. Many of us consider dental clearance before starting bisphosphonate therapy.

Since Mrs. K is mildly anemic, iron and vitamin studies are essential before beginning treatment. Testing for amyloid should be considered in patients with nephrotic-range proteinuria, unexplained peripheral neuropathy, and heart failure with preserved ejection fraction. Mrs. K has had a very appropriate and extensive workup,

This is a very commonly asked question today, particularly because we have a plethora of drugs. Drugs for myeloma today fall in the following categories: alkylating agents such as cyclophosphamide and melphalan; steroids such as dexamethasone and methylprednisolone; proteasome inhibitors that include bortezomib, carfilzomib, and ixazomib; the immunomodulatory drugs thalidomide, lenalidomide, and pomalidomide; and the monoclonal antibodies elotuzumab and daratumumab.⁵  There have been multiple randomized trials comparing double drug induction (usually an immunomodulatory drug [IMiD] and steroids or a proteasome inhibitor and steroids) vs triple induction, and IMiD, a proteasome inhibitor, and steroids or an alkylator with a proteasome inhibitor and steroids, or less frequently an alkylator, an IMiD, and steroids.

In the United States, the combination of lenalidomide bortezomib and dexamethasone is the most commonly used induction regimen for transplant-eligible patients. The SWOG-0777 trial⁶  compared induction therapy with RVd (lenalidomide, bortezomib, and dexamethasone) vs a doublet Rd (lenalidomide and dexamethasone). RVd showed not only a significant better overall response rate (81% vs 71%) but also a significantly improved complete remission rate (15.7% vs 8.4%). This depth-of-response benefit translated into not only a significant benefit in median progression-free survival (PFS) (43 months vs 30 months) but also, more importantly, a significant benefit in median overall survival (OS) (75 months vs 64 months). Other randomized trials have also shown that triple-therapy induction is superior to doublets.

So, what 3 drugs should be used? An alkylator, an IMiD, and steroids? An IMiD, a proteasome inhibitor, and steroids? The French IFM 2013-04 trial compared VTD (bortezomib, thalidomide, and dexamethasone) with CyBorD (bortezomib, cyclophosphamide, and dexamethasone). The overall response rate prior to consolidation therapy with a transplant was significantly better for the combination of an IMiD, proteasome inhibitor, and steroids (92% versus 83%), as was the complete response rate (13% vs 9%). Interestingly, the most common induction treatments that are currently being used in the United States are RVd and CyBorD.⁷ 

Recently, the CIBMTR performed a retrospective analysis looking at outcomes of patients according to the type of inductions they received. For patients undergoing an autologous transplant, both PFS and OS were similar for patients receiving either RVd or CyBorD. The 3-year probability of OS was 67% for RVd and 55% for CyBorD (statistically not significant). There was, however, a trend of improvement in the 3-year PFS for patients receiving RVd compared with CyBorD.⁸  There have been no randomized trials comparing RVd to CyBorD in transplant-eligible patients; however, based on the retrospective data we have, when possible, RVd should be used as induction treatment until we learn more about carfilzomib-based induction.⁹ 

I usually do 4 to 6 cycles before proceeding to collection and an autologous transplant. I recognize that the ideal number of cycles prior to transplant has yet to be resolved. Carfilzomib-based induction is now included in the National Comprehensive Cancer Network guidelines as a acceptable alternative for induction, although in my personal practice, I only use carfilzomib-based induction in the context of a clinical trial.^10-12  Carfilzomib, lenalidomide, and dexamethasone (KRD) is being evaluated in a prospective, randomized phase 3 trial by the Eastern Cooperative Oncology Group, but the earliest readout may be 3 or 4 years away.¹³ 

The anti-CD38 monoclonal antibody daratumumab is making its way into the front-line setting, with the first front-line US Food and Drug Administration approval in May 2018 of daratumumab in combination with bortezomib (velcade), melphalan, and prednisone for transplant-ineligible patients and thus would not be considered appropriate therapy for Mrs. K.^14-16 

The definition of high-risk disease in myeloma continues to evolve. In my practice, I consider patients with high-risk disease if they have R-ISS stage 3 or high-risk cytogenetic abnormalities (deletion 17p; t4,14, t6,14; t14,16; t14,20 and abnormalities of chromosome 1)¹⁷  (Table 3). On protocol, I am using induction with carfilzomib, lenalidomide, and dexamethasone with daratumumab. Off protocol, I am recommending RVd; however, I recognize that the KRd data demonstrating similar 1- and 2-year PFS and OS for standard- and high-risk patients makes it a very appealing regimen for patients with high-risk disease, and since it has been included in the National Comprehensive Cancer Network guideline, it can be used in the United States.^11,12 

For patients with nephrotic-range proteinuria, or for patients with renal failure primarily, I tend to use CyBorD as the primary induction.^13-32  I have made a point to use lenalidomide (particularly after the patient has been stabilized or if patients have a suboptimal response), but one must dose-adjust according to creatinine.¹⁸ 

In the absence of prospective randomized trials comparing 4 cycles to 6 cycles to a response-guided strategy, we are left with only retrospective data. The largest series is from the Mayo Clinic, where 596 patients were analyzed. The median PFS in patients whose induction therapy was ≤ 4 months was 28 months (95% confidence interval [CI], 25-33], compared with 26 months for patients whose induction therapy was >4 months (95% CI, 24-31) (P = .605). There was no significant difference in OS in the 2 groups (P = .904)¹⁹  Although intuitively correct, the practice of delaying autologous hematopoietic cell transplantation (HCT) to deepen to response prior to HCT by changing the induction regimen is also not supported by retrospective analysis. Vij et al identified 539 patients in the CIBMTR database that underwent an autologous HCT having achieved less than a partial response (PR) to first-line induction chemotherapy between 1995 and 2010. Additional pretransplant chemotherapy resulted in deepening responses in 68% of patients, but on multivariate analysis, there was no impact of further pretransplant salvage chemotherapy on treatment-related mortality, risk of relapse, PFS, or OS.²⁰  The inherent biases in both of these retrospective analyses precludes definitive conclusions. In my practice, I recommend 4 to 6 cycles before collection of stem cells and proceeding to autologous HCT. In conclusion, for patients achieving a less than PR to initial induction therapy, including with novel agent combinations, additional pre–autologous stem cell transplantation (pre-ASCT) salvage chemotherapy improved the depth of response and pre–ASCT disease status but was not associated with survival benefit.

Two randomized trials have explored the question of early vs late transplantation in the context of modern induction therapies. In the EMN/HOVON-95 trial, patients who received CyBorD induction for 4 cycles (21-day cycles) underwent Cytoxan mobilization and then were randomized to continuous chemotherapy with bortezomib, melphalan, and prednisone vs 1 or 2 courses of high-dose melphalan (HDM)/ASCT.²¹  A second randomization included consolidation therapy with VRD for 2 cycles or no consolidation therapy with all patients receiving lenalidomide maintenance. This trial, which has been presented at recent meetings of the American Society of Hematology, showed a significant benefit in PFS for patients receiving the high-dose therapy. More importantly, for patients with high-risk disease, either translocation (4;14), translocation (14;16), deletion 17p, or ISS stage 3, there was an OS benefit. The IFM2009 study, also showing a significant PFS benefit for patients receiving early HDM/ASCT, with a median PFS that improves on average of ∼9 months, and at the 4-year mark, ∼40% percent of the patients were still in complete response after HDM/ASCT, compared with ∼30% of patients who did not receive it.²²  Thus, I think that the preponderance of data shows a significant benefit for patients getting early transplantation.

Now, having said that, I am the first to recognize that transplant is a choice. It is a choice the patient makes based on the recommendations that we give them. However, patients need to be informed that there is a price to pay for deciding to delay transplantation; 20% of patients who were randomized to delay transplantation did not undergo a transplant as salvage when they relapsed, and most of patients had to undergo auto HCT within the first 2 years after randomization to a delayed transplant. In my practice, I strongly encourage all patients to proceed to early transplantation, but in patients with low-risk disease who have achieved a complete response to induction therapy, I recognize that long-term disease control is achievable without autologous HCT.

What we have recognized, regardless of whether you are looking at flow cytometry or sequencing, is that MRD testing can identify patients who are going to have better PFS and OS.²²  Essentially, what I believe is happening is we have been thinking that complete response or getting to complete response is what confers the better prognosis in our patients. However, the MRD studies are showing us the achievement of MRD negativity is an even more powerful prognostic factor.²³  It is important to underscore that even in patients with MRD negativity, the disease still recurs; what is still uncertain is whether further intensification of patients who are MRD negative will provide clinical benefit, and this will need to be studied prospectively.

Lastly, it is also important to recognize that we are still significantly underutilizing transplant in the United States today, and there are multiple barriers to access that need to be addressed.^24,25  I think as key opinion leaders, we really need to go out and remind patients and other community oncologists that there is a significant benefit for early transplant that is starting to emerge and that that benefit comes at the time when patients have the lowest disease burden and they are in the best condition, which usually is right after induction therapy.

We now have 2 randomized trials. The first one is the EMN/HOVON trial, which showed that there was a potential benefit for tandem transplants in patients with multiple myeloma who went through an early transplant. Some centers randomized patients to a single vs double transplant. Patients who were randomized to a tandem transplant actually had a significant improvement in their PFS.²¹  In contrast, in North America, the StaMINA trial randomized 750 patients to 1 of 3 arms after HDM/ASCT: lenalidomide maintenance, consolidation with 4 cycles of RVd followed by lenalidomide maintenance, or a second (tandem) HDM/ASCT followed by lenalidomide maintenance. The 38-month PFS was the same in all 3 arms; the OS also appears to be the same, and perhaps with longer follow-up, this may change. The trial has been criticized primarily because 30% of the patients randomized to the tandem HDM/ASCT did not receive that intervention, and the groups of patients were different, because patients were allowed to enroll in the study any time within a 4- to 12-month period of having started any induction chemotherapy.²⁶ 

From a US practice standpoint, it is hard to justify tandem transplant or further posttransplant consolidation therapy. One can assume that some of the differences between the StaMINA trial and the EMN02 study were that lenalidomide was not part of the induction therapy in the clinical trial and patients in the StaMINA trial were allowed to receive a variety of induction treatments. In addition, patients were allowed to register on StaMINA anywhere between 4 and 12 months of beginning induction chemotherapy; thus, the patients who participated in the StaMINA trial are likely to be different from those who participated in the EMN02 trial. In the United States, the practice is not going to shift toward tandem transplants in general, even for high-risk patients, unless we start seeing that subset of patients benefiting from tandem transplants in a long-term follow-up of the 0702 trial.

Today, given the preponderance of data between all randomized trials, the meta-analysis would suggest that lenalidomide maintenance should be considered the standard of care.²⁷  My standard is to start lenalidomide by 5 mg for 21 days out of a 28-day cycle ∼90 days posttransplant. If the counts tolerate this dose well, then I go up to 10 mg for 21 of 28 days. I try to make sure that patients do not have any serious side effects. For patients who get gastrointestinal disturbance or diarrhea, I start them on cholestyramine as a way of mitigating that symptomatology. I have found that most patients can tolerate 5 to 10 mg maintenance dosing.²⁸  On only rare occasions am I combining lenalidomide with a proteasome inhibitor for patients with high-risk disease, although more and more, I am considering this might be, based on the data from Emory, a reasonable approach.²⁹ 

Lenalidomide maintenance is generally well tolerated. Cytopenias can be seen and should be monitored for, particularly early after HCT. Patients should be advised to hold lenalidomide during upper respiratory tract or other infectious episodes. Diarrhea, which is a common side effect leading to discontinuation, can be managed with cholestyramine or dietary manipulation. Rash and fatigue have also been reported. The current standard of care is to continue lenalidomide until progression or patient intolerance. Of note, all patients should be advised of the risk of second primary malignancies that may occur with lenalidomide maintenance. These malignancies are usually hematologic and usually occur during the first 3 years of maintenance.

We currently have a series of phase 2 trials in patients who have MRD positivity and are still in a plateaus phase on lenalidomide maintenance to look at the potential value of adding another agent to try to upgrade the response and increase the fraction of patients who achieve an MRD-negative state. Outside of that, the main reason to use MRD positivity is to encourage patients to remain on lenalidomide maintenance therapy and be compliant. On rare occasions, I have stopped maintenance in patients who are MRD negative who have significant intolerance to lenalidomide maintenance.

Mrs. K is now relapsing. There are 4 patterns of relapse: biochemical or asymptomatic relapse; the classical relapse, which shows with a paraprotein progression and organ damage; the plasma cell leukemic relapse; and the extramedullary relapse.³⁰  All of these are associated with a different prognosis.

Mrs. K is now relapsing, and it is important to document whether she has a clinical or biochemical relapse to determine the urgency of reestablishing disease control. In patients who present with high-risk disease, I have serious conversations about proceeding to triple reinduction, consolidation, and maintenance, even if they only have a biochemical relapse. In Mrs. K’s case, based on the CASTOR and POLLUX data, I would propose a daratumumab-containing regimen (either daratumumab, bortezomib, and dexamethasone or daratumumab, lenalidomide, and dexamethasone).^32,33  Since she has been on lenalidomide maintenance, I would probably like to do the change in class and thus reinduce her with 4 cycles of daratumumab, bortezomib, and dexamethasone and, depending on her response, consider a second autograft, continued treatment, or even an allogeneic HCT (particularly if she had a suboptimal response to treatment). Based on the CASTOR and POLLUX trial data, Mrs. K should have an 80% chance of achieving a PR and a 60% chance of a very good PR. Of note, 3 recent meta-analysis have been published suggesting that among all available salvage regimens, daratumumab-based combinations were associated with superior outcomes^34-36 

My philosophy has been that the depth of response is important at every stage of the disease. For frontline therapy, depth of response predicts long-term PFS. For salvage therapy, depth of response also predicts outcome.³⁷  I do think that this is an area where response-adapted treatment is very appropriate. We all recognize that there is a significant burden of treatment but that the benefits in regard to PFS are significant for patients achieving a major response to salvage therapy; thus, consideration of another high-dose melphalan consolidation with autologous HCT in a patient like Mrs. K is very appropriate. Based on retrospective data from single and registry analysis and the UK-MRC data with high-dose melphalan consolidation, I would strongly encourage Mrs. K to proceed to a second autologous transplant.^38,39  I would seriously consider an allogeneic HCT if she had a suboptimal response to salvage or a short second remission duration.

I recognize that allogeneic transplants should be explored in the context of a clinical trial whenever possible, but if a clinical trial is not available, then I believe that serious considerations should be given to allografting, particularly for young patients with multiply relapse disease. The evidence to support this practice is primarily retrospective but includes the following:

1. Large registry analysis showing long-term disease control and likely cures for allograft recipients, even in the setting of multiple relapses.^38-40 

2. Retrospective donor vs no-donor comparisons from the Italian myeloma group showing a potential advantage for allografting in which long term outcomes of 169 patients with multiple myeloma in first relapse after failing autologous HCT were compared with 90 patients without a donor who were treated with multiple lines of salvage treatment with bortezomib and/or immunomodulatory agents. PFS at 7 years was 18% in the donor group and 0% in the no-donor group. OS at 7 years was 31% in the donor group and 9% in the no-donor group. By multivariate analysis, chemosensitivity to salvage treatments and presence of a suitable donor were significantly associated with better PFS and OS.⁴¹ 

3. The potential for improved postrelapse survival in allograft recipients as demonstrated by a recent retrospective analysis of the CIBMTR comparing postrelapse OS after autologous/allogeneic HCT vs tandem autologous HCT. The 6-year postrelapse OS was better in the auto/allo group than in the auto/auto group (44% vs 35%; P = .05). The authors hypothesize that this improvement is due to a better response to salvage therapy, such as immunomodulatory drugs, potentiated by a donor-derived immunologic milieu.⁴² 

These data led to a consensus statement from myeloma experts endorsing the use of allogeneic HCT in certain patient populations and clinical situations.⁴³  In my practice, I strongly encourage patients who have failed 1 or 2 lines of prior therapy who have a donor available, are young, and are willing to take the risk to undergo allografting, as this is likely the option that will provide them with the best chance for long-term disease control and potential cure. I agree there are a lot of exciting other therapies out there, such as chimeric antigen receptor T cells and bispecific T-cell engagers, but there is no reason why we should not think about combining the potent graft-versus-myeloma effect with these other therapies.⁴⁴  In the ASCT setting, we need to explore novel maintenance strategies as well as better platforms to continue to improve outcomes and give patients with multiply relapsed myeloma a long life, with a good quality of life, with a minimum burden of therapy.

Sergio Giralt, Adult BMT Service Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065; e-mail: giralts@mskcc.org.