Recently, Sara Gandolfi, MD; Claudia Paba Prada, MD; and Paul G. Richardson, MD, discussed the treatment of younger patients with multiple myeloma, balancing disease control with the effects on quality of life. Below, we summarize their approach.
This material was repurposed from “How I treat the young patient with multiple myeloma,” published in the September 13, 2018, edition of Blood.
- In younger patients with newly diagnosed MM, active treatment should be initiated as early as possible.
- Several factors should be considered during the planning of a treatment strategy, including logistics, out-of-pocket cost, drug availability, social considerations, comorbidities, and patient preference.
- Standard induction treatment should include a triplet regimen of containing IMiD, PI, and steroids.
- Given the rapidly changing treatment paradigm and the efficacy of novel agent combinations, AHCT can reasonably be kept in reserve for patients who do not wish to initially pursue high-dose therapy.
- Post-induction continuous therapy with lenalidomide is recommended, with the addition of PIs as clinically appropriate.
- New directions of research include the role of monoclonal antibodies, vaccines, cellular therapy, and small molecules.
Multiple myeloma (MM) is rare in people younger than 30 years, with a median age at diagnosis of 70 years; however, 37 percent of patients diagnosed with MM are younger than 65 years. For these “younger patients,” the issue of optimal treatment strategies is especially germane, with the goal being to improve long-term outcomes while minimizing the impact of treatment-related toxicities.
Here, we provide a practical approach to the management of younger patients (<65 years) with newly diagnosed MM, with a focus on novel treatment approaches, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies.
When to Start Treatment
The definition of active MM relies on clinicopathologic criteria that require evidence of end-organ damage attributable to the underlying clonal plasma cell disorder. We treat patients with active MM per the revised 2014 International Myeloma Working Group (IMWG) criteria, which requires the presence of at least one myeloma-defining event and three specific biomarkers (TABLE).
Further research is required to identify markers of disease progression in patients with smoldering MM (SMM), so we counsel younger patients with SMM who are eligible for early intervention to consider participation in clinical trials as part of their overall treatment strategy, together with careful observation and the use of bisphosphonates for bone loss.
Given the heterogeneity of MM, risk stratification is a challenge. Several studies have validated multiple biologic factors influencing risk and prognosis in MM, and we recommend both the International Staging System (ISS) and the Revised ISS (R-ISS) prognostic scores.
ISS is a simple tool that includes β2-microglobulin, serum albumin, and information on tumor burden and disease impact on the host; the R-ISS adds cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) and lactate dehydrogenase (LDH) to the ISS to stratify patients with newly diagnosed MM into three risk groups. In addition, host-related factors, such as age, performance status, comorbidities, and frailty, should be considered when choosing treatment strategy.
Choice of Initial Treatment
The incorporation of novel agents in MM treatment has resulted in a major improvement in overall survival (OS), with induction regimens containing three or more drugs (including PIs and IMiDs) appearing to be the best choice for initial therapy. Our proposed guidelines for the management of MM patients is presented in the FIGURE.
In our practice, patients who are not eligible for or decline to participate in a clinical trial are treated with lenalidomide, bortezomib, dexamethasone (RVD) for six to eight cycles as initial treatment or other combinations, followed by hematopoietic cell collection; autologous hematopoietic cell transplantation (AHCT) also is considered, with maintenance to follow.
Another combination to be considered is cyclophosphamide, bortezomib, dexamethasone (CyBorD), although a recent randomized trial found that the triplet regimen containing a PI and an IMiD is superior to CyBorD. However, this regimen is particularly useful and part of our practice in patients with acute renal failure. Similarly, in patients with underlying neuropathy, we favor carfilzomib, lenalidomide, dexamethasone (KRD), given its minimal neurotoxicity and remarkable efficacy. This regimen may be especially valuable in younger patients at a lower risk for vascular toxicity and cardiac complications.
The Role of Transplant
High-dose chemotherapy followed by AHCT is still considered a standard of care in eligible patients with newly diagnosed MM, but the depth and duration of response achieved with the triplet combination of IMiD, PI, and dexamethasone and its favorable tolerability is now challenging this paradigm. A rigid approach to AHCT upfront use outside of clinical studies is now difficult to justify and, given the acute and long-term toxicities of AHCT, the role of transplant as part of upfront treatment is an area of active research.
Again, participation in prospective trials is encouraged as the treatment paradigm continues to evolve and important unanswered questions remain. Specifically, a key issue is the identification of patient- and disease-specific markers, with the goal of exposing only those who benefit from early AHCT to the procedure.
For those who are ineligible for or decide not to participate in clinical trials, AHCT remains an appropriate option. For patients preferring to delay AHCT after induction/remission therapy, we encourage them to harvest stem cells as soon as a sustained best response is reached (e.g., very good partial response or better).
Randomized clinical trials have shown superior response rates with tandem AHCT, but the effects on survival have been less clear. Given these results and the concerns of cumulative long-term marrow toxicity from double high-dose alkylation, we do not recommend routine tandem AHCT outside of a clinical trial.
Given that the results of several trials comparing AHCT and allogeneic hematopoietic cell transplantation (alloHCT) in the upfront setting have failed to show any consistent benefit with alloHCT, and the non-relapse mortality rate has been significantly higher with alloHCT, it is not recommended as a firstline approach. However, a reduced-intensity approach alloHCT can be considered in the salvage setting for younger patients with good performance status and high-risk cytogenetic features, preferably in the context of a clinical trial.
Consolidation following AHCT consists of a short course of multi-agent therapy with a goal of improving the depth of the response and prolonging clinical benefit. Several randomized trials have evaluated different post-AHCT approaches, and all have shown an improvement in depth of responses but did not provide an OS benefit.
Ongoing trials like BMT-CTN 0702, which is evaluating the addition of RVD consolidation or a second AHCT versus a single AHCT followed by lenalidomide maintenance, are still preliminary, and other trials have shown a progression-free survival (PFS) benefit with consolidation treatment. Given the differing results, our approach is to offer two to four cycles of RVD after AHCT in high-risk patients and for those who do not achieve complete response after transplant.
Maintenance and Continuous Therapy
Despite the improvement in PFS and OS with novel approaches and AHCT, relapses are inevitable for most patients with MM, primarily due to incomplete eradication of residual disease. Maintenance therapy is intended to prolong and deepen the response to previous induction, with or without AHCT.
Although first attempts at maintenance therapy using conventional chemotherapy, steroids, or interferon-alpha proved disappointing, the introduction of novel agents has markedly restored the potential of maintenance therapy to improve clinical benefit.
Our standard of care for post-AHCT consolidation is lenalidomide maintenance, which is offered to all patients undergoing AHCT, with dose adjustments and schedule change according to tolerability. Patients with high-risk disease characteristics, like del17p, are offered the addition of bortezomib. For patients who are not willing to participate in clinical trials and who chose to delay AHCT, we offer continuous therapy with both lenalidomide and bortezomib.
Ideally, maintenance should be administered until disease progression; however, this approach is not always feasible, and patients may require dose adjustment, schedule changes, and treatment discontinuation if toxicity emerges.
Minimal Residual Disease and Response Assessment
Response criteria in MM rely on serum and urine measurement of monoclonal proteins and bone marrow assessment. Recently, the IMWG has incorporated the measurement of minimal residual disease (MRD), via multicolor immunofluorescence flow cytometry and gene sequencing with sensitivity of up to 10−5, into MM response criteria.
Meta-analyses have confirmed that MRD-negative status after treatment of patients with newly diagnosed MM is associated with significant improvement in survival and support the integration of MRD assessment in clinical trials. However, another study showed that approximately 25 per-cent of patients with MRD-negative disease still experienced relapse at 36 months, despite better PFS and OS curves than patients with MRD-positive disease. Newer approaches for measuring MRD, such as single-cell gene sequencing and serum cell-free DNA, may more accurately assess MRD and complement existing methods.
For younger patients with newly diagnosed MM, general supportive measures include adequate hydration, low-impact exercise, weight control, avoidance of nephrotoxic drugs, prevention of neuropathy, and pain management.
It is critical to monitor infection risk, and antiviral prophylaxis is recommended in patients receiving PIs to minimize the development of herpes zoster reactivation.
When IMiDs are used, thromboprophylaxis should be initiated. For patients at a low risk for thrombosis, daily aspirin is associated with a low rate of deep vein thrombosis; for patients at higher risk for deep vein thrombosis given other factors (such as prior history, immobility, and obesity), therapeutic anticoagulation using low-molecular-weight heparin or warfarin is recommended. Newer direct oral anticoagulants appear to be a feasible new approach.
To prevent skeletal events, we recommend the use of intravenous bisphosphonates (such as zoledronic acid and pamidronate), regardless of whether bone lesions have been detected. Overall, the benefits of bisphosphonate therapy should be weighed with their toxicities, and preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. The RANKL inhibitor denosumab was recently approved by the U.S. Food and Drug Administration for the prevention of skeletal-related events.
Other measures of supportive care include evaluation and management of neuropathy, cytopenias, and diarrhea common to PIs and IMiDs, with neuropathy an area of particular importance.
The wide availability of options allows a tailored approach and also offers improved efficacy. Immune function in MM has recently generated great interest and is an active area of research, with several ongoing studies of checkpoint inhibition in combination with IMiDs, as well as monoclonal antibodies, all of which have shown outstanding activity in advanced disease.
Other new directions for research include vaccines, cellular therapy, and small molecules, such as histone deacetylase inhibitors and other targeted therapies, as well as bone-targeting agents, including denosumab. Participation in large phase III trials investigating the best approach in younger patients with newly diagnosed MM is strongly recommended and should be considered for all eligible patients.