The Evolving Era of Novel Therapies in Multiple Myeloma

Joshua Richter, MD Joshua Richter, MD
Clinical Assistant Professor at Rutgers
Division of Myeloma
John Theurer Cancer Center
Hackensack University Medical Center
Hackensack, New Jersey

Multiple myeloma (MM) is an incurable hematologic malignancy that classically arises from a pre-malignant condition known as monoclonal gammopathy of undetermined significance (MGUS). In 2016, it is estimated that there will be 30,330 new cases of myeloma and an estimated 12,650 people will die of this disease.1 With an ever-widening array of therapeutic options, survival rates have improved dramatically over the last decade. Alongside advances in treatment, there have been new developments in the understanding and application of diagnostic and prognostic techniques that incorporate biomarkers and cytogenetic abnormalities.

Smoldering (asymptomatic) myeloma has traditionally been described as patients who have ≥10% marrow plasmacytosis and/or 3 g/dL of an M-spike without “CRAB” symptoms:

C: Calcium elevation (>11 mg/dL or >1 mg/dL higher than ULN)
R: Renal insufficiency (creatinine clearance <40 mL/min or serum creatinine >2 mg/dL)
A: Anemia (Hb <10 g/dL or 2 g/dL < LLN)
B: Bone disease (≥1 lytic lesions on skeletal radiography, CT, or PET-CT)

The standard of care has been to monitor these patients without administering anti-myeloma therapy, until they develop symptoms. Although some of these patients will never progress to symptomatic disease, extensive analysis revealed that three independent criteria were consistent with ≥80% risk of progression within two years.2 These factors, termed myeloma-defining events (MDEs), are:

  • Clonal bone marrow plasma cell percentage ≥60%
  • Involved:uninvolved serum free light chain ratio ≥100, provided the absolute level of the involved light chain is ≥100 mg/L
  •  >1 focal lesions on MRI that is ≥5 mm in size

Patients with any of these factors are now deemed to have malignancy biomarkers which support the need for therapy, regardless of end-organ dysfunction.

Cytogenetic evaluations continue to play a key role in the prognostication of outcomes in myeloma. Standard techniques used for genetic risk stratification include routine karyotyping, fluorescence in situ hybridization (FISH), and gene-expression profiling (GEP). Karyotyping typically reveals cytogenetic aberrations in 20-30% of myeloma patients.3 Given this technique’s lack of sensitivity, it remains insufficient as a stand-alone approach for genetic evaluation. FISH analysis represents the current standard approach. The specific genetic lesions and their relative frequencies are delineated in Table 1. For maximum efficacy, it is beneficial to enrich the sample with one of several techniques, such as GEP of CD138 plasma cells. MyPRS® is a microarray-based GEP that utilizes a 70-gene panel to ascertain subsequent pathway expression via microarrays. The panel yields a risk score (Figure 1), with higher numbers associated with higher risk, as well as one of seven molecular subtypes (Figure 2).4

Table1. Primary and secondary genetic events detectable by FISH3

Primary genetic events   Secondary genetic events
IgH translocation Gene(s) Frequency (%)   Deletion Gene(s) Frequency (%)
t(4;14) FGFR3/MMSET 15   1p CDKN2C, FAF1, FAM46C 30
t(6;14) CCND3 4   6q 33
t(11;14) CCND1 20   8p 25
t(14;16) MAF 4   13 RB1, DIS3 44
t(14;20) MAFB 1   11q BIRC2/BIRC3 7
  14q TRAF3 38
  16q WWOX, CYLD 35
  17p TP53 7
Hyperdiploidy   Gain
Trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19, 21 NA 50   1q CKS1B, ANP32E 40

Figure 1. MyPRS score4

Figure 1

Figure 2. MyPRS molecular subtypes4

Molecular Subtype GEP cytogenetic abnormality Key Genes Risk Percent
Cyclin-1 CD1 t(11;14) & t(6;14) CCND1 & CCND3 LOW/Standard 7
Cyclin-2 CD2 t(11;14) & t(6;14) CCND1 & CCND3 with CD20 LOW/Standard 14
Hyperdiploidy HY Trisomies 3,5,7,9,11,15,19,21 DKK1 & FRZB LOW/Standard 28
Low Bone Disease LB Trisomies 3,5,7,9,11,15,19,21 & amp 1q21 CCND2 & NF-KB LOW/Standard 14
MAF MF t(14;16), t(14;20) & amp 1q21 MAF-A-B-C HIGH 9
MMSET MS t(4;14) & amp 1q21 MMSET & FGFR3 HIGH 16
Proliferation PR Trisomies 3,5,7,9,11,15,19,21 MAGEA6, CCNB1 & CCNB2 HIGH 11

Ultimately the specific identifiable genetic lesions have ramifications for outcomes in both smoldering and symptomatic myeloma. Regarding smoldering myeloma, higher risk lesions confer a higher rate of progression towards symptomatic disease. For symptomatic myeloma, high-risk genetics confer a worse prognosis, stemming from reduced durations of remission with standard therapies and ultimately a reduced overall survival (Table 2).5

Table 2: Cytogenetic abnormalities and their effect on SMM and MM5Table 2

The International Staging System (ISS) has been the standard prognostic model for many years. The system utilizes two laboratory values: Beta-2 microglobulin (ß2-M) and albumin. Stage I is defined as ß2-M <3.5 mg/dL and albumin ≥3.5 g/dL; stage III is defined as ß2-M ≥5.5 mg/L; and stage II is defined as neither stage I nor stage III. Higher-stage disease has been correlated with poorer survival outcomes (stage I > stage II > stage III). Although this has been the standard for many years, this model has been criticized insofar as it does not take into account the impact of cytogenetic risk. Palumbo, et al., have recently updated the ISS to a revised version (R-ISS) which now incorporates lactate dehydrogenase (LDH) and specific cytogenetic abnormalities into the original classifications.6 The frequency and outcomes for the various stages are summarized in Table 3.

Table 3. Revised International Staging System (R-ISS) for myeloma6
Table 3

What must follow from our ability to better risk-stratify patients based on genetics, is the implementation of a data-driven approach to risk-adapted management of the disease. Ongoing clinical trials seek to answer the question of how to optimally manage high-risk myeloma patients. The International Myeloma Working Group (IMWG) has released consensus statements regarding the management of high-risk patients; specifically focusing on the ability of individual drugs and combination regimens to offset the risk conferred by specific cytogenetic abnormalities.3 The key statements are as follows:

  1. “Thalidomide does not abrogate the adverse effect of t(4;14), t(14;16), t(14;20), and del(17) or del(17p) and gain(1q) CA in TE patients. Conclusive data for elderly or frail patients are not available.”
  2. “Bortezomib partly overcomes the adverse effect of t(4;14) and possibly del(17p) on CR, PFS, and OS. There is no effect in t(4;14) combined with del(17p) in TE patients. In non-TE patients, VMP may partly restore PFS in HR cytogenetics.”
  3. “Lenalidomide partly improves the adverse effect of t(4;14) and del(17p) on PFS, but not OS, in TE patients. In non-TE patients, there are no data suggesting that the drug may improve outcome with HR cytogenetics. Pomalidomide with dexamethasone showed promising results in RRMM with del(17p).”
  4. “Combining a proteasome inhibitor with lenalidomide and dexamethasone greatly reduces the adverse effect of t(4;14) and del(17p) on PFS in NDMM. Carfilzomib with lenalidomide and dexamethasone seems effective in patients with HR cytogenetics. However, with exception of ASPIRE and TOURMALINE [clinical studies], most data were obtained in nonrandomized studies and long-term follow-up has not been reported. The group advises treating NDMM patients with HR cytogenetics with the combination of a proteasome inhibitor with lenalidomide or pomalidomide and dexamethasone.”
  5. “HDT with ASCT is standard therapy for TE patients with NDMM. It contributes to improved outcome across prognostic groups. Double HDT/ASCT combined with bortezomib may improve PFS in patients with t(4;14) or del(17p), and in those with both abnormalities. Although results from stratified randomized trials are not yet available, HDT plus double ASCT is recommended for patients with HR cytogenetics.”
  6. “Allogeneic SCT or tandem auto-allo-SCT may improve PFS in patients with t(4;14) or del(17p). Results are better in an early stage of the disease. The novel treatments may challenge the role of allo-SCT and its use should be restricted to clinical trials.”

CA=cytogenetic abnormalities; TE=transplant eligible; HR=high-risk; PFS=progression free survival; OS=overall survival; CR=complete response; VMP=bortezomib, melphalan, prednisone; RRMM=relapsed/refractory multiple myeloma; NDMM=newly diagnosed multiple myeloma; HDT=high-dose therapy; ASCT=autologous stem-cell transplant; SCT=stem-cell transplant

There are several key take-away points from the IMWG consensus. Proteasome inhibition remains a vital part of the management of high-risk myeloma. Although the data is more robust with bortezomib, the more recently approved carfilzomib and ixazomib may provide similar (if not enhanced) abilities to offset genetically adverse myeloma. Further studies and longer term follow-up are needed for confirmation. Triplet therapy (immunomodulatory drug/proteasome inhibitor/steroid) continues to show superiority as a treatment paradigm, particularly in HR myeloma. Despite the multitude of novel therapies, autologous transplantation continues to be the standard of care in newly diagnosed multiple myeloma patients who are eligible. Patients with high-risk lesions, such as t(4;14) or del(17p) ─ and especially patients with both abnormalities ─ should be considered for more aggressive approaches, including tandem autologous transplants, or even allogeneic transplantation in the appropriate setting.

As the needle is constantly in motion regarding what is considered genetically high-risk disease, newer data is shedding light on a group of patients classically felt to have a better prognosis. The Mayo Clinic’s mSMART guidelines have traditionally classified t(11;14) within the standard risk cohort. Recent work at The University of Texas MD Anderson Cancer Center has raised concern about this classification regarding response to autologous stem cell transplant.7 This has been further confirmed by Kaufman, et al.8 Their findings are summarized in Table 4 and clearly outline the need to re-think our conception of what is high- and standard-risk disease.

Table 4: Outcomes by FISH8

All patients (n=409)24 (21.6–25.4)92 (80.1–99.8)24.4 (21.7–27.7)20.5 (16.5–24.9)92 (80.1–107)80.4 (56.8–107)
t(4;14) (n=41)23.5 (12.9–25.1)NR (53.8–NC)24 (14.1–36.4)12 (5.6–24.9)NR (53.8–NC)NR (28.1–NC)
t(11;14) (n=78)21.7 (16.8–25.2)56.9 (45.7–80.4)23.2 (18.7–27.8)16.2 (9.0–22.4)64 (39.8–81.5)56.9 (49.1–NC)
t(14;16) (n=13)21.7 (6.9–NC)40.9 (17.7–NC)56.6 (6.0–NC)20.5 (16.9–NC)39.9 (8.9–NC)NR (40.9–NC)
t(14;20) (n=5)39.9 (3.1–39.9)65.5 (10.9–65.5)24.8 (3.1–39.9)NR (NC–NC)42.8 (10.9–65.5)NR (NC–NC)
t(14;undefined) (n=63)26.6 (21.0–32.5)92.8 (92.0–NC)24.2 (17.2–30.7)31.2 (15.4–NC)92.8 (92.0–NC)107 (23.3–107)
del(17p)/-17 (n=50)16.9 (13.8–27.7)48.3 (33.1–64.0)22.7 (13.7–30.3)14.9 (7.1–16.8)52.8 (28.5–64.0)40.9 (28.1–NC)

Abbreviations: FISH, fluorescence in situ hybridization; HDT, high-dose therapy; ISS, International Staging System; NR, not reached; NC, not calculable; OS, overall survival; PFS, progression-free survival. Values in parentheses represent 95% confidence intervals of the median.

Biological parameters can be combined with imaging modalities to improve global assessments of patients and their response to therapy. The IMAJEM study, a sub-study of the recently presented IFM/DCFI 2009 trial, sought to elucidate the prognostic role of MRI and PET/CT imaging in myeloma. The IFM/DFCI 2009 study evaluated lenalidomide, bortezomib and dexamethasone (RVD) +/- ASCT (with subsequent maintenance in both arms) in the management of newly diagnosed, transplant eligible myeloma patients. IMAJEM obtained MRI or PET/CT scans for these patients at the time of diagnosis (primary endpoint) as well as after three cycles of RVD induction and prior to the initiation of maintenance therapy (secondary endpoints). Both MRI and PET/CT were effective in detecting bone lesions at the time of diagnosis. PET/CT negativity was prognostic for PFS after 3 cycles of RVD induction, and prognostic for OS prior to the initiation of maintenance therapy.9 Combining PET/CT imaging with standard measures of disease assessment as well as minimal residual disease (MRD) assessment may help to guide long-term treatment strategies for patients.

In a continuing quest towards true personalized medicine, biomarker-driven therapy has been a goal achieved in a number of malignancies, but it has not been the hallmark of myeloma therapy. Yet, several recent studies show promise in that this may be achievable in the near future.

In November of 2015, elotuzumab (Elo) was approved by the FDA, in combination with lenalidomide and dexamethasone, for the management of patients with multiple myeloma who have received one to three prior therapies. Ongoing studies continue to evaluate this molecule with other anti-myeloma therapies. Palumbo, et al., presented data from a clinical trial investigating bortezomib plus dexamethasone with or without elotuzumab (Elo-Vd vs. Vd) at the 2015 ASH meeting. In a subset analysis, patients were stratified by the expression of FcgRIIIa receptor polymorphisms. PFS curves were drawn delineating the differences between the high-affinity and low-affinity sub-groups. In the group treated with Elo-Vd, the median PFS for the high-affinity receptor was 22.3 months compared with 9.8 months in the low-affinity patients.10 Although this testing is not yet commercially available, this may help to guide patients towards maximally effective therapy.

Venetoclax is a BCL-2 inhibitor currently FDA approved for chronic lymphocytic leukemia. It is being studied both as monotherapy and in combination therapy for patients with relapsed and refractory myeloma. As monotherapy, it has shown an overall response rate (ORR) of 24% in patients with t(11;14) and 4% in patients without the translocation. In combination with bortezomib (in both bortezomib-sensitive and -refractory patients) there was an ORR of 58%. The response rates are far more profound in patients with high expression of BCL-2 and t(11;14). In the venetoclax + Vd treated patients, the response rates were 71% vs 22% in BCL-2-high and BCL-2-low, respectively.11,12

The MMRF’s CoMMpass study, along with many other ongoing clinical trials, is seeking to refine the personalized approach to treating myeloma. With four new therapies approved by the FDA in 2015, the number of treatment options is greater than ever. As our armamentarium improves, so must our understanding of when and how to utilize these therapies to minimize toxicity and maximize outcomes.


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