31 Plasma Cell Neoplasms

Ravi Vij and Jesse Keller

QUESTIONS

Each of the numbered items below is followed by lettered answers. Select the ONE lettered answer that is BEST in each case unless instructed otherwise.

Question 31.1 A healthy and active 62-year-old man presents to his primary care physician for a routine annual physical. A complete metabolic panel is significant for an elevated total protein of 10 mg/dL, an albumin of 4 mg/dL, a creatinine of 0.6 mg/dL, and a calcium of 8.8 mg/dL. A complete blood count shows a white blood cell count of 5.2, a hemoglobin of 12 g/dL, and a platelet count of 242. Subsequent serum protein electrophoresis and immunofixation shows an IgG kappa monoclonal peak of 0.9 g/dL. Serum-free light chains show a total kappa-free light chain concentration of 242 mg/dL and a lambda-free light chain concentration of 1.2 mg/dL. A skeletal survey shows no evidence of lytic lesions and a bone marrow biopsy reveals a monoclonal plasma cell population comprising 70% of the core biopsy sample. Which of the following management options should be pursued next?

A. Initiation of antimyeloma therapy

B. Repeat SPEP in 12 months

C. Obtain a HeavyLite Assay

D. Fusion PET/MRI scanning to assess need for therapy

Question 31.2 A 65-year-old man presents to a local emergency room with fatigue, myalgias, and lightheadedness. Laboratory evaluation reveals a white blood cell count of 7.5, a hemoglobin of 6.3 g/dL and a platelet count of 135. Chemistry panel shows a creatinine of 1.56 mg/dL and a calcium of 14.0 mg/dL. Workup of his anemia includes a serum protein electrophoresis that shows a monoclonal protein at a concentration of 4.0 g/dL. Serum immunofixation reveals an IgA kappa monoclonal protein. Bone marrow biopsy shows a kappa-restricted plasma cell population comprising 30% of the core biopsy. Cytogenetics reveal hypodiploidy and FISH studies show t(4;14). Which of the following best characterizes the risk category of this patient’s multiple myeloma?

A. High Risk due to FISH findings of t(4;14)

B. High Risk due to cytogenetic findings of hypodiploidy

C. Intermediate Risk by FISH and cytogenetics

D. Standard Risk by FISH and cytogenetics

Question 31.3 A 52-year-old woman presents to her Oncologist 1 year following an autologous stem cell transplantation for multiple myeloma. She has been continued on maintenance therapy following her transplant and has tolerated this well. She reports that she watched a television documentary about genomics a week prior to her appointment and asks her physician what genomic sequencing has revealed in multiple myeloma. Which of the following is the best response?

A. Genomic sequencing has revealed a conserved set of consistent mutations in TP53 and CCND1 for patients with multiple myeloma.

B. Mutations in VHL are common.

C. Deep sequencing has revealed that there is a consistent pattern of clonal evolution in multiple myeloma.

D. There have been few consistently mutated genes, but the most common include KRAS and NRAS.

Question 31.4 A 69-year-old woman is diagnosed with an IgG lambda multiple myeloma. Her initial labs reveal a monoclonal peak of 4.5 g/dL, with lambda-free light chains of 120 mg/dL and kappa-free light chains of 1.1 mg/dL. A bone marrow biopsy showed 50% involvement by a lambda-restricted plasma cell population. She began induction with lenalidomide and dexamethasone and attained a very good partial response after four cycles of therapy. She undergoes autologous stem cell transplant and on workup 100 days post-transplant, a bone marrow biopsy shows no evidence of persistent plasma cells. Serum protein electrophoresis and immunofixation are negative for any evidence of monoclonal protein. Serum-free light chains are repeated and are normal. She has minimal residual disease testing performed as part of a clinical trial, which shows her to have persistent disease by multiparameter flow cytometry (MFC). What would be the appropriate information to pass onto the patient regarding this finding?

A. She needs to have the testing repeated using next-generation–based sequencing technology.

B. The patient should undergo repeat ASCT with a goal to obtain minimal residual disease (MRD) negativity.

C. MRD positive patients have inferior PFS when compared to patients achieving stringent CR who are MRD negative.

D. There are no differences in outcomes among patients achieving a CR regardless of MRD status.

Question 31.5 A 59-year-old man has a new diagnosis of multiple myeloma made after he presented with a monoclonal peak of 6.0 g/dL, IgG-Lambda by serum immunofixation. CBC showed a hemoglobin of 9.5 g/dL and a metabolic panel revealed no abnormalities. Bone marrow biopsy reveals evidence of 65% involvement by a lambda-restricted monoclonal plasma cell population. He is deemed to be an appropriate candidate for autologous transplantation. He starts therapy with bortezomib, lenalidomide, and dexamethasone which he tolerates well. After 3 cycles of therapy, his M-spike has improved to 4.8 g/dL, and after 6 cycles of therapy his M-spike is 4.0 g/dL. Which of the following is the next best step in management?

A. Continue bortezomib, lenalidomide, and dexamethasone until nadir value achieved and then proceed to autologous transplantation

B. Proceed to autologous stem cell transplantation

C. Carfilzomib-based salvage therapy for 4 to 6 cycles and then proceed to autologous transplantation

D. Switch to carfilzomib-based regimen and abandon plans for autologous transplantation

Question 31.6 A patient with a history of multiple myeloma presents to your clinic with a newspaper clipping describing some recent successes with monoclonal antibodies in this disease. The patient is curious about the role of these potential new drugs in therapy and inquires about their mechanism of action. Which of the following is accurate regarding the new medications in this class?

A. In a phase III trial, the PFS difference noted at 1 year was maintained at 2 years on therapy with elotuzumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone.

B. Daratumumab had a high rate of discontinuation due to adverse events.

C. Daratumumab has no activity in patients with extra-medullary disease.

D. In a phase III trial, elotuzumab in combination with lenalidomide and dexamethasone produced responses even in lenalidomide refractory patients.

Question 31.7 A 63-year-old man with a history of multiple myeloma presents to clinic for ongoing evaluation. He was diagnosed 3 years ago, and received induction treatment with bortezomib, lenalidomide, and dexamethasone followed by autologous stem cell transplantation. On workup today, he has evidence of progressive disease with a rising monoclonal protein from 1.0 g/dL to 3.2 g/dL. His performance status is ECOG 0, and the treating physician makes the decision to initiate panibinostat, bortezomib, and dexamethasone. Which of the following regarding panibinostat should the physician inform the patient prior to initiation?

A. Potential for serious and possibly fatal arrhythmia

B. Risk of Stevens–Johnson syndrome

C. Diarrhea is self-limiting and transient

D. Risk for hemolytic uremic syndrome

Question 31.8 A 65-year-old man with a history of multiple myeloma presents for initial evaluation. He was diagnosed 1 year ago and underwent initial induction therapy with bortezomib, cytoxan, and dexamethasone, followed by autologous stem cell transplantation approximately 6 months ago. He was not treated with maintenance therapy following transplant due to his personal preference. He presents now with worsening anemia (hemoglobin 9 g/dL) and a rising M-protein level (0.8 g/dL to 4.5 g/dL). What is the most appropriate statement regarding the role of carfilzomib therapy in this setting?

A. In a phase III trial, patients treated with lenalidomide and dexamethasone had improved progression-free survival compared to those treated with carfilzomib, lenalidomide, and dexamethasone.

B. In a phase III trial, patients treated with the combination of carfilzomib, lenalidomide, and dexamethasone had inferior health-related quality of life compared to those treated with lenalidomide and dexamethasone alone.

C. In a phase III trial, the benefit of carfilzomib (20/56 mg/m²) and dexamethasone was limited to patients who had no prior exposure to bortezomib.

D. In a phase III trial, carfilzomib (20/56 mg/m²) and dexamethasone was associated with a doubling of PFS when compared to bortezomib (1.3 mg/m²) and dexamethasone.

Question 31.9 A 57-year-old previously healthy woman presents to her primary care physician with fatigue and weight loss over the preceding 3 months. Physical examination reveals palpable lymphadenopathy in the axilla bilaterally. Workup is significant for a WBC count of 7.3, a hematocrit of 21%, and a platelet count of 42. A metabolic panel is within normal limits. SPEP and immunofixation reveal an IgM monoclonal protein and a bone marrow biopsy shows a lymphoplasmacytic infiltrate comprising 20% of the marrow. Serum viscosity is within normal limits. She is initially treated with bortezomib, rituximab, and dexamethasone with a partial response. One year later she now has a recurrence of symptoms. A tumor sample is sent for exome sequencing studies. Which of the following is most likely to predict for best response to BTK inhibitor therapy?

A. MYD88 L365P mutation positive and CXCR4 mutation negative

B. MYD88 L365P mutation negative and CXCR4 mutation negative

C. MYD88 L365P mutation positive and CXCR4 mutation positive

D. Presence of CXCR4 WHIM mutation irregardless of MYD88 status

Question 31.10 A 52-year-old man presents to your clinic for an initial consultation. He was referred after he was noted to have lower extremity edema and further workup revealed the presence of a nephrotic syndrome. He underwent a renal biopsy which showed evidence of amyloid deposition, positive by Congo red staining. His labs revealed a kappa-free serum light chain concentration of 140 mg/L and a lambda-free light chain concentration of 2 mg/L. His NT-proBNP is 10,000 ng/L and his troponin is 0.09 ng/mL. His performance status is rated as an ECOG 1. What should be the next step in management?

A. Start cyclophosphamide, bortezomib, and dexamethasone

B. Autologous stem cell transplantation with melphalan 140 g/m²

C. Autologous stem cell transplantation with melphalan 200 g/m²

D. Start therapy with ixazomib-based therapy

ANSWERS

Question 31.1 The correct answer is A.

The International Myeloma Working Group released an update to the criteria for diagnosis of multiple myeloma in 2014 [Rajkumar et al. Lancet Oncol. 2014;15:e538–e548]. Historically defined by the presence of the CRAB (hypercalcemia, renal failure, anemia, or bony disease) criteria, denoting the presence of end-organ damage, the newly updated criteria include a number of radiographic or biochemical criteria. These take into account the potential benefits available to patients from expanding and improved treatment options and data that show early intervention in high-risk asymptomatic patients improves survival [Mateos et al. N Engl J Med. 2013;369:438–447]. The defining criteria for multiple myeloma now include a clonal bone marrow plasma cell population ≥10% or biopsy-proven bony or extramedullary plasmacytoma and one or more of the following defining elements:

• Evidence of end-organ damage attributed to the plasma cell disorder

• Hypercalcemia (>1 mg/dL above ULN or >11 mg/dL)

• Renal insufficiency (CrCl <40 or sCr >2 mg/dL)

• Anemia (Hbg >2 g/L below LLN or an Hbg <10 g/L

• Bone lesions (one or more osteolytic lesions on radiograph, CT or PET-CT)

• Any of the following biomarkers of malignancy:

• Clonal bone marrow population ≥60%

• Involved:uninvolved serum-free light chain ratio ≥100 (The involved free light chain must be ≥100 mg/L)

• >1 focal lesions on MRI

Since this patient’s bone marrow biopsy reveals a monoclonal plasma cell population encompassing 70% of the bone marrow, he meets the diagnosis of multiple myeloma based on the newly established criteria. Additionally, this patient’s ratio of involved:uninvolved serum-free light chains is >100, with an involved chain concentration >100 mg/L. By current definition the patient has overt multiple myeloma and will benefit from treatment with an active antimyeloma regimen. Under prior definitions of multiple myeloma the patient would have been classified as smoldering multiple myeloma, and repeating the SPEP and labs would be a reasonable approach. The HevyLite assay is a novel technique of quantifying intact light and heavy chain monoclonal proteins. It measures intact immunoglobulin proteins by measuring unique junctional epitopes between heavy and light chain constant regions. This is particularly useful for IgA monoclonal proteins which often have limited detection by serum protein electrophoresis, but other roles in multiple myeloma are currently under investigation. Fusion PET-MRI is an evolving imaging strategy in multiple myeloma and its role is currently being evaluated.

Question 31.2 The correct answer is C.

Prognosis in multiple myeloma is dependent on several factors, including age, comorbidities, stage, and disease biology. FISH and cytogenetic studies are ideal to assess for the presence of genetic alterations and are crucial to pursue for newly diagnosed patients. Integrating these factors, a risk classification system for newly diagnosed multiple myeloma has been developed by the Mayo clinic, the Mayo Stratification for Myeloma and Risk-adapted Therapy (mSMART) criteria [Mikhael et al. Mayo Clin Proc 2013;88:360–376]. This divides newly diagnosed patients into risk categories based on cytogenetics, FISH, gene expression profiling (GEP) and plasma cell labeling index studies. High-Risk patients are defined by a high-risk GEP signature, or FISH studies showing deletion of 17p, t(14;16), or t(14;20). Intermediate-risk disease is denoted by a high plasma cell S-phase labeling study, FISH showing t(4;14), 1q gain, cytogenetics with a complex karyotype, deletion 13 or hypodiploidy. Standard risk disease encompasses all other abnormalities. Mikhael et al. report overall survival and incidence rates for mSMART risk classes as follows:

• High-risk: incidence of 20% with a median OS of 3 years

• Intermediate-risk: incidence of 20% with a median OS of 4 to 5 years

• Standard-risk: incidence of 60% with a median OS of 8 to 10 years

Risk-adapted strategies to improve these outcomes have been investigated in multiple myeloma, particularly for patients with high-risk multiple myeloma. In the HOVON-65/GMMG-HD4 trial [Sonneveld et al. J Clin Oncol. 2012;30(24):2946] newly diagnosed multiple myeloma patients were randomized to bortezomib-based induction followed by bortezomib post-transplant maintenance therapy versus thalidomide post-transplant maintenance. Significant improvement in PFS and median OS was seen in 17p-deleted patients who were randomized to bortezomib-based therapy. A further phase II study [Nooka et al. Leukemia. 2014;28(3):690–693] evaluated the efficacy of lenalidomide, bortezomib, and dexamethasone maintenance therapy following autologous transplantation. Given for up to 3 years, followed by lenalidomide maintenance, the study had a median PFS of 32 months and a 3-year OS of 93%. Further research is necessary to determine the most appropriate strategy to mitigate adverse outcomes in patients with high-risk disease.

Question 31.3 The correct answer is D.

The initial study evaluating the genomic architecture of multiple myeloma was published in 2011 [Chapman et al. Nature. 2011;471:467–472]. These findings, which evaluated sequencing of 38 tumor genomes revealed a lack of consistently conserved mutations among individual multiple myeloma genomes. The most frequent mutations included those in NRAS (9/38) and KRAS (10/38). Frequent mutations were also seen in genes involved in RNA processing and protein homeostasis, including DIS3, XBP1, LRRK2, and FAM46C. The NF-kB pathway was the most frequently affected pathway, with mutations and rearrangements noted in 11 NF-kB pathway genes. Additional mutations were seen in histone-modifying enzymes, including HOXA9. One genome contained a possibly clinically actionable mutation in BRAF. An additional analysis genotyping 161 multiple myeloma patients found 7 BRAF mutations, which raised the possibility of benefit from BRAF inhibitors. Overall, there are few consistently mutated genes in the multiple myeloma genome, with the most commonly mutated being NRAS and KRAS.

Two additional studies have investigated an additional 203 patients [Lohr et al. Cancer cell. 2014. 25:91–101] and 67 patients [Bolli et al. Nat Commun. 2014;5] using whole-genome and whole-exome sequencing to identify frequent mutations in multiple myeloma. These studies supported the frequent mutations in KRAS, NRAS, FAM46C, and BRAF. Subclonal structure was investigated in these studies, revealing complex structures with clusters of subclonal variants and driver mutations, including frequent mutations in the same pathway within single patients. Serial sampling revealed diverse patterns of clonal evolution, with significant heterogeneity across samples.

Question 31.4 The correct answer is C.

There is a clear link between depth of response and prolonged survival in multiple myeloma. Autologous stem cell transplantation has been successful in producing deep responses among eligible patients, and deeper responses have been found to be associated with improved clinical outcomes [Lahuerta et al. J Clin Oncol. 2008;26(35):5775–5782]. Likewise, novel agents have allowed an increasing number of transplant ineligible patients to achieve a deep response and overall depth of response has been associated with improved outcomes in this population as well [Gay et al. Blood. 2011;117(11):3025–3031]. With modern regimens capable of producing high rates of CR, it is felt that one needs to define even greater depths of response to distinguish therapies and better prognosticate among individual therapies. The definition of a stringent CR (including normalization of serum-free light chains and absence of clonal PCs in Bone Marrow Biopsy) was meant to address this issue, and achievement of a stringent CR has been shown to be predictive of improved overall survival [Kapoor et al. J Clin Oncol. 2013;31(36):4529–4535].

Modern technology permits us to define yet deeper levels of disease response. Several technologies have been utilized to detect MRD, MFC, next-generation sequencing (NGS), and allele-specific oligonucleotide-based quantitative polymerase chain reaction (ASO-PCR). Levels of detection of these technologies enable the identification of as low as 1 cell in 100,000 for MFC and 1 in 1,000,000 for NGS and ASO-PCR. ASO-PCR analysis is largely a research tool requiring patient-specific probes to be generated for MRD assessment. The clonoSEQ MRD assessment is a commercially available tool, which utilizes NGS of the IgH V(D)J regions to monitor MRD in multiple myeloma patients.

The utility of MRD assessment has been investigated in several clinical trials. In the PETHEMA/GEM 2000 study, patients who were negative by multiparameter flow cytometry for MRD after ASCT had significantly improved PFS and OS rates. Likewise in the MRC Myeloma IX study, MRD negativity after ASCT correlated with improved PFS and OS. This has also been observed in the transplant ineligible population with patients showing molecular CR after induction therapy having a statistically significant improvement in PFS over those with MRD-positivity [Puig et al. Leukemia. 2014;28(2):391–397].

Martinez-Lopez et al. evaluated the clonoSEQ method of monitoring MRD assessment in a study assessing 133 multiple myeloma patients who had achieved at least a very good partial response (VGPR) following frontline therapy [Martinez-Lopez et al. Blood. 2014;123(20):3073–3079]. MRD was assessed by the IgH-V(D)J sequencing technique utilized by the clonoSEQ commercial assay and compared and contrasted with those of the MFC and ASO-PCR techniques. A total of 91% of patients were effectively sequenced using the novel NGS technique, and concordance with the MFC and ASO-PCR techniques was 83% and 85%, supporting the widespread applicability and accuracy of the method. Patients who were MRD negative by sequencing had a significantly longer time to progression (median 80 vs. 31 months, P < 0.001) and overall survival (median not reached vs. 81 months, P = 0.02). A total of 92% of VGPR patients were MRD positive. Time to progression improved continuously with decreasing levels of residual disease detected. Among patients achieving a complete response (CR) the time to progression was longer for MRD negative patients versus those who were MRD positive (131 months vs. 35 months, P = 0.0009).

At this time, MRD assessment remains a research tool. Though several publications now seem to suggest that patients who are MRD negative after a finite period of therapy do better than those who are MRD positive, there is no data to support giving additional therapy to patients who are not MRD negative to improve outcomes. Additionally, there is no current consensus on the definition of MRD negativity with both flow cytometry and deep sequencing–based technology having their advantages and disadvantages.

Question 31.5 The correct answer is B.

The optimal depth of disease response necessary to proceed with autologous stem cell transplantation has been a matter of controversy. Previously, data have suggested that patients with a better pretransplant paraprotein nadir have had improved outcomes [Wang et al. Bone Marrow Transplant. 2010;45:498–504.]. However, some centers had experienced benefit for patients even with disease progression after initial induction therapy [Kumar et al. Bone Marrow Transplant. 2004;34:161–167]. A recently published study evaluated the outcomes of patients who had achieved less than a partial response to initial treatment for their multiple myeloma [Vij et al. Biol Blood Marrow Transplant. 2015;21(2):335–341]. A total of 539 patients were identified who had an ASCT after less than a PR to initial chemotherapy. While additional pretransplant chemotherapy resulted in deepening responses in 68% of patients, there was no impact of pretransplant salvage chemotherapy on treatment-related mortality, progression-free survival, or overall survival. Additional pretransplant therapy for those who achieved less than a PR to initial chemotherapy was not found to be beneficial in this large study. Based on their analysis, switching to carfilzomib-based therapy would likely have little impact. Transplant still offers the best option for prolonged PFS.

Question 31.6 The correct answer is A.

Currently, there are several monoclonal antibodies under investigation in multiple myeloma. Daratumumab targets CD38, and elotuzumab is a CS-1/SLAMF7 targeting antibody. Elotuzumab is postulated to function solely via immune-mediated processes, while daratumumab has dual effects including direct action on multiple myeloma cells as well as immune stimulation targeting tumor cells. The ELOQUENT-2 trial was a phase III trial comparison of elotuzumab in combination with lenalidomide and dexamethasone to lenalidomide and dexamethasone alone [Lonial et al. N Engl J Med. 2015;373:621–631]. The median PFS was 19.4 months for elotuzumab compared with 14.9 months with lenalidomide and dexamethasone. The absolute PFS differences at 1 and 2 years were 11% (68% vs. 57%) and 14% (41% vs. 27%). The hazard ratio for progression of disease at 2 years was 0.70 [0.57–0.85] which implies a 30% overall reduction in risk for disease progression. This long-term response to therapy raises the possibility that a subset of patients may have prolonged benefit with the drug and increases the likelihood that an overall survival benefit may be appreciated with longer-term follow-up. Notably, this trial excluded patients who were refractory to lenalidomide and it is not known if the addition of elotuzumab will prove effective in patients whose disease has progressed on lenalidomide alone.

The SIRIUS trial was a phase II study of single-agent daratumumab in patients who had received >3 lines of prior therapy or were double refractory to a proteasome inhibitor and an immunomodulatory drug [Lonial et al. J Clin Oncol. 2015;33(suppl; abstr LBA8512)]. Among 106 patients with relapsed and refractory multiple myeloma who had been treated with a median of 5 prior lines of therapy (range 2 to 14), single-agent daratumumab produced an overall response rate (ORR) of 29% in this population. Among these responses, 3% were stringent CRs and 12% were a VGPR, despite the late-stage disease population that was enrolled. Responses were seen regardless of age, number, and type of prior therapy, or the presence or absence of extramedullary disease. The median duration of response was 7.4 months with a progression-free survival of 3.7 months (95% CI [2.8, 4.6]) and a 1-year overall survival (OS) rate of 65% (95% CI [51.2, 75.5]). Median OS data are not yet available (not reached). Among enrolled patients, 95% were refractory to a proteasome inhibitor and an immunomodulatory drug. A total of 42% were refractory to bortezomib, lenalidomide, carfilzomib, pomalidomide, and/or thalidomide. The SIRIUS study also showed that daratumumab had a response rate of 20% in patients with extramedullary disease. Overall, daratumumab was well tolerated with no discontinuations due to adverse events attributable to the drug.

Question 31.7 The correct answer is A.

Panibinostat is a histone deacetylase (HDAC) inhibitor that was approved by the FDA in combination with bortezomib and dexamethasone for use in patients with multiple myeloma who had received at least two lines of prior therapy, including bortezomib and an immunomodulatory drug. The efficacy of panibinostat has been investigated in a large phase III study, the PANORAMA-1 trial [San-Miguel et al. Lancet. 2014;15:1195–1206]. In this study, 768 patients with relapsed/refractory multiple myeloma who had received between 1 and 3 prior lines of therapy were randomized to receive either panibinostat, bortezomib, and dexamethasone or bortezomib and dexamethasone. With a median follow-up of 6.5 months, median progression-free survival was longer in the panibinostat group (12 months) versus patients treated with a doublet (8.1 months). The overall response rate was not different between groups (61% for the panibinostat arm versus 54.6%). Survival data continue to mature, but were not different between groups. Serious adverse events were reported in 60% of the panibinostat patients and 42% of the placebo group. Diarrhea was common (68%) in panibinostat patients and was severe (requiring IV fluids or hospitalization) in 25% of patients. Cardiac deaths were increased on the panibinostat arm, prompting a Boxed Warning over the risk of ischemic events or arrhythmia. Excessive diarrhea is also included in this warning due to its high incidence in the panibinostat-treated patients. Recommendations for management of diarrhea for patients on panibinostat include initiation of antidiarrheal medications at the first sign of symptoms and interruption of dose until symptom resolution for those with at least 4 stools per day. Panibinostat may be resumed at its prior dose for those with 6 or less stools per day, and dose adjustments are necessary for those with ≥7 stools daily. There was no increase in the rates of hemolytic uremic syndrome or Stevens–Johnson syndrome among patients taking panibinostat. Thrombocytopenia was a common toxicity, occurring in 67% of panibinostat patients and 37% of the bortezomib and dexamethasone arm. Platelet counts <50 should be monitored weekly, while a drop below 25 or any evidence of bleeding should result in holding panibinostat until improvement in counts (>50) and a resumption of panibinostat at a lower dose.

Question 31.8 The correct answer is D.

The ASPIRE trial was a randomized, open-label, multicenter phase III study of carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) in patients with relapsed multiple myeloma [Stewart et al. N Engl J Med. 2015;372:142–152]. The patients all had relapsed multiple myeloma with 1 to 3 prior lines of treatment, and patients with lenalidomide were eligible so long as they had not progressed on lenalidomide and dexamethasone. With a median follow-up of 32 months, the primary endpoint, progression-free survival, was superior for the three-drug combination (26.3 months vs. 17.6 months; P = 0.0001), and median OS was not reached for either cohort. The Kaplan–Meier 24-month OS rates were 73.3% in the three-drug regimen and 65.0% in the two-drug regimen. Grade 3 or higher adverse events were reported in 83.7% of the three-drug group and 80.7% of the two-drug regimen. There were similar rates of trial discontinuation due to adverse events in the three- and two-drug regimens (15.3% vs. 17.7%). Other side effects occurred at similar rates in the two arms: dyspnea (2.8% in KRd vs. 1.8% in Rd), cardiac toxicity (3.8% in KRd and 1.8% in Rd), and peripheral neuropathy (17.1% in KRd and 17.0% in Rd). There appeared to be a higher rate of high blood pressure in the KRd arm (14.3 percent vs. 6.9 percent). Patient-reported health-related quality of life was higher in the KRd arm as compared to the Rd arm.

Evaluating the role of doublet therapy in relapsed and refractory multiple myeloma, the ENDEAVOR trial was a large phase III comparison of the second-generation proteasome inhibitor carfilzomib in combination with dexamethasone to bortezomib and dexamethasone [Dimopoulos et al. J Clin Oncol. 2015:33(suppl; abstr LBA8509)]. It demonstrated that carfilzomib at a dose of 56 mg/m² resulted in a PFS of 18.7 months compared with 9.4 months for bortezomib (1.3 mg/m²) and dexamethasone. The benefit was seen in both patients who had prior exposure to bortezomib (15.6 months vs. 8.1 months) and no prior bortezomib exposure (not reached vs. 11.2 months). This benefit was also maintained across age subgroups. The median duration of treatment was 40 weeks for carfilzomib/dexamethasone versus 27 weeks for bortezomib and dexamethasone. A total of 23% of patients receiving carfilzomb and dexamethasone required a dose reduction due to toxicity compared with 47% of patients receiving bortezomib and dexamethasone. Treatment with carfilzomib was associated with higher rates of hypertension (25% vs. 9%) and somewhat higher rates of cardiac failure (8% vs. 3%).

Question 31.9 The correct answer is A.

MYD88 is a protein that interacts in toll-like receptor and IL-1 signaling and has been implicated in prolonged B-cell survival. Activating point mutations in MYD88 such as the L265P mutation have been implicated in the pathogenesis of Waldenstrom’s macroglobulinemia (WM) [Hunter et al. Blood. 2014;123(11):1637–1646]. This study, likewise, found frequent activating CXCR4 mutations in patients with WM. These mutations in CXCR4 are similar to germline mutations detected in patients with the WHIM syndrome (warts, hypogammaglobulinemia, infection, and myelokathexis). At least 30 different WHIM mutations have been described in WM, and in vitro tumor cells engineered to express CXCR4 WHIM receptors have been shown to have decreased ibrutinib-related apoptosis [Cao et al. Leukemia. 2015;29:169–176]. Ibrutinib has been recently investigated in WM and approved by the FDA for treatment of these patients. This approval was based on findings from a phase II study of ibrutinib in 63 patients with symptomatic WM who had received at least one prior treatment. This study found an overall response rate (ORR) of 90.5% and a median time to response of 4 weeks among the study population [Treon et al. NEJM. 2015:372:1430–1440]. Estimated progression-free survival and overall survival at 2 years were 69% and 95%, respectively. Responses to ibrutinib were found to differ by MYD88 and CXCR4 mutational status. The highest response rates were among patients with MYD88L265P mutations who were CXCR4 wild-type, with a 100% ORR in this population. This was followed by patients who had MYD88L265P mutations who were CXCR4WHIM mutated, with an 85.7% ORR. MYD88L265P and CXCR4 wild-type patients had a 71.4% ORR. As such, best responses are seen in MYD88L265P mutated patients who are CXCR4 wild-type.

Question 31.10 The correct answer is A.

The optimal treatment of amyloidosis is not clear at this time and treatment on clinical trials is often prioritized when possible. Up to eight cycles of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) have been found in a series of 43 patients to have an overall hematologic response rate of 81.4%, including a complete response (CR) rate of 41.9% and VGPR of 51.4% [Venner et al. Blood. 2011;119(19):4387–4390]. This has established CyBorD as a key therapy for patients with AL amyloidosis.

Autologous stem cell transplantation has been investigated in phase II studies and has been found to produce long-term durable remissions in AL amyloidosis patients [Gertz et al. Bone Marrow Transplant. 2004;32(4):149–154]. It remains a mainstay of treatment for patients who are eligible. Determination of this eligibility is largely a case-by-case decision, but general guidelines include the following: appropriate physiologic age, Troponon T <0.06 ng/mL, no more than two organs significantly involved, ECOG ≤2, New York Heart Association functional class I or II, creatinine clearance ≥30 mL/min, and NT-proBNP <5,000 ng/L. Given this patient’s elevated troponin and NT-proBNP, he is ineligible for transplantation at this time.

Ixazomib, a novel oral proteasome inhibitor, has been investigated in relapsed/refractory multiple myeloma as a single agent and as combination therapy (with lenalidomide and dexamethasone). It has shown impressive outcomes in early trials. In a phase I study of 60 patients who were heavily pretreated with a median of 4 prior lines of therapy (88% with prior bortezomib), ixazomib had a response rate of 15% (PR or better) with stable disease in 76% of patients [Richardson et al. Blood. 2014;124(7):1038–1046]. Investigation of ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma patients revealed excellent tolerability with 37% achieving a very good partial response or better.

Corresponding chapter in Cancer: Principles & Practice of Oncology, Tenth Edition: 112 (Plasma Cell Neoplasms).